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Emerging Data on Type 1 Diabetes and COVID-19 Reassuring – Medscape

October 10th, 2020 9:51 am

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Most people with type 1 diabetes do not appear to be at increased risk for hospitalization or death from COVID-19 compared to the general population, new research suggests.

Two retrospective studies of type 1 diabetes and COVID-19 were published in the October issue of Diabetes Care.

One, by Roman Vangoitsenhoven, MD, PhD, of University Hospitals Leuven, Belgium, and colleagues, found no evidence of increased hospitalization for COVID-19 among people with type 1 diabetes during the first 3 months of the pandemic in Belgium.

The other, from Maria Vamvini, MD, of the Joslin Diabetes Center, Boston, Massachusetts, and colleagues, showed that age and glycemic control didn't differ significantly between adults with type 1 diabetes hospitalized for COVID-19 and those hospitalized for other reasons.

Previous data from the UK Biobank and the Type 1 Diabetes (T1D) Exchange support these findings.

Altogether, these results suggest that although the risk for death from COVID-19 is higher overall among people with type 1 diabetes, that increased risk is mostly limited to a subset of particularly vulnerable patients, said Catarina Limbert, MD, PhD, during a press briefing at the virtual annual meeting of the European Association for the Study of Diabetes (EASD).

"Those with type 1 diabetes dying from COVID-19 were a specific population," stressed Limbert, of the University Center of Central Lisbon and Hospital Dona Estefania, Lisbon, Portugal.

"They had hemoglobin A1c levels above 10% and were over age 50 with a long diabetes duration. They were the more fragile, who couldn't survive the severity and aggressiveness of the virus. Good glucose control is a good sign and protective," she added.

Daniel Drucker, MD, of Mount Sinai Hospital, Toronto, Canada who spoke at the EASD press briefing regarding potential mechanisms involved in COVID-19 morbidity in diabetes reiterated the importance of glycemic control.

He showed a slide with the following advice for patients with both types of diabetes during the pandemic in addition to the general and now-familiar physical distancing, personal hygiene, hand washing, and wearing of masks:

Prepare a list of all medications, written and on the phone.

Consider supplies of medications, test strips, and continuous glucose monitoring equipment.

Don't neglect exercise, diet, and blood glucoseand blood pressure control.

Use telemedicine and devices to communicate with healthcare professionals.

Maintain appropriate levels of hydration, exercise, and glucose and ketone monitoring.

Optimize glycemic control whenever possible.

In hospitalized patients with type 2 diabetes, medications may need adjustment. Insulin is often the preferred glucose-lowering prescription.

In the Belgian study, medical records were analyzed for a total of 2336 patients with type 1 diabetes who received care at two specialist diabetes centers. The hospital admission rate was compared with national population data.

Overall, 0.21% (n = 5) of the patients with type 1 diabetes were admitted to the hospital with COVID-19, similar to the 0.17% (n = 15,239) of the general population, as of April 30, 2020 (P = .76).

During the same period, 127 individuals with type 1 diabetes were hospitalized for reasons other than COVID-19, including poor glycemic control (22%), diabetic ketoacidosis (8%), planned surgery (21%), diabetic foot problems (5%), and delivery (5%).

"It is noteworthy that the number of hospitalizations for reasons other than COVID-19 exceeded by far the number of COVID-19related hospitalizations," Vangoitsenhoven and colleagues write.

"Interpretation of adverse outcomes of people with type 1 diabetes during the COVID-19 epidemic should therefore be performed cautiously, as overinterpretation of the impact of COVID-19 itself on adverse outcomes in people with type 1 diabetes is likely," they conclude.

The Boston study, which was smaller, involved retrospective chart reviews of seven patients with type 1 diabetes hospitalized with COVID-19 and another 28 patients hospitalized for other reasons, all during the period from March to May 2020. The groups didn't differ in outpatient insulin doses corrected for weight or in glycemic control in the months preceding admission.

Diabetic ketoacidosis (DKA) occurred in one patient with COVID-19 and in two of the non-COVID patients. Both groups had significant preexisting diabetes-related complications, including nephropathy in more than half of each group and receipt of an organ transplant with immunosuppression in 14% of each group.

The composite outcome intensive care unit (ICU) admission, intubation, or death occurred in two COVID-19 patients (both cases involved ICU admission without intubation, and both patients recovered) and in four non-COVID patients, of whom two died.

The two groups showed "remarkable" similarity in age and glycemic control, although the COVID-19 patients were more likely to be Black (four vs two), consistent with other retrospective studies.

None of the patients had new-onset type 1 diabetes, which contrasts with the 15% seen in the T1D Exchange study.

Just 1 of the 7 patients with COVID-19 (14%) had DKA, compared with 30% of the confirmed and probable COVID-19 patients in the T1D Exchange study.

The significant difference in age about 52 years in the current study vs 21 years in the T1D Exchange study might explain those differences, Vamvini and colleagues say.

Limbert has received grants and personal fees from Abbott, Ipsen, and Sanofi. Vangoitsenhoven has disclosed no relevant financial relaitonships. Vamvini was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Drucker receives research support, consulting fees, and/or lecture fees from Novo Nordisk, Merck, Pfizer, and Intarcia.

Diabetes Care. 2020 Oct;43:e118-e119. Vangoitsenhoven et al, Full text; 2020 Oct;43:e120-e122. Vamvini et al, Full text

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Emerging Data on Type 1 Diabetes and COVID-19 Reassuring - Medscape

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A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes – Science Advances

October 10th, 2020 9:51 am

INTRODUCTION

Insulin-producing cells do not exist in isolation, and their environment has substantial effects on their architecture and function. In addition to the adjacent , delta, ghrelin, pancreatic polypeptide, and other endocrine cells, the exocrine pancreas, vasculature, and innervation all modify cell organization and insulin release (1). Islets are innervated by autonomic parasympathetic and sympathetic fibers, as well as by sensory fibers (2, 3). Evidence from many studies over the past century has identified a critical role for neural signals in modulating insulin and glucagon release to regulate blood glucose (4). For example, anticipatory signals increase insulin release upon food consumption but before any changes in blood glucose, and neural signals suppress insulin and stimulate glucagon release to counteract hypoglycemia (4). Since central nervous system (CNS) and nerve stimulation studies demonstrate that neural signals can override the effects of circulating glucose (5, 6), neural modulation is an attractive target for therapies to improve metabolic control.

Our current understanding of islets and their innervation largely relies on traditional histological techniques using immunolabeled structures in thin sections. These studies have provided a wealth of knowledge about islet structure at high resolution. However, pancreata are highly heterogeneous (7), with distinct regional embryological origins. Sections also lack landmarks to precisely and consistently identify the location of internal structures (8). Until now, laborious serial sectioning and reconstruction have been needed to deliver information about islet anatomy throughout the pancreas. In addition, thin filamentous structures, such as nerves, are difficult to quantify and trace over large volumes using this approach. Recent studies have applied confocal imaging of small pieces and thick sections of cleared pancreatic tissue to examine endocrine innervation (914). These have revealed dense nerve processes within both mouse and human islets. However, given the heterogeneity in the pancreas, there is a clear need for high-resolution, organ-wide imaging to accurately quantify and map regional variation and to assess the three-dimensional (3D) relationship between islets and their environment in health and disease.

Here, we used a tissue-clearing technique, iDISCO+ (15), to determine the 3D distribution of insulin-producing cells, glucagon-producing cells, and neurofilament 200 kDa (NF200)positive innervation across the whole pancreas in healthy animals and in mouse models of diabetes. NF200 is a pan-neuronal marker expressed in sympathetic, sensory, and vagal neurons but, unlike other neural markers, is not expressed in pancreatic endocrine cells (1618). NF200 is expressed in small and large myelinated and small unmyelinated fibers (19), so examining NF200+ fibers provides a comprehensive overview of pancreatic innervation. In addition, NF200 protein levels are altered by nerve damage and repair (2022), so NF200 intensity may reflect remodeling of pancreatic nerves. Using whole-organ 3D imaging and analysis, we readily quantified cell volume and provide detailed information about islet distribution and heterogeneity in mouse and human pancreatic tissue from healthy and diabetic donors. We quantified the dense endocrine innervation and its regional variation and demonstrated significant differences between innervated and noninnervated islets. Islet nerve density is significantly increased in diabetic nonobese diabetic (NOD) mice, with streptozotocin (STZ) treatment, and greater in pancreatic tissue from diabetic human donors. We systematically quantified intrapancreatic ganglia and nerve contacts with and cells to demonstrate that these are largely preserved in diabetes. These findings constitute a 3D atlas of pancreatic innervation for pancreas and diabetes investigators examining pancreatic innervation, the regional heterogeneity in the healthy pancreas, and responses to metabolic disease. Our studies suggest that diabetes is associated with significant remodeling of neural inputs into islets and that neural contacts with endocrine cells are preserved in diabetes.

We applied tissue clearing and whole-organ 3D imaging to examine cell mass, expressed as cell volume, and islet number, as well as spatial distribution in whole pancreata from C57BL/6 mice (Fig. 1, A to C, and movies S1 and S2).

(A) Pancreatic dissection. Photo credit: A.A., Icahn School of Medicine at Mount Sinai. (B) Duodenal (left) and splenic (right) pancreas, maximum projection (1.3). Scale bars, 500 m. (C) Pancreata, maximum projection at 4 (left) and 12 (right). Scale bars, 500 and 200 m. (D) cell volume. (E) Insulin+ islets per cubic millimeter. (F) Insulin intensity (normalized to whole pancreas). (G) Insulin+ islet volume distribution (left axis) and median volume (right axis). Islets per group: 27,092/12,260/14,832. (H) 3D projection of insulin, NF200+ exocrine innervation, and NF200+ surfaces within insulin+ islets (yellow). (I) Exocrine nerve volume. (J) Endocrine nerve volume per insulin+ islet. (K) Endocrine nerve volume/islet volume. (L) Left: 3D model of pancreatic innervation (NF200, white) and insulin (green). Right: Distance transformation analysis with islet surfaces pseudocolored based on distance from the nearest nerve surface. Scale bar, 500 m. Boxed area magnified in the right panel. Scale bar, 200 m. Data are shown as means SEM or median 95% confidence interval as indicated. Analyses by unpaired t test, *P < 0.05 and **P < 0.01. T, total; D, duodenal; S, splenic. N = 7 (D to G) and N = 5 (I to K).

The total cell volume made up 1.31 0.17% of the total pancreatic volume (Fig. 1D), with a greater cell volume in the splenic region. In line with previous reports (23, 24), there were 3874 264.2 islets per pancreas, with 1822 230.4 in the duodenal and 2052 129 in the splenic regions. Islet density (islet number per cubic millimeter) did not differ significantly across the pancreas (Fig. 1E). Insulin intensity showed significant regional variation with intensity in the duodenal pancreas being 25% greater than that in the splenic region (Fig. 1F).

We next examined islet distribution throughout the pancreas to determine whether there were regional differences in cell volume per islet (Fig. 1G). Islets with cell volumes between 1000 and 50,000 m3 were the most abundant (39.29%), followed by islets in the 50,000 to 499,999 m3 range (36.58%). Very large islets (>500,000 m3) comprised 20% of the islet population, and insulin+ structures with volumes below 1000 m3, consisting of five or fewer cells, were the least abundant (3.13%).

There are reported differences in the origins of nerves innervating the duodenal and splenic pancreas (25). Therefore, we hypothesized that there may be regional variations in pancreatic innervation. Thus, we next analyzed the 3D distribution of the pan-neuronal marker NF200 in the healthy mouse pancreas to determine regional variations and relationship to islets (Fig. 1H and movies S3 to S5).

The exocrine nerve volume was 40% greater in the duodenal pancreas compared with the splenic region (Fig. 1I). Pancreatic islets were highly innervated compared to exocrine tissue, with an endocrine nerve density over sixfold greater than the exocrine nerve density. In addition, there was significant regional variation in islet innervation. Nerve volume per islet in the duodenal region was almost double that in the splenic region (Fig. 1J). This difference was more pronounced when the endocrine nerve volume was corrected for cell volume (Fig. 1K). These findings are consistent with marked regional variation in the density of islet innervation.

The proximity of nerves and endocrine cells may have important biological consequences. Autonomic neurotransmission occurs over 1 to 2 m (26), but endocrine and immune cells may influence nerve growth, repair, and function over longer ranges (27, 28). As a result, we examined the proportion of islets in contact with NF200+ fibers and the distance of each islet from the closest NF200+ fiber (Fig. 1L and movie S6). Only 6.1% of islets contained or were in contact with NF200+ fibers, with no significant difference between duodenal and splenic regions (Fig. 2A). The proportion of innervated (NF200+) islets increased with islet volume (fig. S1C). Most islets were within 250 m of an NF200+ fiber, and islets in the duodenal pancreas were significantly closer to nerves than those in the splenic pancreas (fig. S1A).

(A) Distribution of insulin+ islets (<1.6 and >1.6 m from the nearest nerve). Islets per group: 25,310/10,030/15,280. (B) Mean insulin+ islet volume NF200+ innervation; islets per group: 11,869/929/4690/325/7179/604. (C) Total insulin+ islet volume NF200+ innervation. (D) NF200 intensity sum normalized for insulin+ islet volume; islets per group: 5174/4530/2264/687/2196/1788/701/330/2978/2742/1563/357. (E) Intrapancreatic ganglia (NF200, magenta) and cells (insulin, green). Arrows mark ganglia. Scale bar, 50 m. (F) NF200+ intrapancreatic ganglia per cubic millimeter. (G) Intrapancreatic ganglia volume. Ganglia per group: 123/43/80. (H) Distance between intrapancreatic ganglia and insulin+ islets. Ganglia per group: 123/43/80. (I) cells contacting nerves per islet. Islets per group: 69/40/29. Data are shown as means SEM or median 95% confidence interval as indicated. Analyses by Kruskal-Wallis test with Dunns test (B to D) or unpaired t test (F to I), ***P < 0.001. T, total; D, duodenal; S, splenic. N = 5 (A to D), N = 3 (F to H), and N = 4 (I).

To test the hypothesis that innervated islets differ from those without innervation, we then analyzed islet volume based on whether islets were innervated by NF200+ fibers, hypothesizing that neural signals may play a role in determining islet size. NF200-innervated islets were 10-fold larger than islets without NF200 innervation (Fig. 2B and fig. S1B), and as a result, innervated islets made up 43% of the total cell volume in the pancreas (Fig. 2C). Both innervated and noninnervated islets in the splenic region were larger than those in the duodenal pancreas (Fig. 2B).

Next, we analyzed the intensity of NF200+ immunostaining within each islet. NF200 protein levels are associated with structural stability of nerves and increased conduction velocity, so NF200+ immunostaining intensity may have functional correlates (29, 30). While the largest islets were more likely to be innervated, the intensity of NF200+ immunostaining was twofold greater in the smallest islets compared to the largest islets and greater in subpopulations of duodenal islets (Fig. 2D).

These data demonstrate that innervated islets are a small fraction of the total islet number but are significantly larger than islets without NF200 innervation and form a substantial portion of the total cell volume. These findings suggest the potential involvement of NF200+ nerves in islet development and cell growth.

Intrapancreatic ganglia integrate inputs from the sympathetic and parasympathetic nervous systems and provide significant islet innervation (31). Regional differences in ganglia size in the pancreas have been reported (32). Intrapancreatic ganglia are sparse (21.5 2.5 ganglia/mm3; Fig. 2, E and F), with an average volume of 83,467 10,646 m3 (Fig. 2G) and located close to islets (47.3 5.7 m; Fig. 2H). There were no significant regional differences in ganglia density, size, or location.

To assess whether islet innervation could directly influence endocrine cell function through neural signals, we quantified the number of cells contacting NF200+ nerves. Only 9.4 2.2% of cells contacted NF200+ nerves (Fig. 2I) with no regional difference. As expected, a larger number of cells contacted nerves in large islets compared to small islets (fig. S1D), but the proportion of cells contacting NF200+ nerves did not differ with islet size (fig. S1E). In aggregate, these data provide a comprehensive 3D atlas of the anatomy and NF200+ innervation of the entire mouse endocrine and exocrine pancreas that can be used as a benchmark to assess the effects of specific pancreatic innervation during development and in disease.

The 3D relationships between islets and innervation across the whole endocrine pancreas are largely unknown in diabetes. Hence, we determined how pancreatic anatomy and cell innervation were affected in a mouse model of type 1 diabetes (T1D). NOD mice provide a model of diabetes with autoimmune cell destruction and spontaneous T1D development. We examined the 3D structure of NF200+ innervation and islets in nondiabetic NOD mice (average nonfasting blood glucose, 115 4 mg/dl) and diabetic NOD mice (average nonfasting blood glucose, 495 62 mg/dl; Fig. 3A and movies S7 and S8).

(A) Pancreata from nondiabetic and diabetic NOD mice [maximum projection at 1.3 (top), 4 (middle), and 12 (bottom); scale bars, 2000, 500, and 200 m]. (B) cell volume. (C) Insulin+ islets per cubic millimeter of pancreatic tissue. (D) Insulin intensity (normalized against total pancreas, nondiabetic). (E) Insulin+ islet volume distribution (left axis) and median volume (right axis). Islets per group: 11,404/6285/5119/4057/2203/1854. (F) Exocrine nerve volume. (G) Endocrine nerve volume per insulin+ islet. (H) Endocrine nerve volume by islet volume. (I) Distribution of insulin+ islets located <1.6 and >1.6 m from the nearest nerve. (J) Mean insulin+ islet volume NF200+ innervation. Islets per group: 8815/857/4296/436. (K) Total insulin+ islet volume NF200+ innervation. (L) NF200 intensity sum normalized for insulin+ islet volume. Islets per group: 4941/3341/1209/383/2862/1586/189/73. (M) Intrapancreatic ganglia per cubic millimeter. (N) Intrapancreatic ganglia volume. Ganglia per group: 112/82. (O) Distance between intrapancreatic ganglia and insulin+ islets. Ganglia per group: 111/54. (P) cells contacting nerves per islet. Islets per group: 28/14. Data are shown as means SEM or median 95% confidence interval where indicated. Analyses by one-way ANOVA with Tukeys test (B to D and F to G), Kruskal-Wallis with Dunns test (H and J to L), or unpaired t test between diabetic and nondiabetic groups (H). *P < 0.05, **P < 0.01, and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 7 nondiabetic and N = 7 diabetic (B to E, P); N = 8 nondiabetic and N = 7 diabetic (F to L); N = 6 nondiabetic and N = 6 diabetic (M to O).

Across the whole pancreas, islet density and cell volume in female nondiabetic NOD mice were similar to that seen in male C57BL/6 mice (Figs. 1, D and E, and 3, A to C). In female diabetic NOD mice, the cell volume was significantly lower across the whole pancreas, reduced to 10% of the volume in nondiabetic NOD mice in both splenic and duodenal regions (Fig. 3B). The islet number was also significantly reduced in diabetic NOD mice, particularly in the splenic, but not duodenal pancreas (Fig. 3C). However, the intensity of insulin immunostaining was preserved in the remaining islets that were detected in diabetic NOD mice (Fig. 3D). There was a significant inverse correlation between blood glucose levels and both islet number and cell volume (fig. S2A).

The volume distribution of insulin+ islets in nondiabetic NOD mice was also comparable to C57BL/6 mice (Fig. 3E). However, islet volume distribution was significantly shifted in diabetic NOD mice, with marked loss of larger islets. Insulin+ islets over 50,000 m3 were reduced by more than half, and the median islet volume decreased by more than 50%. The loss of large islets was particularly notable in the duodenal pancreas (Fig. 3E).

Together, these data demonstrate marked decreases in insulin+ islet number and volume and marked alterations in islet volume distribution in diabetic compared to nondiabetic NOD mice, particularly in the duodenal pancreas. Our data also suggest that the remaining islets in diabetic NOD mice maintained their insulin content.

Previous studies have reported alterations in pancreatic innervation in mouse models of diabetes (13, 3336). Therefore, we examined pancreatic innervation in NOD mice to determine effects on nerve density in the different regions of the pancreas (movies S9 and S10).

Nerve density in insulin+ islets was increased more than twofold in diabetic NOD mice (Fig. 3, G and H), particularly in the splenic pancreas. Islet nerve density in the splenic pancreas positively correlated with blood glucose (fig. S2C). The regional differences in endocrine nerve density observed in C57BL/6 mice were absent in nondiabetic NOD mice. There was no difference in exocrine nerve density between nondiabetic and diabetic NOD mice and no correlation with blood glucose (Fig. 3F and fig. S2B).

Previous studies suggest that neural signals contribute to cell survival (37), so increased islet innervation could result from differences in the susceptibility of innervated and noninnervated islets to immune destruction. To test this, we examined the proportion of NF200+ islets (islets containing or in contact with NF200+ fibers) in NOD mice. We did not see any significant change in the proportion of NF200+ islets (14.6 versus 9.8% islets in nondiabetic and diabetic NOD mice, respectively; Fig. 3I). However, the proportion of NF200+ islets was increased in a subset of islets with volumes between 50,000 and 500,000 m3 in diabetic NOD mice (fig. S2F). The median distance between islets and nerves was similar in diabetic and nondiabetic NOD mice for the total pancreas but significantly reduced in the splenic pancreas (fig. S2D).

In keeping with the results in C57BL/6 mice, NF200+ islets were significantly larger than NF200 islets in both diabetic and nondiabetic NOD mice (Fig. 3J), although, as expected, the average volume of both NF200 and NF200+ islets decreased in diabetic NOD mice. Innervated insulin+ islets remained 60% of the total cell volume in both diabetic and nondiabetic NOD mice (Fig. 3K).

In published studies, the intensity of NF200 immunostaining decreases with nerve damage and increases in nerve regeneration (20, 22). To indirectly assess the effects of autoimmune diabetes on nerve integrity in islets, we examined the intensity of NF200 immunostaining in diabetic and nondiabetic NOD mice and found that the intensity of NF200 immunostaining was significantly increased in islets from diabetic NOD mice (Fig. 3L).

We next examined intrapancreatic ganglia to determine whether autoimmune diabetes altered their distribution or size. There was no significant difference in intrapancreatic ganglia density (18.9 5.2 versus 28.2 10.1 ganglia/mm3, nondiabetic versus diabetic NOD mice, respectively; Fig. 3M) or volume (61,779 5961 versus 59,348 6977 m3, nondiabetic versus diabetic NOD mice, respectively; Fig. 3N), but the distance between intrapancreatic ganglia and islets increased fourfold in diabetic NOD mice (40 5.3 versus 171.7 17.6 m, nondiabetic versus diabetic, respectively; Fig. 3O).

Next, we examined the proportion of cells in contact with NF200+ fibers in nondiabetic and diabetic NOD mice. Despite a significant increase in islet nerve density, there was no significant change in the proportion of cells contacting nerves in diabetic NOD mice (Fig. 3P).

Autoimmune cell destruction principally affects cells in NOD mice resulting in islets composed primarily of glucagon+ cells. The changes in cell innervation in mouse models of diabetes are largely unknown. In diabetic NOD mice, glucagon staining is clearly present, but glucagon+ cells from a single islet may form several clusters rather than a clearly defined, single islet (Fig. 4, A and B). As previously reported (38), the ratio of glucagon to insulin volume (Fig. 4C) was significantly increased in diabetic NOD mice (movies S11 and S12). In nondiabetic NOD mice, NF200 nerve density in cell clusters was markedly higher than nerve density in insulin+ islets. Nerve density in diabetic NOD mice was unchanged (Fig. 4D). The proportion of innervated cell clusters was similar to that of innervated insulin+ islets in nondiabetic NOD mice and increased twofold in diabetic NOD mice (Fig. 4E). In keeping with increased NF200 nerve density in cell clusters of nondiabetic NOD mice, the proportion of cells contacting NF200+ fibers was more than fivefold higher than cells contacting NF200+ fibers in nondiabetic NOD mice. However, the proportion of cell nerve contacts did not change in diabetic mice (Fig. 4F).

(A) Maximum projections of light-sheet images of pancreatic samples from nondiabetic and diabetic NOD mice stained for insulin (green), NF200 (magenta), and glucagon (blue) and imaged at 4 magnification. Scale bars, 200 m. (B) cell volume corrected for pancreatic volume in NOD mice. (C) Glucagon+ cell volume as a percentage of insulin+ cell volume in NOD mice. (D) NF200+ nerve volume within glucagon+ cell clusters in NOD mice. (E) Glucagon+ cell cluster volume (left axis) and median nerve distance (right axis) in NOD mice. (F) Percentage of cells contacting nerves per islet. Number of islets: 23/16. Data are shown as mean SEM or as median 95% confidence interval where indicated. Analyses by one-way ANOVA with Tukeys test (D) or Kruskal-Wallis with Dunns test (B, C, and E). *P < 0.05. T, total; D, duodenal; S, splenic. N = 3 nondiabetic and N = 3 diabetic NOD mice.

In summary, insulin+ islet nerve density and NF200 immunostaining are increased in the surviving insulin+ islets of diabetic NOD mice, and cell contacts with NF200+ fibers are preserved. cell nerve density and cell contacts with NF200+ fibers are greater than contacts with cells, and cell nerve density also increases in diabetic NOD mice.

On the basis of our findings in NOD mice, we hypothesized that nerve density may progressively increase in surviving islets during the development of diabetes. To test this hypothesis, we examined the time course of changes in insulin+ islets and pancreatic nerves in mice with STZ-induced diabetes, as well as in age- and sex-matched C57BL/6 mice. Diabetes secondary to multiple low-dose STZ treatment is likely induced by both direct cell toxicity and islet inflammation. Therefore, using a standard 5-day low-dose STZ model, we examined NF200, insulin, and glucagon staining in mice sacrificed 5 and 15 days after completion of STZ treatment (nonfasting blood glucose: 259 18 and 430 17 mg/dl, respectively) and compared these to untreated littermate controls (nonfasting blood glucose: 123 9 mg/dl; Fig. 5A and movies S13 and S14).

(A) Pancreata at days 5 (left) and 15 (right) after STZ treatment, maximum projections at 1.3 (top), 4 (middle), and 12 (bottom). Scale bars: 1000, 500, and 200 m. (B) cell volume. (C) Insulin+ islets per cubic millimeter. (D) Insulin intensity (normalized against total pancreas, control). (E) Insulin+ islet volume distribution (left axis) and median volume (right axis). Islets per group: 10,479/4682/5797/10,091/5162/4929/14,380/7543/6837. (F) Exocrine nerve volume. (G) Endocrine nerve volume per insulin+ islet. (H) Endocrine nerve by islet volume. Data are shown as mean SEM or as median 95% confidence interval where indicated. Analyses by one-way ANOVA with Tukeys test for comparison between control, STZ day 5, and STZ day 15, and unpaired t test for comparison between duodenal and splenic pancreas (B to D and F to H) or Kruskal-Wallis with Dunns test (E); *P < 0.05, **P < 0.01, and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 5 control, N = 6 STZ day 5, and N = 7 STZ day 15 (B to E); N = 6 control, N = 5 STZ day 5, and N = 5 STZ day 15 (F to H).

First, we analyzed islet number and total cell volume to determine the time course and effects of STZ treatment, hypothesizing that STZ may differentially affect these parameters in different pancreatic regions. As expected in this model, total cell volume was reduced to 40% of control, and intensity of insulin immunostaining was decreased by 50% with STZ treatment (Fig. 5, B to D). Islet number and cell volume negatively correlated with blood glucose in STZ-induced diabetes (fig. S3A). STZ treatment did not significantly alter the distribution of cell volumes throughout the pancreas, suggesting that its effects were uniform across islets of all sizes (Fig. 5E). However, there was a significant decrease in the individual islet volume, first in the duodenal pancreas at day 5 and later at day 15 in both the duodenal and splenic regions. These findings demonstrate that STZ treatment progressively reduces total cell volume, intensity of insulin immunostaining, and the volume of individual islets, with significant differences in the time course and extent of these changes between duodenal and splenic pancreas.

We next examined pancreatic innervation in STZ-treated mice to determine the time course and regional distribution of effects on nerve density (movies S15 and S16). Nerve density in the exocrine pancreas was significantly increased 15 days after STZ treatment (Fig. 5F and fig. S3B). STZ treatment significantly increased islet innervation and islet nerve density by twofold on day 5 (Fig. 5, G and H). Islet nerve density was significantly correlated with blood glucose (fig. S3A).

To test the hypothesis that neural signals may play a role in cell preservation, we assessed whether STZ treatment had differential effects on islets based on whether they contained NF200+ nerves or not. STZ treatment led to a progressive increase in the proportion of NF200+ islets across the duodenal and splenic pancreas (Fig. 6A) and all islet sizes (fig. S3F) but did not reach significance (P = 0.14). STZ treatment significantly reduced the distance between insulin+ islets and NF200+ fibers on day 5, primarily in the splenic pancreas (fig. S3D). In both control and STZ-treated mice, innervated islets are significantly larger than noninnervated islets but decline in volume with STZ treatment (Fig. 6B). The total volume of innervated islets, but not of noninnervated islets, significantly decreased with STZ treatment (Fig. 6C) but remained 54% of the remaining total cell volume.

(A) Distribution of insulin+ islets located <1.6 and >1.6 m from the nearest nerve. (B) Mean volume for insulin+ islets NF200+ innervation. Islets per group: 10,199/929/5300/366/9837/1022. (C) Total volume for insulin+ islets NF200+ innervation. (D) Intensity of NF200 immunolabeling normalized for insulin+ islet volume. Islets per group: 3013/2762/1837/605/2842/1791/1057/336/5800/3274/1500/386. (E) Ganglia per cubic millimeter. (F) Volume of intrapancreatic ganglia. Ganglia per group: 114/73/97. (G) Distance between intrapancreatic ganglia and insulin+ islets. Ganglia per group: 114/73/97. (H) Percentage of cells contacting nerves per islet. Islets per group: 69/28/69. Data are shown as means SEM or as median 95% confidence interval where indicated. Analyses by Kruskal-Wallis with Dunns test (B to D) for comparison between control, STZ day 5, and STZ day 15, and unpaired t test for comparison between duodenal and splenic pancreas (E to H). *P < 0.05, **P < 0.01, and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 6 control, N = 5 STZ day 5, and N = 5 STZ day 15 (A to D); N = 6 control, N = 3 STZ day 5, and N = 3 STZ day 15 (E to H).

To determine whether STZ-induced diabetes modified the expression of NF200, we assessed changes in intensity of NF200 immunostaining in relation to insulin+ islet volume and time after treatment (Fig. 6D). The intensity of NF200 immunostaining (corrected for cell volume) was significantly increased in the largest islets (>500,000 m3) 5 days after STZ treatment and by twofold to fourfold in all islets at 15 days after STZ treatment. These findings demonstrate that STZ treatment increases exocrine and endocrine nerve density and NF200 expression, results that are in keeping with increased nerve growth.

We next examined intrapancreatic ganglia in mice treated with STZ to determine whether cell destruction changed their density or size. While STZ treatment did not change intrapancreatic ganglion density or distance from the islet, there was a 30% decrease in ganglion volume 15 days after STZ treatment (Fig. 6, E to G). Similar to our findings in NOD mice, although islet nerve density increased with STZ treatment, the proportion of cells contacting NF200+ fibers did not change significantly (Fig. 6H).

We next assessed cell volume and nerve density in cell clusters in STZ-treated mice. STZ treatment increased the ratio of glucagon+ to insulin+ cell volume, but total glucagon+ cell volume was reduced after 15 days (Fig. 7, A to C, and movie S17). NF200 nerve density in cell clusters was significantly increased in STZ-treated mice (Fig. 7D), but the proportion of innervated cell clusters did not change (Fig. 7E). Similarly, the proportion of cells contacting NF200+ fibers was not significantly altered by STZ treatment (Fig. 7F).

(A) Pancreata at days 5 (left) and 15 (right) after STZ treatment. Insulin, green; NF200, magenta; glucagon, blue. Imaged at 4 magnification. Scale bars, 200 m. (B) Quantification of cell volume corrected for pancreatic volume in STZ-treated mice. (C) Quantification of glucagon+ cell volume as a percentage of insulin+ cell volume in STZ-treated mice. (D) Quantification of NF200+ nerve volume within glucagon+ cell clusters in STZ-treated mice. (E) Glucagon+ cell cluster volume (left axis) and median nerve distance (right axis) in STZ-treated mice. (F) Percentage of cells contacting nerves per islet. Islet number: 98/37/53. Data are shown as means SEM or as median 95% confidence interval where indicated. Analyses by one-way ANOVA with Tukeys test (C to D) or Kruskal-Wallis with Dunns test (B and E). *P < 0.05, **P < 0.01, and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 6 control, N = 4 STZ day 5, and N = 6 STZ day 15.

In summary, 3D representation faithfully represents the progressive reduction in islet number, cell volume, and intensity of insulin immunostaining in response to STZ treatment. Further, STZ treatment increases insulin+ islet nerve density, the proportion of innervated islets, and intensity of NF200 immunostaining. cell nerve density is increased with STZ treatment, but the proportion of and cells that are in contact with NF200+ fibers is not significantly altered in STZ-treated mice.

Islet innervation differs between species (3, 39) and the 3D relationships between islets and pancreatic nerves in healthy versus diabetic patients remain largely unknown. To assess these, islets and NF200+ innervation were examined in small, cleared pancreatic samples from healthy human donors and donors with type 2 diabetes (T2D; Table 1) by light-sheet imaging to assess islet distribution and relationship to innervation (Fig. 8A and movies S18 and S19).

CVA, cardiovascular accident; HbA1c, hemoglobin A1C; N/A, not applicable; PFA, paraformaldehyde; M, male; F, female.

(A) Maximum projections of pancreatic samples from human donors without (C1 to C5) and with type 2 diabetes (DM2; D1 to D3) at 1.3. Scale bars, 1000 m. (B) cell volume. (C) Insulin+ islets per cubic millimeter. (D) Insulin+ islet volume distribution (left axis) and median volume (right axis). (E) Exocrine nerve volume. (F) Endocrine nerve volume per insulin+ islet. (G) Endocrine nerve volume corrected for insulin+ islet volume. (H) Distribution of insulin+ islets located at <1.6 and >1.6 m from nerves. Islets per group: 28,315 control and 6790 DM2. (I) Mean volume of insulin+ islets NF200+ innervation. Islets per group: 25,519/236/7448/345. (J) Total volume of insulin+ islets NF200+ innervation. (K) Intrapancreatic ganglia (NF200, magenta; confocal, 20). Boxed areas magnified in lower panels with cell bodies indicated by arrows. Scale bars, 50 m (top) and 25 m (bottom). (L) Ganglia per cubic millimeter. (M) Volume of intrapancreatic ganglia. Ganglia per group: 31/12. (N) Distance between intrapancreatic ganglia and insulin+ islets. Ganglia per group: 31/12. (O) cells contacting nerves per islet. Islets per group: 73/28. Data are shown as means SEM or as median 95% confidence interval where indicated. Analyses by unpaired t test (B to G and L to M), Mann-Whitney test (H), or Kruskal-Wallis with Dunns test (I to J). *P < 0.05, **P < 0.01, and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 5 control and N = 3 DM2.

As expected, total cell volume (Fig. 8B) and islet number (Fig. 8C) were highly variable (40). The cell volume (as a percentage of the total pancreatic sample volume) was lower in the diabetic donors, varying between 0.47 and 2.2% in the control group and 0.85 and 0.97% in the diabetic group. Islet numbers ranged from 66 to 200 islets/mm3 in the control group to 58 to 287 islets/mm3 in the diabetic group. While islet number per cubic millimeter was greater in humans than in mice, the cell volume (%) was very similar in murine and human tissues. The cell volume distribution in nondiabetic pancreata was not significantly different to that in mice (Fig. 8D). Larger islets were disproportionately reduced, and the mean volume of an individual islet was significantly lower in diabetic compared to healthy individuals.

In human samples from healthy donors, NF200+ innervation was similar between endocrine (0 to 0.89% nerve volume per islet) and exocrine tissue (0.06% to 0.94% nerve volume per exocrine tissue; Fig. 8, E to G). Exocrine nerve volume, endocrine nerve volume per islet, islet nerve density, and proportion of innervated islets were greater in diabetic individuals (Fig. 8H). In nondiabetic individuals, innervated insulin+ islets are significantly larger than those without innervation, in line with the findings in mice, but innervated insulin+ islets are a smaller proportion of the total islet volume than seen in mouse pancreata. In diabetic individuals, innervated islets are significantly smaller than in nondiabetic individuals (Fig. 8, I and J).

We next assessed intrapancreatic ganglia in human pancreatic samples. Human intrapancreatic ganglia were larger than those found in mice (Fig. 8K), but ganglion density and distance from islets were similar to C57BL/6 and nondiabetic NOD mice. There was no significant difference in ganglia size between nondiabetic and diabetic donors (Fig. 8, L to N). Last, we examined contacts between NF200+ nerves and cells. The proportion of cells in contact with NF200+ fibers was half of that in control mice (4.15 versus 9.44%) and was preserved in individuals with diabetes (6.07%; Fig. 8O).

Together, cell volume and distribution in human pancreata were comparable to murine pancreata, and innervated islets were significantly larger than noninnervated islets. In samples from individuals with diabetes, exocrine and endocrine innervation as well as proportion of innervated islets were increased, and nerve contacts with cells persist.

The pancreas is composed of multiple cell types, is richly vascularized, and is densely innervated by sympathetic, parasympathetic, and sensory nerves. We wanted to compare our analyses of pancreatic innervation using the pan-neuronal marker, NF200, with pathway-specific pancreatic innervation. Using a modified iDISCO+ protocol specifically optimized for pancreatic tissue, we examined tyrosine hydroxylase (TH) immunolabeling to mark sympathetic nerve fibers (movie S20) and vesicular acetylcholine transporter (VAChT) immunolabeling to identify parasympathetic nerve fibers (movie S21) across the mouse pancreas. There was more TH+ (Fig. 9, A to D) and VAChT+ (Fig. 9, H to K) innervation than NF200+ innervation in both the exocrine and endocrine pancreas. In keeping with our findings examining NF200+ fibers, TH and VAChT nerve density were threefold to more than sixfold greater in the endocrine than in the exocrine pancreas. The proportion of islets containing or in contact with TH+ fibers was 27.7% (Fig. 9E) compared to 35.0% for VAChT+ fibers (Fig. 9L). In line with our findings with NF200, both TH (Fig. 9F) and VAChT (Fig. 7M) innervated islets were significantly larger than noninnervated islets, and as a result, the majority of insulin+ islet volume is composed of innervated islets (Fig. 9, G and N).

(A) Maximum projections of TH and insulin. Scale bars, 2000 m at 1.3 and 200 m at 4. (B) TH+ exocrine nerve volume. (C) TH+ endocrine nerve volume per insulin+ islet. (D) TH+ endocrine nerve volume by insulin+ islet volume. (E) Distribution of insulin+ islets located at <1.6 and >1.6 m from TH+ nerves. Islets per group: 10,610/4773/5837. (F) Mean insulin+ islet volume for insulin+ islets with and without TH+ innervation. Islets per group: 8542/3314/4699/1320/3843/1994. (G) Total volume for insulin+ islets with and without TH+ innervation. (H) Maximum projections of VAChT and insulin. Scale bars, 2000 m at 1.3 and 200 m at 4. (I) VAChT+ exocrine nerve volume. (J) VAChT+ endocrine nerve volume per insulin+ islet. (K) VAChT+ endocrine nerve volume corrected for insulin+ islet volume. (L) Distribution of insulin+ islets located at <1.6 and >1.6 m from VAChT+ nerves. Islets per group: 12,661/7165/5496. (M) Mean volume for insulin+ islets with and without VAChT+ innervation. Islets per group: 8542/3314/4699/1320/3843/1994. (N) Total volume for insulin+ islets with and without VAChT+ innervation. Data are shown as means SEM or as median 95% confidence interval where indicated. Analyses by unpaired t test (B to E and I to L) or Kruskal-Wallis with Dunns test (F, G, M, and N). **P < 0.01 and ***P < 0.001. T, total; D, duodenal; S, splenic. N = 5.

The optimized iDISCO+ protocol was also effective for labeling fibers expressing TRPV1 (transient receptor potential cation channel, subfamily V, member 1) and synapsin (fig. S4). In addition, we applied a novel alternative approach to visualize islet vasculature by combining insulin immunolabeling with fluorophore-tagged dextran or CD31 antibody, followed by optical clearing using ethyl cinnamate (ECi) to preserve fluorescence while allowing for additional immunostaining tissue (fig. S4) (41). These data demonstrate that modification of optical clearing protocols allows for visualization of multiple markers in pancreatic tissue.

In summary, NF200, TH, and VAChT immunostaining all demonstrate that large islets have enriched islet innervation and that large innervated islets represent at least half of total pancreatic islet volume. However, analysis of pancreatic innervation using TH and VAChT immunostaining suggests that endocrine nerve density is greater than revealed by NF200 immunostaining.

Tissue clearing, 3D imaging, and unbiased image analysis have been widely used in the CNS to provide new insights into anatomical pathways and patterns of regional activation. However, there have been few applications in peripheral organs such as the pancreas. Whole-organ clearing and imaging are especially suited for the mapping of filamentous structures, particularly to delineating innervation across large distances that can be difficult to achieve using traditional serial sections and 2D imaging. Tissue clearing has been used previously in thick pancreatic sections (350 to 1000 m) (9, 10, 12, 4244) and small pieces of pancreatic tissue (11) and then imaged with optometry or high-magnification confocal microscopy for detailed analysis [see (4547) for review]. This has provided important information about islet characteristics and structural relationships over a close range. In particular, previous studies using 3D imaging in pancreatic sections, fetal tissue, and young mice have provided data about islet innervation (9, 10, 13, 14, 42, 48). Our data extend these important published studies. Different pancreatic regions have diverse embryological origins and variations in islet density and function and are supplied by neurons from different extrapancreatic ganglia. Without assessing pancreatic structure across the whole organ, our understanding and quantification of pancreatic anatomy, including possible regional differences, are incomplete and possibly inaccurate.

Tissue clearing and volume imaging of the pancreas provided several new insights. Innervation of the endocrine pancreas is significantly enriched compared to the surrounding exocrine pancreas, with marked regional variation. Islets are closely associated with pancreatic innervation, and innervated islets are significantly larger than noninnervated islets, in both mouse and human. Intrapancreatic ganglia are sparse and close to islets. Almost half of cells and a tenth of cells contact NF200+ fibers, irrespective of islet size or location. Last, islet nerve density and expression of NF200 are increased in the remaining islets of two mouse models of T1D, with temporal and regional differences, and greater in human T2D, in keeping with nerve remodeling.

3D imaging across the whole pancreas provides straightforward measurement of multiple islet characteristics and identifies significant regional differences that would be laborious or impossible to obtain by serial sectioning. We readily measured cell volume across multiple pancreata, and our findings are in agreement with previous studies at 1 to 2% in mouse pancreas (24) and at 1 to 4% in human pancreas (49, 50). Increased islet volume in the splenic pancreas is in keeping with previous observations using 2D histology, in isolated islets and in transgenic mice (51, 52). Intensity of insulin immunostaining was significantly lower in the splenic pancreas. The splenic pancreas contains significantly larger islets, and previous studies report lower insulin immunostaining intensity and fewer insulin granules in large islets, while other studies demonstrate lower c-peptide content in cells from the splenic pancreas (53, 54). Our approach also facilitates rapid analysis of islet volume distribution across the pancreas. The majority of islets were between 1000 and 500,000 m3, equivalent to islet diameters of 12 to 98 m (assuming spherical islets), with around a fifth of islets having volumes larger than 500,000 m3. Whole-organ imaging demonstrated significant differences in islet biology between diabetes models. Islet number and cell volume were reduced in diabetic NOD mice, with the intensity of insulin immunostaining relatively preserved in some islets and a notable shift to small islets. Islet number and volume were also reduced with STZ treatment, but intensity of insulin immunostaining was markedly reduced, and size distribution was minimally altered. Together, these observations validate tissue clearing and 3D imaging as a reliable straightforward method to assess cell volume and other characteristics across the entire pancreas.

Whole-tissue 3D imaging confirmed dense pancreatic innervation and revealed markedly greater nerve density in the endocrine pancreas, over sixfold greater than in the exocrine pancreas of mice. These findings confirm the results of previous studies reporting close association between islets and nerves using 2D histology and 3D examination of pancreatic sections (3, 9, 10). We extended these findings to show that endocrine NF200+ innervation was not uniform throughout the pancreas but enriched in the duodenal portion. These regional differences may reflect the distinct embryological origins of the duodenal and splenic regions. Further studies will determine whether regional differences in pancreatic innervation contribute to reported regional differences in islet composition, size, function, and susceptibility to immune loss.

3D analysis of islets and innervation across the whole pancreas revealed previously unknown features of the close anatomical relationship between islets and nerves. In mice and human samples, innervated islets are a relatively small fraction of all islets by number, but they are, on average, 10-fold larger than noninnervated islets. As a result, innervated islets represent around half of the total cell volume. The large volume of innervated islets is in accordance with a role for neural signals in islet development and maintenance. In both mice and zebrafish, cells aggregate close to pancreatic nerves in development, and islet architecture is disrupted by loss of neural signals (55, 56). There is also close physical association between nerves and islets in human embryos, particularly in the middle and late trimester, when there is rapid development of the endocrine pancreas (55). Less is known about the role of neural signals in cell maintenance, but vagotomy reduces cell replication in rats (57). Vagotomy disrupts the afferent and efferent signals to several intra-abdominal organs, so further studies are needed to determine whether loss of neural signals, specifically to the pancreas, disrupts islet structure and function during development and after birth.

Islets are closely associated with the pancreatic duct and highly vascularized, so it is possible that the proximity between nerves and islets is related to innervation of the duct or vessels. Islet blood vessels are richly innervated, and neural signals have marked effects on islet blood flow (58). However, several studies suggest that vascular signals actually reduce endocrine cell differentiation during development, and in zebrafish, islets remain densely innervated even in the absence of islet vascularization.

Although NF200-innervated islets are large, on average, NF200 immunostaining intensity is greater in smaller innervated islets. NF200 expression has been linked to nerve diameter and conduction velocity, so it is possible that differences in NF200 immunostaining intensity may have functional consequences (29, 30). In human pancreata, small islets have a greater proportion of cells compared to other endocrine cell types and higher insulin content (59). Similarly, small rat islets were functionally superior to larger islets in ex vivo studies and after transplantation (60). In keeping with previous work (3), NF200+ nerves contact a small proportion of cells in each islet, with no proportional differences between pancreatic regions or islet sizes. The proportion of innervated cells is similar to the percentage of cells that are reported to act as hub cells in the islets, and hub cells are reported to be modulated by cholinergic agonists (61). Although a minority of cells contact NF200+ nerves, neural signals could influence activity across multiple cells through electrical coupling. In contrast, and in keeping with previous work (3), NF200+ nerves contact a much greater proportion of cells, which lack gap junctions. Whether variation in NF200 immunostaining intensity or proximity of individual cells to nerves contributes to functional heterogeneity of cells is currently unknown and warrants further studies.

The development of diabetes in NOD mice and in STZ-treated mice is associated with rapid and significant increases in islet nerve density. In NOD mice, increased nerve/islet volume suggests that nerve volume may be preserved, while cell volume is reduced in surviving islets. The proportion of innervated cell clusters increased in diabetic NOD mice. In STZ-treated mice, nerve volume per islet, nerve density per islet, and nerve density in cell clusters are all increased. These findings suggest that increased nerve density is restricted to the remaining insulin+ islets in NOD mice, while both cell and cell nerve density is increased in STZ-treated mice. The increases in insulin+ islet nerve density in diabetic NOD and STZ-treated mice are similar in magnitude to nerve density changes in response to physiologically relevant stimuli. In the CNS, fasting leads to an almost twofold increase in agouti related neuropeptide (AgRP)/neuropeptide Ypositive (NPY+) terminals in the paraventricular nucleus, a major pathway regulating food intake (62). In the peripheral nervous system, skin inflammation increased sensory nerve density twofold and was associated with increased sensitivity to thermal and mechanical stimuli (63). Further studies will be required to test the functional consequences of increased islet nerve density.

The intensity of NF200 immunostaining was significantly increased in the islets of diabetic NOD and STZ-treated mice. NF200 staining intensity increases in response to nerve regeneration (20, 21), so up-regulation of NF200 may reflect ongoing regeneration of islet innervation. These findings, and the time course of the increased nerve density with STZ treatment, are highly suggestive of nerve regeneration; reported rates of nerve regrowth after crush injury are up to 4 mm/day, and restoration of electrical activity in peripheral nerves after chemical injury occurs within days. Our findings may be responses to STZ directly, to hyperglycemia, and to inflammatory processes and/or interactions between endocrine cells and neurons to regulate neural density. Increased nerve density is reported in response to inflammation in several tissues and their adjacent structures, and these changes can either be protective or exacerbate inflammation (64, 65). Increased insulin+ islet nerve density in NOD mice, and the increase in exocrine and endocrine nerve density in STZ-treated mice, may reflect the major sites of immune activity/inflammation. Both hyperglycemia and STZ treatment increase cell production of nerve growth factor (NGF) (66). Its receptor, tyrosine kinase receptor A (TrkA), is expressed on both sympathetic and sensory nerves, and previous 2D imaging studies report that sensory and sympathetic nerve density are increased with STZ treatment (33). In previous studies, NGF overexpression in cells significantly increased sympathetic islet innervation (67). The cross-talk between nerves and islets in healthy versus diabetic tissue remains largely unstudied.

There is considerable variability in the reported changes in cell mass in models of diabetes. In our studies in diabetic NOD mice, cell volume was not significantly higher as a proportion of total pancreatic volume, but the ratio of to cell volumes was significantly increased (Fig. 4, B and C). Similar to our findings, Plesner et al. (68) describe a non-significant increase in cell mass in prediabetic and diabetic NOD mice and a significant increase in the proportion of cells/islet area in diabetic NOD mice. Our longitudinal studies show changes in cell volume with time after STZ treatment, with a significant decrease 2 weeks after the completion of treatment. This is in keeping with previous studies (69), but the cell response to STZ treatment has also been described to increase (70), to remain unchanged (71), or to vary with time after STZ treatment (72).

In our studies, and cell contacts are maintained in diabetic NOD and STZ-treated mice. One limitation of our assessment is that we quantify the number of endocrine cells contacting nerves, but we cannot quantify the number of contacts per endocrine cell. It is possible that the number of contacts with or cells is modified in diabetes. Sympathetic fibers also contact delta cells and vasculature to a lesser extent (3) in mouse islets. Further work is needed to determine whether NF200+ fibers contact delta cells or other islet structures and the effects of diabetes and STZ treatment on these contacts.

Our results examining innervation in NOD mice are consistent with recent 3D imaging of thick pancreatic sections (9, 13) reporting regions with increased innervation in these mice. Prior 2D studies have reported loss of islet sympathetic innervation in NOD mice (35), but these studies used different neural markers and examined NOD mice with longer duration of diabetes. It is possible that the increased islet innervation in NOD mice we observe is lost with increasing duration of diabetes. Alternatively, there may be pathway-specific changes such that sympathetic innervation is reduced, but parasympathetic and/or sensory innervation are increased, leading to an increase in NF200+ innervation found in our studies. Future studies using iDISCO+ will be required to dissect the longitudinal changes and contribution of specific neural pathways in mouse models of T1D, as well as the associations between innervation and immune infiltration.

There are several differences between mouse and human islets as well as similarities between these species. Human cell volume (%) was similar to the proportion of insulin+ islets in C57BL/6 mice. Islet size distribution was also remarkably similar between mouse and human pancreata. Similar to the findings in mice, intrapancreatic ganglia in human tissue are sparse and close to islets, but they are markedly larger, of the order of 200 neurons on average. There have been conflicting results about islet innervation in human versus murine samples. In our studies, the proportion of innervated islets and the finding that innervated islets were larger than noninnervated were similar in both humans and mice. Initial 2D imaging reported reduced islet innervation in human samples, but recent data from optically cleared human samples using markers for sympathetic nerves suggest that human islets, like mouse islets, have a dense neural network (9, 11). In keeping with previous studies examining TH+ fibers in human pancreatic samples (3, 11), innervation density is similar in human exocrine and endocrine pancreas. We found that NF200+ innervation is present in human islets, in keeping with previous studies demonstrating TH+ fibers in islets (3, 11), but at a lower density than mouse islets. A smaller proportion of human cells contact NF200+ fibers compared to mouse islets.

There are also similarities between innervation in STZ-treated mice and in samples from T2D individuals. In pancreata from T2D donors, nerve volume per islet, nerve density, and the proportion of innervated islets are all increased. The human tissue samples we analyzed provide a snapshot of islets and innervation from postfixed tissue as well as from individuals with variable comorbidities, age, and time from death. These factors likely contribute to the sample variability, in line with previous human data (73). In aggregate, our data suggest that islet innervation is present in human islets, albeit at lower levels than mouse islets, and innervation appears to be at least preserved, possibly increased, in human T2D individuals. The increase in exocrine innervation in pancreatic tissue from T2D donors may reflect more generalized pancreatic pathology that is increasingly recognized as a feature of T2D. One limitation of our studies is that we did not examine insulin islets by glucagon staining in the human samples, so it is unknown whether whole islet nerve density or cell contacts are altered in T2D. Further studies examining specific neural pathways and further endocrine cell types in human pancreatic tissue are required to fully assess normo- and pathophysiological species differences.

Our studies using NF200 as a neural marker do not differentiate between parasympathetic, sympathetic, and sensory fibers. Using an optimized iDISCO+ protocol, we examined sympathetic and parasympathetic innervation in wild-type mice, and many findings mirror those seen with NF200+ innervation. Similar to our findings using NF200, both sympathetic and parasympathetic endocrine innervation are enriched compared to exocrine innervation, and innervated islets are significantly larger than noninnervated islets. These findings differ from published studies that show similar TH+ innervation density in exocrine and endocrine tissue (74). However, previous reports analyzed innervation in female mice sampling cryosections every 400 m rather than innervation across the whole pancreas. The proportion of innervated-to-noninnervated islets is also greater when assessed using sympathetic and parasympathetic markers. The distribution of TH+ and VAChT+ innervation differs, with several large volume TH+ fibers contributing to higher TH+ volume compared to VAChT+ innervation in the exocrine pancreas. In keeping with previous reports in adult mice (75, 76), we observed occasional TH+ cells. We excluded these, as far as possible, based on their morphology, volume, and overlap with insulin immunostaining, but it is conceivable that our estimate of TH+ innervation may be an overestimate. TH+ and VAChT+ endocrine innervation are higher than for NF200. However, while NF200 has been reported to be expressed in a wide range of myelinated and unmyelinated fibers, our results and previous studies suggest that NF200 does not label all fibers (19), and it is possible that we may have overlooked alterations in NF200 fibers in our studies. Alternative pan-neuronal markers have significant limitations. For example, protein gene product 9.5 (PGP9.5) is expressed in islet endocrine cells and innervation. Pathway-specific markers are also imperfect. TH labels most, but not all, sympathetic nerve fibers since there are also populations that are TH but express NPY (77). VAChT immunostaining is primarily in the terminal neuronal arborization and so visualizing larger cholinergic nerve fibers may be incomplete (78). While there are similarities among innervation patterns with NF200, TH, and VAChT, our studies do not allow us to determine whether the changes in pancreatic innervation with diabetes are generalized or specific to sympathetic, parasympathetic, or sensory pathways. Future work will assess important pathway-specific changes in pancreatic innervation and their contacts with specific endocrine cell types in both mouse and human metabolic disease. One disadvantage of iDISCO+ is that it does not preserve endogenous fluorescence. Therefore, we also developed and validated a novel alternative approach that combines immunostaining and tissue clearing with ECi for use in adult murine tissues (41). This preserves endogenous fluorescent signals while allowing for antibody labeling of additional targets. ECi clearing also provides a less toxic alternative to iDISCO+ (41). A combination of fluorescently tagged dextran to delineate blood vessels, immunostaining for innervation and islets, and ECi tissue clearing will allow us to further assess the organ-wide association between innervation, islets, and vasculature.

In summary, we have used whole-organ tissue clearing and imaging to create a 3D atlas mapping islets and innervation across the pancreas as a tool to quantify cell mass, define islet characteristics, map pancreatic innervation, and assess the anatomical interaction between islets and innervation in healthy and diabetic mice and humans. This approach demonstrates dense islet innervation and identifies distinguishing features of innervated islets and the regional differences. Such regional variations illustrate the importance of whole-organ imaging when assessing pancreatic anatomy. Our studies confirm that innervation is present in human islets and directly contacts cells. We demonstrate that islet innervation is markedly increased in diabetic NOD mice, STZ-treated mice, and likely in diabetic human pancreata. In combination with up-regulation of NF200 immunostaining, this suggests increased rapid reorganization of pancreatic innervation and possible nerve growth within islets. Future studies will identify the neurochemical characteristics, time course, and functional consequences of these changes. Intrapancreatic ganglia and nerve contacts in islets are maintained in diabetes. The tissue clearing and imaging approaches we have used and optimized are broadly applicable to investigating pancreatic structures and innervation in other diseases, such as pancreatitis and pancreatic cancer, and are relevant to imaging vasculature and innervation in other organs. Our data also have important translational implications. Our data suggest that the close association between islets and pancreatic nerves is maintained in human T2D; therefore, the anatomical pathways that would allow for targeted neuromodulation to regulate pancreatic function are preserved. Defining pancreatic neurocircuitry is crucial to understanding neural regulation of pancreatic function, as it elucidates anatomical pathways for direct effects on endocrine cells. Future studies will determine critical interactions between cells and nerves, whether variation in islet innervation density is associated with differences in islet function, and whether metabolic disease leads to functional deficits in islet innervation independent of structure.

Ad libitum fed C57BL/6 mice were maintained under controlled conditions (12-hour light/12-hour dark cycle, 22C). NOD mice (NOD/ShiLtJ, the Jackson Laboratory, Bar Harbor, ME, USA) and STZ-treated mice were used to model T1D. Female NOD mice aged 12 to 16 weeks with two consecutive blood glucose measurements of >300 mg/dl (morning, nonfasting) were termed diabetic. Littermates with blood glucose <200 mg/dl were used as nondiabetic controls. Multiple low-dose STZ-treated mice (males, aged 10 weeks) were generated by treating C57BL/6N mice (Charles River, Wilmington, MA, USA) intraperitoneally with freshly made STZ (40 mg/kg; Sigma-Aldrich, St. Louis, MO) in citrate-saline buffer (pH 4.5) for five consecutive days and euthanizing them at 5 or 15 days following the final STZ injection. NonSTZ-treated littermates were used as controls. All protocols were approved by the Institutional Animal Care and Use Committee.

Mice were anesthetized with isoflurane (3%) and perfused with heparinized saline followed by 4% paraformaldehyde (PFA; Electron Microscopy Sciences, Hatfield, PA, USA). Pancreata were dissected, cleared of adipose tissue, divided into duodenal and splenic regions (Fig. 1A), with the gastric lobe included with the duodenal lobe, and postfixed overnight in 4% PFA at 4C. For antibody evaluation experiments, small pancreatic samples (2 to 3 mm diameter) were assessed. On the following day, the tissue was washed in phosphate-buffered saline (PBS; 3) before proceeding with optical clearing protocols.

Human samples (Table 1) were obtained from Prodo Laboratories Inc. (Aliso Viejo, CA, USA) and postfixed in 4% PFA. Since human samples were processed upon acquisition and not simultaneously as with mouse tissue, we could not compare staining intensity between samples. All samples were harvested from the superior margin of the tail of the pancreas.

Whole-organ staining and clearing were performed using iDISCO+ (15). Dissected pancreata were dehydrated [20, 40, 60, 80, and 100% methanol at room temperature (RT)], delipidated [100% dichloromethane (DCM; Sigma-Aldrich, St. Louis, MO, USA)], and bleached in 5% H2O2 (overnight, 4C). Pancreata were rehydrated (80, 60, 40, and 20% methanol) and permeabilized [5% dimethyl sulfoxide/0.3 M glycine/0.1% Triton X-100/0.05% Tween-20/0.0002% heparin/0.02% NaN3 in PBS (PTxwH)] for 1 day. Pancreata were then placed in blocking buffer [PTxwH + 3% normal donkey serum (Jackson ImmunoResearch, West Grove, PA, USA)] at 37C overnight. Samples were incubated with primary antibodies (table S1) in blocking buffer for 3 or 6 days (small pancreatic pieces and hemipancreata, respectively) at 37C. After five washes with PTxwH at RT (final wash overnight), samples were incubated with secondary antibodies in blocking buffer (1:500) for 3 or 6 days. Samples were washed with PTxwH (five times, RT) and PBS (five times, RT), dehydrated with a methanol gradient, then washed in 100% methanol (three times, 30 min each) and DCM (three times, 30 min each), and then transferred to dibenzyl ether (DBE; Sigma-Aldrich) to clear. Primary antibody specificity was confirmed in pancreatic tissue from reporter mice expressing tdTomato in defined neural populations. There was no immunolabeling without primary antibodies using iDISCO+ or ECi. A modified iDISCO+ protocol used 0.5% Triton X-100 and 0.1% Tween-20 for the permeabilization, blocking, and primary and secondary antibody buffers.

A modified ECi tissue clearing protocol was used for samples from animals injected intravenously with fluorophore-tagged dextran (100 m, 25 mg/ml) or a direct conjugated CD31 antibody (100 m, 50 mg/ml). Tissue was harvested, postfixed, and washed with PBS as described above. Samples were incubated with 3% H2O2 (10 min, RT), washed in PBS with 0.2% Triton X-100 (Ptx2; three times over 3 h, RT), and incubated overnight in PTx2 + heparin (10 mg/ml; PTwH) and 3% normal donkey serum at RT. Samples were incubated with primary antibodies in PTwH with 3% normal donkey serum (2 days, RT) followed by PTwH washes (four times over 4 hours). Samples were incubated with secondary antibodies in PTwH with 3% normal donkey serum (2 days, RT), followed by PTwH washes as above. Optical clearing was achieved by incubating samples in 50% ethanol, 70% ethanol, 100% ethanol (all pH 9, 4 hours, 4C), 100% ethanol (pH 9, overnight, 4C), and finally one wash and one overnight incubation (RT) in ECi (Sigma-Aldrich) before imaging.

Z-stacked optical sections were acquired with an UltraMicroscope II (LaVision BioTec, Bielefeld, Germany; 1.3, 4, or 12 magnification with dynamic focus with a maximum projection filter). Human samples were imaged at 1.3 with dynamic focus and with multiple Z-stacks acquired at 4 with 20% overlap and tiled using the plugin TeraStitcher through the ImSpector Pro software (LaVision BioTec). Spatial resolutions of light-sheet images were 5 m by 5 m by 5 m at 1.3, 1.63 m by 1.63 m by 5 m at 4, and 0.602 m by 0.602 m by 2 m at 12.

Small mouse pancreatic sections were imaged in glass-bottom eight-well chambers (Ibidi, Grfelfing, Germany) filled with immersion media DBE or ECi and imaged using an inverted Zeiss LSM 880 confocal microscope with a 10 [numerical aperture (NA), 0.3] objective and a step size of 5 m. Spatial resolution for confocal images acquired at 10 was 1.67 m by 1.67 m by 5 m.

Imaris versions 9.1 to 9.3.1 (Bitplane AG, Zrich, Switzerland) were used to create digital surfaces covering the islets (1.3 and 4 images) and innervation (4 images) to automatically determine volumes and intensity data. Volume reconstructions were performed using the surface function with local contrast background subtraction. For detection of islets, the threshold factor corresponded to the largest islet diameter in each sample. For detection of nerves, the threshold factor was set to 12.2 m. A smoothing factor of 10 m was used for islets analyzed at 1.3, and a factor of 3.25 m was used for analysis of islets and nerves at 4. For detection of TH+ nerves, TH+ cells (75, 76) were manually removed from the final TH+ nerve surface by excluding volumes below 120 m3 residing within insulin+ islets and overlapping with insulin staining. The Imaris Distance Transform Matlab XTension function was used to calculate the distance of each islet surface from the innervation surface. Distances of islets are reported as the intensity minimum of the distance transformation channel (intensity 0 = islet touching nerve) for each islet surface to the nerve surface as calculated by the distance transformation operation. In confocal images, digital surfaces were created to cover nerves and individual cells, cells, or ganglia. For detection of ganglia, a region of interest was manually created around each individual ganglion to create a digital surface specifically covering cell bodies, but not nerve fibers. The Imaris Distance Transform Matlab XTension was then used as above to determine the distance between ganglia and insulin+ islets or the distance between nerves and individual or cells with a distance of 0 indicating a nerve contact. Limitations to our analyses of endocrine cell contacts include the following: We may not have captured / cells with lower staining intensity; in some cases, we could not completely separate adjacent endocrine cells and therefore counted multiple adjacent cells as a single cell; our method quantifies the number of endocrine cells contacting nerves but does not allow for quantification of number of contacts per endocrine cell.

Data are shown as means SEM. Distribution was assessed by Shapiro-Wilk test. Significance was determined by unpaired two-way t test or one-way analysis of variance (ANOVA) with post hoc Tukeys multiple comparisons test (Gaussian distribution), Mann-Whitney test, or Kruskal-Wallis test followed by Dunns multiple comparisons test (nonparametric distribution). Significance was set at an level of 0.05.

Acknowledgments: Funding: A.A. was supported by a senior postdoctoral fellowship from the Charles H. Revson Foundation (grant no. 18-25) and a postdoctoral scholarship from the Swedish Society for Medical Research (SSMF). This work was supported by the American Diabetes Association Pathway to Stop Diabetes Grant ADA #1-17-ACE-31 and, in part, by grants from the NIH (DK105015, P-30 DK020541, U01MH105941, R01NS097184, OT2OD024912, and UC4DK104211), JDRF (2-SRA-2017-514-S-B), and the Alexander and Alexandrine Sinsheimer Scholar Award. This work was supported in part by a Mindich Child Health and Development Institute Pilot and Feasibility Grant. Microscopy and image analysis were performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai. We wish to thank the Human Islet and Adenoviral Core (HIAC) of the NIDDK-supported Einstein-Sinai Diabetes Research Center (DRC) and the families of the donors. Author contributions: A.A., A.G.-O., A.F.S., and S.A.S. conceived and designed the study and interpreted the data. A.A. performed all light-sheet experiments and analyzed and interpreted the data. A.A., M.J.-G., and R.L. performed confocal experiments and analyzed and interpreted the data. C.R., M.J.-G., and A.A. provided STZ-treated mice. C.R. and A.G.-O. provided NOD mice and human samples. N.T. and Z.W. provided technical and methodological input. A.A. and S.A.S. drafted the manuscript with input from all other authors. All authors approved of the final submitted version of this paper. Competing interests: S.A.S. is a named inventor of the intellectual property, Compositions and Methods to Modulate Cell Activity, and is a co-founder of, consults for, and has equity in the private company Redpin Therapeutics (preclinical stage gene therapy company developing neuromodulation technologies). The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes - Science Advances

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Pets of the week: A young cat with a brother, and a kissy cat with diabetes – Duluth News Tribune

October 10th, 2020 9:51 am

Watson and his brother Sherlock Holmes found themselves at Helping PAWS Pet Rescue in Washburn because they weren't getting good care at their previous home. Watson is a super friendly cat who really like people. He even likes to hug them. He has a mellow nature but also likes to play, as he's on the younger side. Watson would love a home with a cat friend, or with his brother.

Rolly is an orange tiger-and-white domestic short hair cat who is about 9 years old. He found himself at Animal Allies after his previous home could no longer care for him. Rolly is sweet, easygoing and loving, looking to receive endless love and attention. He enjoys giving hugs and even kisses from time to time. Because he has diabetes, he has been around at the shelter for awhile and is ready for a permanent home.

To adopt a cat or dog in the Northland, call:

Animal Allies, Duluth, 218-722-5341, animalallies.net.

Chequamegon Humane Association, Ashland, 715-682-9744, chaadopt.org.

Contented Critters Shelter, Makinen, 218-638-2153, contentedcritters.org.

Helping PAWS Pet Rescue, Inc., 715-373-2222, helpingpawswi.org.

Humane Society of Douglas County, Superior, 715-398-6784, hsdcpets.com.

Mesabi Humane Society, Virginia, 218-741-7425, mesabihumanesociety.org.

Northern Lights Animal Rescue, 218-729-1485, adoptapet.com/adoption_rescue/66719-northern-lights-animal-rescuers-inc-twig-minnesota.

Oreos Kitty Sanctuary, 218-591-7200, email oreosadoptions@yahoo.com.

Precious Paws Humane Society of Chisholm, 218-254-3300, preciouspaws2011@hotmail.com or pphsc.com.

Range Regional Rescue in Hibbing, 218-262-1900.

Star of the North Humane Society, Itasca County, 218-245-3732, starnorth.weebly.com/about-us.html.

Warm Fuzzies Animal Rescue Inc., Warmfuzzies2020@gmail.com, 218-576-8534, warmfuzzies.petfinder.com

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Tandem Diabetes Care to Announce Third Quarter 2020 Financial Results on November 5, 2020 – Business Wire

October 10th, 2020 9:51 am

SAN DIEGO--(BUSINESS WIRE)--Tandem Diabetes Care, Inc. (NASDAQ: TNDM), a leading insulin delivery and diabetes technology company, plans to release its third quarter 2020 results after the financial markets close on Thursday, November 5, 2020. The Company will hold a conference call and simultaneous webcast on the same day at 4:30 pm Eastern Time (1:30 pm Pacific Time), to discuss its third quarter 2020 financial and operating results.

Conference Call/Webcast Details:Date: November 5, 2020Time: 4:30 pm Eastern Time (1:30 pm Pacific Time)Toll Free Dial-In Number: (855) 427-4396International Dial-In Number: (484) 756-4261Conference ID: 8072078Webcast Link: https://edge.media-server.com/mmc/p/mp7mdi2q

An archive of the webcast will be available for 30 days following the event on Tandem Diabetes Cares Investor Center website located at http://investor.tandemdiabetes.com in the Events & Presentations section.

About Tandem Diabetes Care, Inc.

Tandem Diabetes Care, Inc. (www.tandemdiabetes.com) is a medical device company dedicated to improving the lives of people with diabetes through relentless innovation and revolutionary customer experience. The Company takes an innovative, user-centric approach to the design, development and commercialization of products for people with diabetes who use insulin. Tandems flagship product, the t:slim X2 insulin pump, is capable of remote software updates using a personal computer and features integrated continuous glucose monitoring, and optional automated insulin delivery technology. Tandem is based in San Diego, California.

Follow Tandem Diabetes Care on Twitter @tandemdiabetes, use #tslimX2 and $TNDM.Follow Tandem Diabetes Care on Facebook at http://www.facebook.com/TandemDiabetes.Follow Tandem Diabetes Care on LinkedIn at http://www.linkedin.com/company/TandemDiabetes.

Tandem Diabetes Care is a registered trademark and t:slim X2 is a trademark of Tandem Diabetes Care, Inc.

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Lilly and Dexcom team up on new program to help improve diabetes management – PRNewswire

October 10th, 2020 9:51 am

INDIANAPOLIS and SAN DIEGO, Oct. 7, 2020 /PRNewswire/ --Eli Lilly and Company (NYSE: LLY) and DexCom, Inc. (NASDAQ: DXCM) announced today a joint program for U.S. healthcare providers (HCPs) about Lilly's new rapid-acting mealtime insulin Lyumjev (insulin lispro-aabc injection, 100 units/mL and 200 units/mL), now available in U.S. pharmacies, and Dexcom G6 CGM Systems. The program is designed to help clinicians use data to inform diabetes management, including giving visibility to the benefits of a new mealtime insulin.

HCPs treating type 1 and type 2 diabetes will be able to assess their patients' glucose levels and time in range with Dexcom G6 or Dexcom G6 Pro, either in blinded or unblinded mode, helping them quickly identify adult patients who struggle to manage their postprandial glucose (PPG) levels (glucose levels following meals) and who may benefit from a treatment like Lyumjev. As PPG is often overlooked as a significant contributor to A1C,1 this partnership also aims to elevate PPG monitoring as an important component of diabetes treatment management.

"When it comes to treating diabetes, our partnership with Dexcom has the potential to be meaningful for HCPs who want to help their patients who may be struggling to manage their blood glucose levels after meals," said Adrienne Brown, vice president, U.S. Diabetes and Connected Care, Lilly. "Through this program, we can inspire confidence as clinicians and their patients evaluate new treatment options by showcasing how using these resources together can inform diabetes care."

Lilly and Dexcom will enhance HCP education by jointly sharing information about Lyumjev and the Dexcom G6 and G6 Pro through a variety of channels.

"We are thrilled to partner once again with a leader in diabetes care like Lilly," said Rick Doubleday, chief commercial officer at Dexcom. "Our goal is that the real-time data provided through Dexcom G6 and Dexcom G6 Pro will allow healthcare providers to help their patients with diabetes make more informed decisions, measure and evaluate their time in range, and have more visibility to the potential benefits of transitioning to a new mealtime insulin such as Lyumjev."

Those interested in learning more about Dexcom CGM or getting started on the Dexcom G6 should visit Dexcom.com. The Dexcom G6 is covered by 98 percent of private insurance in the U.S., by Medicare and by Medicaid in many states across the country. Dexcom also recently launched a patient assistance programavailable to currentU.S.customers who lost their health insurance coverage due to the impacts of COVID-19.

Lyumjev is a novel formulation of insulin lispro, developed to speed the absorption of insulin into the bloodstream and reduce A1C levels in adults with diabetes. In clinical studies, Lyumjev provided superior reduction in blood sugar spikes compared with Humalog (insulin lispro injection) when blood sugar was measured 1 and 2 hours after a meal. Lyumjev was approved by the FDA on June 15, 2020. HCPs can now prescribe Lyumjev, which is available for pharmacies nationwide to order. People who have commercial insurance can visit http://www.Lyumjev.com to access the Lyumjev Savings Card. For people without insurance coverage, Lyumjev is also included in the Lilly Insulin Value Program for $35 by calling the Lilly Diabetes Solution Center at (833) 808-1234. Operators at the Solution Center are available Monday through Friday from 8 a.m. to 8 p.m. (ET). Lilly is in discussions with insurance providers to make the new rapid-acting insulin available to as many people as possible.

People with diabetes and their HCPs who have questions about Lyumjev can visit http://www.Lyumjev.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979), Monday through Friday from 9 a.m. to 8 p.m. ET.

Terms, conditions, and limitations apply to Lilly savings cards and the Dexcom patient assistance program. See the companies' respective websites for additional details. The Lilly savings card is not available to those patients with government insurance such as Medicaid, Medicare, Medicare Part D, TRICARE/CHAMPUS, Medigap, DoD, or any State Patient or Pharmaceutical Assistance Program. TRICARE is a registered trademark of the Department of Defense (DoD), DHA.

PURPOSE and SAFETY SUMMARY

Important Facts About LYUMJEV (LOOM-jehv) and Humalog (HU-ma-log)

All Lyumjev and Humalog products contain insulin lispro.

Warnings

Do not take Lyumjev or Humalog if you have:

Do not reuse needles or share your insulin injection supplies with other people. This includes your:

You or the other person can get a serious infection. This can happen even if you change the needle.

Do notchange the type of insulin you take or your dose, unless your doctor tells you to. This could cause low or high blood sugar, which could be serious.

Do notuse a syringe to remove Lyumjev or Humalog from your prefilled pen. This can cause you to take too much insulin. Taking too much insulin can lead to severe low blood sugar. This may result in seizures or death.

Lyumjev and Humalog may cause serious side effects. Some of these can lead to death.The possible serious side effects are:

dizziness or lightheadedness

sweating

confusion

headache

blurred vision

slurred speech

shakiness

fast heartbeat

anxiety

irritability

mood change

hunger

If you are at risk of having severely low blood sugar, your doctor may prescribe a glucagon emergency kit. These are used when your blood sugar becomes too low and you are unable to take sugar by mouth. Glucagon helps your body release sugar into your bloodstream.

a rash over your whole body

trouble breathing

a fast heartbeat

sweating

a faint feeling

shortness of breath

extreme drowsiness

dizziness

confusion

swelling of your face, tongue, or throat

Common side effects

The most common side effects of Lyumjev andHumalog are:

low blood sugar

allergic reactions

reactions where you have injected insulin

skin thickening or pits at the injection

site

itching

weight gain

rash

Other most common side effects with Humalog include swelling of your hands or feet.

These are not all of the possible side effects. Tell your doctor if you have any side effects. You can report side effects at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Before using

Talk with your doctor about low blood sugar and how to manage it. Also tell your doctor:

How to take

Read the Instructions for Use that come with your Lyumjev or Humalog. Be sure to take your Lyumjev or Humalog and check your blood sugar levels exactly as your doctor tells you to. Your doctor may tell you to change your dose because of illness, increased stress, or changes in your weight, diet, or physical activity level. He or she may also tell you to change the amount or time of your dose because of other medicines or different types of insulin you take.

Before injecting your Lyumjev or Humalog

You can inject your insulin dose yourself, or you can have a trained caregiver inject it for you. Make sure you or your caregiver:

When you are ready to inject

Staying safe while taking your Lyumjev or Humalog

To stay safe while taking your insulin, be sure to never inject Lyumjev U-200 in your vein, muscle, or with an insulin pump. Also be sure not to:

Learn more

For more information, call 1-800-545-5979 or go to http://www.Lyumjev.com or http://www.humalog.com

Thissummaryprovidesbasic information about Lyumjev and Humalog. It does not include all information known about these medicines. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your doctor. Be sure to talk to your doctor or other health care provider about your insulin lispro product and how to take it. Your doctor is the best person to help you decide if these medicines are right for you.

Please see Lyumjev Full Prescribing Informationincluding Patient Prescribing Information

Please see Humalog Full Prescribing Informationincluding Patient Prescribing Information

LyumjevTM is a trademark and Humalogis a registeredtrademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

UR HI CON BS 15JUN2020

About Diabetes

Approximately 34 million Americans2 (just over 1 in 10) and an estimated 463 million adults worldwide3 have diabetes. Type 2 diabetes is the most common type internationally, accounting for an estimated 90 to 95 percent of all diabetes cases in the United States alone1. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.

About Dexcom CGMThe Dexcom G6 provides data-driven insights that are designed to allow people with diabetes to improve their insulin therapy and condition management. Dexcom G6 capabilities include continuous glucose readings, the elimination of routine fingersticks,* proactive and predictive alerts and alarms, remote glucose monitoring and more. The G6 Pro is also the first and only single use, professional CGM available in blinded and unblinded mode that allows healthcare providers to view data about a patient's glucose patterns over a single 10-day period. Through Dexcom CLARITY a diabetes management application offered for both patients and physicians HCPs can access data remotely, regardless of whether their patients are using the personal or professional version of G6.

About DexCom Inc.

DexCom, Inc. empowers people to take control of diabetes through innovative continuous glucose monitoring (CGM) products. Headquartered in San Diego, California, Dexcom has emerged as a leader of diabetes care technology. By listening to the needs of patients, caregivers, and clinicians, Dexcom simplifies and improves diabetes management around the world.

About Lilly Diabetes

Lilly has been a global leader in diabetes care since 1923, when we introduced the world's first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research, collaboration and quality manufacturing we strive to make life better for people affected by diabetes and related conditions. We work to deliver breakthrough outcomes through innovative solutionsfrom medicines and technologies to support programs and more. For the latest updates, visit http://www.lillydiabetes.com/or follow us on Twitter: @LillyDiabetesand Facebook: LillyDiabetesUS.

About Eli Lilly and Company

Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at lilly.comand lilly.com/newsroom. P-LLY

*If your glucose alerts and readings from the G6 do not match symptoms or expectations, use a blood glucose meter to make diabetes treatment decisions.

Separate Follow app required.

2020 Dexcom, Inc. Dexcom, Dexcom G6 and Dexcom Follow are registered trademarks of Dexcom, Inc. in the U.S., and may be registered in other countries. All rights reserved.

This press release contains forward-looking statements(as that term is defined in the Private Securities Litigation Reform Act of 1995)aboutLyumjev (insulin lispro-aabc injection) as a treatment to improve glycemic control in adults with type 1 and type 2 diabetes, and a joint program between Eli Lilly and Company and DexCom, Inc. designed to help U.S. healthcare providers use data to inform diabetes management and reflects Lilly's current beliefs. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there is no guarantee that Lyumjevwill be commercially successful or receive additional regulatory approvals. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

PP-UR-US-0211 10/2020Lilly USA, LLC 2020. All rights reserved.

References

1. Hershon, K., Hirsh, B., and Odugbesan, O. Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease. Clinical Diabetes. 2019; 37 (3): 250-269. Available at: https://clinical.diabetesjournals.org/content/37/3/250.article-info2. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept. of Health and Human Services; 2020. 3. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: International Diabetes Federation, 2019. Available at: http://diabetesatlas.org.

SOURCE Eli Lilly and Company

http://www.lilly.com

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Diabetes Night at the Drive-In in Idaho Falls – Idaho Falls Magazine

October 10th, 2020 9:51 am

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What We’re Reading: Nobel Prize in Chemistry Awarded; Improving Diabetes Management; COVID-19 Vaccine Trial Still on Hold – AJMC.com Managed Markets…

October 10th, 2020 9:51 am

Two women are awarded the Nobel Prize in Chemistry for CRISPR; Eli Lilly partners with DexCom, Inc; the US arm of AstraZenecas coronavirus disease 2019 (COVID-19) vaccine trial remains halted.

Jennifer A. Doudna, PhD, University of California, Berkeley, and Emmanuelle Charpentier, PhD, Max Planck Institute for Infection Biology, have been awarded the Nobel Prize in Chemistry for their discovery of CRISPR gene editing technology. CRISPR involves removing problematic DNA through the use of RNA as its guide molecule and replacing it, if necessary, with healthy DNA. Diseases that hope to be cured with CRISPR genetic therapies include hemophilia, type 1 diabetes, and Rett syndrome. A patent dispute is ongoing, however, for CRISPR, between Doudna and Charpentier and Feng Zhang, PhD, Broad Institute, who many believe also deserves credit for his work in this space.

The new program aims to enhance the ability of health care providers to better manage their patients with type 1 or 2 diabetes, according to the press release from Eli Lilly, through the use of the Dexcom G6 or Dexcom G6 Pro continuous glucose monitoring system. A main focus of this joint effort between Eli Lilly and DexCom is management of postprandial glucose levels (that following meals), which the release calls a significant contributor to A1C [glycated hemoglobin], for which Lillys new rapid-acting mealtime insulin, Lyumjev (insulin lispro-aabc) is now available. Most private insurance companies, as well as Medicare and Medicaid in many states, cover the Dexcom G6.

The phase 3 coronavirus disease 2019 (COVID-19) vaccine trial, jointly led by AstraZeneca and Oxford University, which was first halted in early September, remains on hold, but only in the United States, reported STAT. Patients have so far only received their first dose of the potential vaccine (or a saline placebo) through the double-blinded trial; a booster shot was supposed to be administered 4 weeks later, but the trial timeline is still unclear so that has not happened as of yet. AstraZeneca has not commented on how it will handle the participants who cant get their second dose, although data on everyone who has been administered at least the first dose will be included in the full analysis set.

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What We're Reading: Nobel Prize in Chemistry Awarded; Improving Diabetes Management; COVID-19 Vaccine Trial Still on Hold - AJMC.com Managed Markets...

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U of T’s Medicine by Design invests $1 million to advance new ideas in regenerative medicine – News@UofT

October 10th, 2020 9:50 am

Patients with cystic fibrosis experience recurrent lung infections that eventually destroy their airways, shortening their average life expectancy to 50 years in Canada. Current drug treatments, which target a malfunctioning pathway in cells that causes the infections, are costly and have varying effectiveness.

Now, with funding from Medicine by Design, a researcher at the Hospital for Sick Children (SickKids) is combining stem cells, gene editing and computational modelling to try to hijack an alternative cell pathway in the hopes of restoring lung function in these patients.

If successful, our study will be the first to provide proof-of-concept that this alternative approach to treating cystic fibrosis is effective, saysAmy Wong, a scientist working in developmental and stem cell biology at SickKids who is also an assistant professor in the department of laboratory medicine and pathobiology in the University of Torontos Temerty Faculty of Medicine.

Wongs project is one of seven across U of T and its affiliated hospitals that have been awarded 2020New Ideas AwardsandSeed Fundawards from Medicine by Design. Through a $1 million investment, Medicine by Design is supporting research aimed at advancing new concepts expected to be important to regenerative medicine in the coming years. The funded projects will have potential impacts in diseases and conditions such as vision loss, amyotrophic lateral sclerosis (ALS), intestinal disease in premature babies and more.

Supporting novel strategies and approaches is crucial to moving regenerative medicine into the future, saysMichael Sefton, executive director of Medicine by Designand a University Professor at U of Ts Institute of Biomedical Engineeringand thedepartment of chemical engineering & applied chemistry in the Faculty of Applied Science & Engineering.

Our 2020 New Ideas project portfolio integrates mathematical modelling, physics and computational biology with stem cell biology and biomedical engineering, and strengthens engagement with clinicians who are key to translating our research into patient impact. We are particularly delighted this year to support so many outstanding early-career researchers, who will ensure Toronto remains a global leader in regenerative medicine for years to come.

Wong is one of three investigators to receive a 2020 New Ideas Award, which is valued at $100,000 per year for up to two years. Four additional projects were selected for Seed Fund Awards of $100,000 each for one year to further develop their potential.

Medicine by Design selected the funded projects from among 36 short-listed proposals, which were evaluated and ranked through an external peer review process. Applications were submitted by clinicians and researchers at U of T and its affiliated hospitals from a wide range of disciplines including biochemistry, biomedical engineering, developmental and stem cell biology, immunology, neuroscience and surgery.

Medicine by Design builds on decades of made-in-Canada excellence in regenerative medicine dating back to the discovery of stem cells in the early 1960s by Toronto researchers James Till and Ernest McCulloch. Regenerative medicine uses stem cells to replace diseased tissues and organs, creating therapies in which cells are the biological product. It can also mean triggering stem cells that are already present in the human body to repair damaged tissues or to modulate immune responses. Increasingly, regenerative medicine researchers are using a stem cell lens to identify critical interactions or defects that prepare the ground for disease, paving the way for new approaches to preventing disease before it starts. Medicine by Design is made possible thanks in part to a $114-million grant from theCanada First Research Excellence Fund.

Current cystic fibrosis drug treatments target a genetic mutation that causes epithelial cells, which line the airway and act as a barrier against viruses, to function improperly. The mutation affects the function of an important ion channel in cells, called CFTR, which helps to maintain the right balance of fluid in the airways. Poor function causes mucosal obstructions in the airways and prevents clearance of foreign pathogens, which leads to chronic infections and ultimately destroys airway tissue.

In her project, Wong will explore an alternative ion channel in the epithelial cells to determine if it can be hijacked and used to compensate for the lack of function caused by the mutant CFTR. The research will be conducted using a combination of stem cell-derived lung models, gene editing and computational modelling.

Wongs project builds on decades of cystic fibrosis research at SickKids, where the cystic fibrosis gene was first identified 30 years ago.

To date, more than 2,000 mutations in the cystic fibrosis gene have been identified, says Wong. SickKids scientists and U of T researchers have become the epicentre of incredible cystic fibrosis research to understand how this disease works at the genetic and molecular level.

Wong says that, while the idea of targeting an alternative pathway is not necessarily ground-breaking on its own, its the array of tools now available that makes the idea a potential game changer.

We have access to an incredible resource of primary cells and stem cells from more than 100 individuals with cystic fibrosis harbouring various mutations. Wong says.Our lab has developed human lung models from stem cells that can be used to model lung disease such as cystic fibrosis. And with new advanced tools in single-cell genomics and gene-editing, coupled with key collaborations for computational modelling, we are poised to find new therapeutic targets for cystic fibrosis.

Leo Chou, an assistant professor at the Institute of Biomedical Engineering, andHyun Kate Lee, an assistant professor in the department of biochemistry in the Temerty Faculty of Medicineboth Medicine by Design New Investigators are also leading 2020 New Ideas projects.

Chou, along with co-investigatorsJulie Lefebvre, a scientist at SickKids and U of T assistant professor of molecular genetics, andValerie Wallace, a senior scientist at the Krembil Research Institute, University Health Network and a U of T professor of laboratory medicine and pathobiology and ophthalmology, will focus on cell transplantation in the retina, a process that has demonstrated encouraging pre-clinical results such as partial vision restoration in several animal disease models.

Recent research had demonstrated that this restoration is a result of the transfer of proteins complex molecules required for the structure, function and regulation of the bodys tissues between host tissue and donor cells. But the scope of that transfer process is not well understood. Chous project will develop an imaging approach to detect the transfer of mRNA molecules between host and donor cells. The outcomes from this project will inform the future design of cell transplantation therapies and lead to novel methods to deliver therapeutics. This project could improve therapies for retinal diseases and visual impairments, and inform strategies for other degenerative disorders.

Lee and co-investigatorPenney Gilbert,an associate professor at the Institute of Biomedical Engineering, will look at a common but not well-understood structure called the neuromuscular junction (NMJ), which mediates communication between neurons and muscles throughout the body. Defects in NMJ integrity and function underlie fatal diseases such as ALS. NMJ diseases, which affect more than 500,000 people globally, lack effective treatments. This project will use stem cells derived from reprogrammed skin cells of healthy people to develop NMJs in culture. Through high-resolution imaging, the healthy human NMJs will be studied both on their own and along with NMJs built from ALS patient cells. Through this work, the research team aims to identify genes to target to improve the health of NMJs, which could eventually help prevent or delay NMJ degeneration and even promote regeneration.

Michael Garton, an assistant professor at the Institute of Biomedical Engineering, has received a Seed Fund award to tackle the challenge of translating the genetic tools of synthetic biology an area of research that aims to create or redesign biological components using engineering methods into effective medical therapies against a number of diseases.

But they are difficult to translate into human therapies, Garton says, because the bodys T-cells immune cells that detect and destroy cells containing foreign material will identify these tools as foreign and destroy them.

Instead of switching off the T-cells, Gartons goal is to use computational modelling and high-throughput screening to selectively turn off the bodys foreign antigen display system so the immune system will still respond to foreign invaders when necessary, but allow cells containing synthetic tools to survive. If successful, this approach could enable a new generation of synthetic biology-enhanced cell therapies for a range of diseases.

Medicine by Design funding will help to facilitate the integration of synthetic biology and regenerative medicine and aid the development of cell-based therapies that perform better than nature, says Garton.

Other Seed Fund projects will encompass research in repairing the heart after paediatric cardiac surgery, treating an intestinal emergency in premature babies and creating a database for cell lineage paths.

John Parkinson, a senior scientist at SickKids and a U of T professor of biochemistry and molecular genetics, along with co-investigatorsJason Maynes, Wasser Chair in Anesthesia and Pain Medicine at SickKids and a U of Tassociate professor of anesthesiology and biochemistry, andWilliam Navarre, an associate professor in the department of molecular genetics, will investigate manipulating the microbiome, or community of microorganisms in the gut, to improve cardiac repair in post-operative treatment of a congenital heart disorder. Through a process that will identify prebiotics in breast milk that help enhance the production of molecules that research has shown can aid cardiac repair, the team will organize both observational (how disease alters the microbiome) and interventional (how the microbiome alters the disease) multi-site trials, which will provide the opportunity to immediately translate findings into changes in patient care regimens and improve outcomes.

CliniciansAgostino Pierro, a surgeon at the Division of General and Thoracic Surgery at SickKids and a U of T professor of surgery and physiology, and Philip Sherman, a senior scientist and gastroenterologist at the Division of Gastroenterology, Hepatology and Nutrition at SickKids and U of T professor of dentistry, pediatrics and laboratory medicine and pathobiology, have proposed a novel way of enhancing gut repair for a common intestinal emergency in premature babies, called necrotizing enterocolitis (NEC). A leading cause of death for these infants, NEC causes complications such as blindness, intellectual disability, repeat hospitalizations and gut damage even in those that survive. This project will look at whether intestinal organoids organ-like structures grown in the laboratory from stem cells that mimic some of the functions of native intestines can potentially stimulate repair of the gut and recovery from NEC. The project will define how to best transplant organoids, identify how the organoids protect the intestine from injury and assess if organoid transplantation is a valid new treatment for NEC.

Lincoln Stein, who is head of adaptive oncology at the Ontario Institute for Cancer Research and a professor in the department of molecular genetics at U of T, has received seed funding to build a database called Cytomics Reactome, which will be freely available to Canadian and international researchers. The database will build on recent technologies that open the door to the possibility of deciphering cell lineage paths the series of steps that lead a young, undifferentiated cell into a specialized one at single-cell resolution. To accelerate the path from basic research to clinical application, the database will systematically organize pre-existing knowledge of cell lineage paths into a comprehensive, interactive and easily accessible map that can serve as a framework for interpretation and integration of the latest experimental findings.

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Nature Publishes New Research from Vir Biotechnology Demonstrating the Capacity of Enhanced Monoclonal Antibodies to Induce Protective Adaptive…

October 10th, 2020 9:50 am

SAN FRANCISCO, Oct. 09, 2020 (GLOBE NEWSWIRE) -- Vir Biotechnology Inc. (Nasdaq: VIR) today announced the publication of preclinical research in an influenza animal model highlighting a new mechanism for enhancing the efficacy of monoclonal antibodies to treat viral infection and induce a protective response. Data demonstrate that selective engagement of an activating Fc receptor on dendritic cells by antiviral monoclonal antibodies induced protective CD8+ T cell adaptive responses. The paper, entitled Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection, was published in the October 8, 2020 online edition of Nature.

In the past several years, we've gained a better understanding of how integral Fc mediated effector functions of monoclonal antibodies are for their therapeutic efficacy in pre-clinical models of neoplastic, infectious and inflammatory diseases, said Jeffrey V. Ravetch, M.D., Ph.D., study senior author and Theresa and Eugene M. Lang Professor and Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller University. These approaches have been successfully applied to anti-tumor therapeutics and have resulted in improved clinical outcomes in a variety of oncologic diseases. Our present studies have uncovered a significant new mechanism by which antibodies, through their Fc region, can not only engage innate immune responses but activate adaptive T cell responses, thereby stimulating protective anti-viral immunity in these models.

The research published in Nature focuses on the role of the Fc domain of monoclonal antibodies, regions with the capacity to bind to other immune cells through a family of receptors (the Fc receptors). By engineering antibodies with modified Fc domains to enhance binding to specific Fc receptors on innate immune cells, investigators observed an enhanced protective immune response. Certain modifications (GAALIE variants) were associated with activation of dendritic cells, as well as antiviral effector T-cells, indicating induction of the adaptive arm of the immune system, which is responsible for long-term immunity. Based on this research, monoclonal antibodies programmed with improved effector function represent a potential new approach in the design of therapeutic antibodies for both the prevention and treatment of infectious diseases.

By observing and learning from our bodys powerful natural defenses, we have discovered how to maximize the capacity of antibodies through the amplification of key characteristics that may enable more effective treatments for viral diseases, said Herbert Skip Virgin, M.D., Ph.D., study co-author and executive vice president, research, and chief scientific officer of Vir. These data may have significant implications across a wide range of infectious diseases, and we look forward to exploring the vaccinal potential of the GAALIE-engineered antibodies we are advancing through clinical development VIR-3434 for chronic hepatitis B and VIR-7832 for SARS-CoV-2.

The preclinical study was conducted by Dr. Ravetch and Stylianos Bournazos, Ph.D., of the Laboratory of Molecular Genetics and Immunology at The Rockefeller University, in collaboration with Dr. Virgin and Davide Corti, Ph.D., senior vice president of antibody research at Virs subsidiary Humabs BioMed SA.

This type of exceptional collaborative partnership between cutting-edge science and clinical application has the potential to significantly improve our ability to address infectious diseases, stated Dr. Virgin.

Vir is currently evaluating several monoclonal antibodies that have been Fc engineered to include the XX2 vaccinal mutation (or GAALIE variant) for which Vir has licensed exclusive rights for all infectious diseases.

About VIR-3434VIR-3434 is a subcutaneously administered HBV-neutralizing monoclonal antibody designed to block entry of all 10 genotypes of HBV into hepatocytes and also to reduce the level of virions and subviral particles in the blood. VIR-3434 has been engineered to have an extended half-life as well as to potentially function as a T cell vaccine against HBV in infected patients.

About VIR-7832VIR-7832 is a monoclonal antibody that has shown the ability to neutralize SARS-CoV-2 live virus in vitro. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as SARS), indicating that the epitope is highly conserved, which may make it more difficult for escape mutants to develop. VIR-7832 has been engineered with the potential to enhance lung bioavailability, have an extended half-life, and function as a therapeutic and/or prophylactic T cell vaccine. VIR-7832 is being developed by Vir and its partner GlaxoSmithKline plc(LSE/NYSE: GSK) as part of their broader collaboration to research and develop solutions for coronaviruses, including SARS-CoV-2.

About Vir BiotechnologyVir Biotechnology is a clinical-stage immunology company focused on combining immunologic insights with cutting-edge technologies to treat and prevent serious infectious diseases. Vir has assembled four technology platforms that are designed to stimulate and enhance the immune system by exploiting critical observations of natural immune processes. Its current development pipeline consists of product candidates targeting hepatitis B virus, influenza A, SARS-CoV-2, human immunodeficiency virus and tuberculosis. For more information, please visitwww.vir.bio.

Vir Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as potential, may, will, could, expect, plan, anticipate, believe, estimate, goal, intend, candidate, continuing, developing and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Virs expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding the ability of enhanced Fc mediated effector functions in enhancing the efficacy of monoclonal antibodies to treat viral infections and inducing a protective response in animal models, using an oncological therapeutic approach and enhanced effector function in the treatment of infectious diseases, the vaccinal potential of specifically engineered antibodies in the treatment of chronic hepatitis B and SARS-CoV-2, and statements around the companys plans to explore the vaccinal potential of engineered antibodies as it advances through clinical development of VIR-3434 for the treatment of chronic hepatitis B and VIR-7832 for SARS-CoV-2. Many factors may cause differences between current expectations and actual results including unexpected safety or efficacy data observed during preclinical or clinical studies, challenges in treating chronic hepatitis B and neutralizing SARS-CoV-2, difficulty in collaborating with other companies or government agencies, and challenges in accessing manufacturing capacity. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Virs filings with theU.S. Securities and Exchange Commission, including the section titled Risk Factors contained therein. Except as required by law, Vir assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

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SCV News | COVID-19 Testing Facility Coming to SCV – SCVNEWS.com

October 10th, 2020 9:50 am

PerkinElmer, the Massachusetts-based diagnostics company that partnered with California to improve COVID-19 testing efficiency and capacity, has signed a lease in Valencia and could open a testing facility in early November, officials confirmed Wednesday.

The company is set to operate at a 134,287-square-foot industrial building that sits on nearly 14 acres of land at 28454 Livingston Ave.

Previous businesses located there have included Stellar Microelectronics, a full-service electronics manufacturing services provider; and NEO Tech, a provider of manufacturing and supply chain technology, which now operates in Chatsworth.

PerkinElmer signed the lease in early September, according to Holly Schroeder, president and CEO of the Santa Clarita Valley Economic Development Corp.

As of Thursday, an estimated 40 job openings, ranging from molecular genetics scientist to customer support, were listed as based in Valencia on PerkinElmers website.

The diagnostics company has not yet provided many other details of their plans, according to Schroeder.

Requests to confirm the companys testing facility location in Valencia and to receive additional information about the lab have not been returned, but officials with the California Health and Human Services Agency have said details would be released in the coming weeks.

As we get closer to the opening of the lab, which is currently slated for early November, well have additional details to share on location, read an emailed statement from the California Department of Public Health.

In late August, the California Hospital Association a member of the states testing task force confirmed in a newsletter the location will be in Valencia with an opening date of Nov. 1.

The testing facility is expected to increase the number of daily COVID-19 tests up to 150,000 by that date, Gov. Gavin Newsom announced in August.

The partnership is also expected to decrease the average turnaround time to 24-48 hours (it now stands at about five to seven days), as well as drive down costs, which now average around $150-$200 per test, the Hospital Association said in a statement, adding that all hospitals will be eligible to use the lab and that it will simultaneously allow for COVID-19 and flu testing.

News of the lease comes as the U.S. National Institutes of Healths Rapid Acceleration of Diagnostics (RADx) initiative has awarded Ellume USA LLC in Valencia $30 million for scale-up and manufacturing of its COVID-19 antigen tests, officials announced Tuesday.

Antigen tests can diagnose a COVID-19 infection, as they can detect certain proteins in the virus, within minutes and are relatively inexpensive, according to the Centers for Disease Control.

Funds are expected to cover Ellumes two unique test cartridges that can return accurate results in 15 minutes or less. One cartridge testing nasal swabs can be read out on two platforms by health care professionals, at the point of care or in laboratory settings for higher throughput. A second cartridge is being developed for home use with a self-administered nasal swab, according to the National Institutes of Health.

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Alumni Spotlight- Procopio brothers and the biology of college life – Knight Crier

October 10th, 2020 9:50 am

Submitted Photo

Kyle and Dylan Propcopio, Class of 2020 NPHS grads

The electric buzz backstage before a performance is a feeling known very well to both Dylan and Kyle Procopio.

The dynamic duo reminisce on their time at North Penn with smiles. While at the high school, they were assistants to the Stage Manager in all NPHS theatre productions, cabinet participants in Thespian Troupe, and members of SGS (Stimulation Gaming Society) and National Honors Society. Additionally, they were tremendously involved in Boyscout Troop 51.

Currently studying at Millersville University, the Procopios are both majoring in biology. Kyle, with a concentration in molecular genetics, and Dylan with a double major in secondary education.

Did you have a favorite class you attended while at NP?

Kyle- Definitely Genetics and Embryology with Mr. Christopher! Both Dylan and I enjoyed the curriculum and his teaching style.

Do you plan on being involved in theatre in some aspect during college?

Dylan- Yes! I had a wonderful experience during my involvement with NPHS theatre. I plan on participating in stage crew here at Millersville in any capacity. But, everything is on hold until the pandemic settles down.

What was the transition like from NPHS to Millersville?

Kyle- I was a little nervous about going to Millersville since the coronavirus is still happening. But even with some serious precautions, the transition was pretty smooth. We both found a strong group of friends. And even though the school is a little bigger, it definitely feels like home.

What inspired you to go into biology education?

Dylan- I always loved biology! During boy scouts, I was in charge of instructing some of the newer guys in our troop. I taught them certain nature skills and survival tactics, and I really found it rewarding.

What words of wisdom would you like to give current students at North Penn?

Kyle- Make the most of your time at North Penn! Of course, remember time management is important, but dont forget to make time with friends and activities youre interested in. Those are the memories that will last you a lifetime.

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NVR: 4 UPGRADED Stocks to Ride the Q4 Rally – StockNews.com

October 10th, 2020 9:50 am

The market is in an interesting place. We have very strong price action with the market melting up and the Russell 2000 (IWM) leading. This is despite expectations that the market would see some selling due to the upcoming election, failure to reach an agreement on a stimulus package, and rising coronavirus case counts.This type of market action implies that the bad news has already been discounted. Under these conditions, traders and investors should look to buy fundamentally sound stocks. Our POWR Ratings can help you identify these stocks.

Lets take a look at four of the more intriguing POWR Rating upgrades: NVR (NVR), Masimo (MASI), NeoGenomics (NEO), and Workiva (WK).

NVR(NVR)

Building and selling homes, condos, and townhouses are one of the better ways to make money in 2020. This is NVRs business. With homes selling like gangbusters, NVR is raking in the cash. The companys homes are mainly built on a pre-sold basis. NVR also has a mortgage banking service and title service business.

Chances are you have seen NVR operating under the moniker of Ryan Homes, Heartland Homes, and/or NVHomes. The POWR Ratingsshow NVR has A grades in the Buy & Hold and Trade grade components. The stock is ranked 12th of 21 in the Homebuilders space. Home construction in the United States was up more than 22% this summer. Building permit applications are up nearly 20% from June. This is the perfect time to own homebuilder stocks such as NVR.

Masimo(MASI)

Health monitoring systems have quickly advanced, proving capable of accurately measuring everything from pulse rate to blood oxygen saturation levels. MASI makes such systems. The companys systems also monitor blood constituency including total hemoglobin, breathing, and brain activity.

MASI has A grades in each POWR Rating component. The stock is ranked in the top 25 of 140 in the Medical Devices & Equipment category. Of the seven analysts who have studied MASI,five recommend buyingit while two recommend holding and none advises selling.

MASIs quarterly revenue is up more than 30% on a year-over-year basis. MASIs system shipments are also up 174% on a year-over-year basis. The strong demand combined with the aging baby boomer segment of the population should help MASI return to its 52-week high of $258 by years end.

NeoGenomics(NEO)

Genetics diagnostic testing specialists waging war against cancer are at the forefront of medical technology. Such testing is the fastest growing lab industry segment. NEO testing services range from molecular genetic testing to cytogenetics, flow cytometry, anatomic pathology, and fluorescence in-situ hybridization. NEO helps hospital personnel, urologists, pathologists, oncologists, and other medical professionals do their jobs that much better.

NEO is a POWR Ratings beast with A grades in the Buy & Hold and Trade components along with B grades in the remaining components. Furthermore, NEO is ranked in the top 20 of 58 publicly traded companies in the Medical Diagnostics/Research category.

TipRanks shows theaverage analyst price target for NEO is $42.57, indicating it has a 10% upside. Even if NEOs business falters amidst the recession, the companys balance sheet is in tip-top shape with $331 million in cash. Ride NEOs profitable growth wave to new heights and you will be more than happy with your investment.

Workiva(WK)

Cloud platforms that help businesses gather, analyze, and manage important business data in a near-instantaneous manner are becoming that much more important as business shifts to the web. WK provides such solutions. WK clients include those in a wide array of industries ranging from telecom to transportation, consumer goods, real estate, media, financial services, energy, healthcare, and beyond.

WK has A grades in two of the four POWR Components (Buy & Hold and Trade) along with a top 20 rank in the Software Business space. WKs price return year-to-date is 39%. WK had a 2018 price return of 67%. The stocks three-year price return is 164%. The icing on the cake is theanalysts average price target of $65.25, meaning WK is poised to pop another 10%.

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NVR shares were trading at $4,366.20 per share on Friday afternoon, up $17.80 (+0.41%). Year-to-date, NVR has gained 14.65%, versus a 9.38% rise in the benchmark S&P 500 index during the same period.

Patrick Ryan has more than a dozen years of investing experience with a focus on information technology, consumer and entertainment sectors. In addition to working for StockNews, Patrick has also written for Wealth Authority and Fallon Wealth Management. More...

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City of Hope leads novel clinical trial to treat cancer patients with COVID-19 – The Cancer Letter

October 10th, 2020 9:50 am

publication date: Oct. 9, 2020

In a new clinical trial, City of Hope is investigating a treatment for cancer patients with COVID-19 by repurposing leflunomide, an anti-inflammatory drug for rheumatoid arthritis, which is inexpensive and has few serious side effects.

Patients treated for cancer in the past two years may also be eligible.

FDA has recently approved the start of a phase I trial. At a later date, a phase II randomized clinical trial may take place if the first trial finds leflunomide to be safe and tolerable for these patients. City of Hope plans to work with other local medical centers who are treating cancer patients for SARS-CoV-2, the virus that causes COVID-19, to enroll them in the trial.

There are currently few effective drugs against COVID-19, and our clinical trial targets a critical high-risk group cancer patients whose immune systems are already weak, Steven T. Rosen, City of Hope provost and chief scientific officer, and the Irell & Manella Cancer Center Directors Distinguished Chair and Morgan & Helen Chu Directors Chair of the Beckman Research Institute, said in a statement. Our hope is that leflunomide will eradicate COVID-19 in cancer patients, providing the medical community with an effective therapy against this devastating virus.

Sanjeet Dadwal, City of Hope chief of the Division of Infectious Diseases, is the principal investigator on the trial.

For the phase I trial, all patients will receive leflunomide and may also be able to simultaneously receive other standard of care treatments for COVID-19. They may receive remdesivir, an antiviral therapy. Patients with acute respiratory distress syndrome may receive the steroid, dexamethasone, and patients with complications of COVID-19 such as cytokine release syndrome, which can lead to multiple organ failure, can receive the antibody tocilizumab.

If the phase I trial is found to be a safe and tolerable treatment, then a phase II randomized, double-blind trial will open at a later date. About half the patients will receive leflunomide with standard of care therapies to treat COVID-19, and the other half will receive a placebo and standard of care drugs as well.

Leflunomide is an oral and generic anti-inflammatory drug approved by FDA to safely treat autoimmune diseases such as rheumatoid arthritis. The therapy has also been used in cancer patients with cytomegalovirus with tolerable side effects.

Laboratory experiments performed at City of Hope and Wuhan, China, indicate that leflunomide has high potential to shut down viral replication by preventing the synthesis of viral RNA, the genetic material. It also downregulates the expression of ACE 2, a receptor for COVID-19 cell entry. A small clinical trial using leflunomide in China also demonstrated the therapy has potential antiviral drug against COVID-19.

In a phase I clinical study, City of Hope treated patients with advanced multiple myeloma with leflunomide. The therapy stabilized their disease with tolerable side effects.

NCI has funded the trial with a P30 grant supplement for COVID-19 research projects. City of Hope is one of a few cancer centers that has received such funding during the pandemic.

City of Hope also received funding from private donors, including The Elias, Genevieve and Georgianna Atol Charitable Trust and The Norman and Sadie Lee Foundation.

Novel CAR T-cell lymphoma therapy developed at MCW advances to phase II study

A novel cancer therapy studied and developed at the Medical College of Wisconsin with promising clinical outcomes is leading to a larger phase II trial to improve on the current standard of care.

Results of phase I of the first-in-the-world double targeted CAR T-cell therapy clinical trial were published in Nature Medicine.

This is a novel, cell-based treatment against cancer targeting two proteins (antigens CD19 and CD20) on the surface of cancer cells. This CAR T-cell therapy trial began in October 2017 and resulted in safe and promising outcomes for patients with relapsed and refractory B cell non-Hodgkin lymphomas which are cancers of the immune system.

MCW researchers collected patient T cells and then used a specially engineered virus to augment their ability to identify and kill cancerous cells and effectively destroy the lymphoma. While phase I focused on safety and feasibility of the treatment, a multi-institutional phase II is being developed to determine the true efficacy and understand how the nuances of the treatment process can result in excellent outcomes for a larger subset of patients.

All patients in the clinical trial had failed prior treatments and their cancer had relapsed. Within 28 days of the CAR-T cell therapy, 82 percent responded positively. Six months later, more than half of the patients cancer remained in remission. A higher dose of the treatment correlated with a prolonged remission, a trend the researchers plan to study further in the trials second phase.

The new treatment genetically alters a persons own immune cells to target cancer cells in a unique and personalized fashion, a significant departure from more routine chemotherapy.

The cell product used for treatment was manufactured using the CliniMACS Prodigy device, which is part of an automated CAR T cell manufacturing platform developed by Miltenyi Biotec.

Housed at the Froedtert & MCW Clinical Cancer Center, the CliniMACS Prodigy device enabled the research team to conduct the CAR T-cell immunotherapy through a self-contained, desktop system, producing new cells ready to be infused back into a patients bloodstream within 14 days. With the device, the entire process was performed locally at Froedtert Hospital.

This research was made possible through philanthropic dollars raised by the Childrens Wisconsin Foundation and the MACC Fund and their support of the Cell Therapy Lab at MCW.

MD Anderson researchers identify characteristics of infused CAR T cells associated with efficacy and toxicity in large B-cell lymphoma

Researchers at MD Anderson Cancer Center have identified molecular and cellular characteristics of anti-CD19 CAR T cell infusion products associated with how patients with large B-cell lymphoma respond to treatment and develop side effects.

The research team also found that early changes in circulating tumor DNA one week after CAR T cell therapy may be predictive of treatment response in a particular patient. The paper was published online in Nature Medicine.

CAR T cell therapy is highly effective against LBCL, corresponding author Michael Green, associate professor of lymphoma and myeloma, said in a statement. However, we experience two main clinical challenges: achieving long-term remission and managing treatment-associated adverse events.

This study suggests that, within the first week of therapy, clinicians may be able to identify a subset of patients who may experience more poor outcomes or adverse treatment reactions, said Green. This would allow the care team to adjust therapy to improve efficacy or to act to mitigate toxicity.

For this study, researchers performed single-cell analysis on CAR T cells to study gene expression profiles in the infused cells. CAR T cells were collected from those remaining in infusion bags following treatment of 24 patients with LBCL. These genetic profiles were compared to treatment responses, determined at three months post-infusion by PET/CT scan.

When we look at the characteristics of the infused CAR T cells, we found that samples from patients who were less responsive to treatment had exhausted T cells, whereas those who experienced complete responses had T cells expressing memory signatures, co-corresponding author Sattva Neelapu, professor of lymphoma and myeloma, said in a statement. Additionally, one cellular signature of T cell exhaustion was more commonly found in patients who exhibited a poor molecular response, and poor molecular response is generally associated with less-positive, long-term outcomes.

Further, the researchers analyzed early molecular responses in the patients by monitoring changes in circulating tumor DNA from treatment to one week post-infusion. The magnitude of change in tumor-associated DNA corresponded with response, suggesting that patients who displayed an early molecular response were more likely to experience a clinical response to treatment.

When we examined the infusion product, we found that a cell population with characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with development of high-grade neurotoxicity, Green said. Detecting these cells may subsequently lead us to identify patients who would be at higher risk of developing neurotoxicity, allowing us to provide prophylactic treatment with agents that target the specific cellular features.

Further examination may lead to insights into the types and attributes of the cells present within the CAR T infusion product.

This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important, said co-corresponding author Linghua Wang, assistant professor of Genomic Medicine. Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.

These findings will help researchers develop clinical interventions that can block or target these cells. They also plan to validate the capacity of circulating tumor DNA to accurately predict patients long-term outcomes.

This research was supported in part by the B-cell Lymphoma Moon Shot, part of MD Andersons Moon Shots Program. With support from the Moon Shot and the Cancer Prevention & Research Institute of Texas, the research team plans to utilize PDX models of disease that relapsed following anti-CD19 CAR T cell therapy to preclinically test interventions that could lead to better treatment responses or to prevention of adverse side effects.

Other research support came from the Schweitzer Family Fund, NCI (P30 CA016672) and start-up research funds from MD Anderson. A full list of co-authors and their disclosures can be found here.

MD Anderson researchers: Cancer mutations accumulate in distinct regions based on structure of genome and mutational causes

A study from researchers at MD Anderson Cancer Center indicates that mutations found in cancers do not accumulate randomly, but are found in distinct patterns that vary based on the three-dimensional organization of the genome in the cell as well as the underlying factors causing the mutations.

Mutations caused by external factors, such as ultraviolet light or tobacco smoke, led to mutations in different regions than internal factors, such as defects in DNA damage repair or proofreading machinery. The findings, published in Nature Genetics, are important for understanding what factors may be driving mutations in a given cancer and may point to new therapeutic targets.

DNA is not randomly organized within the nucleus, and we found that this structure is strongly correlated with how cancer cells accumulate mutations, lead author Kadir Akdemir, instructor of genomic medicine, said in a statement. We know there are certain processes causing mutations in cancer cells, but we dont always understand the underlying causes. These findings should give us a clue as to how cancer accumulates mutations, and perhaps we can target and kill cancer cells by leveraging the mutations they accumulate.

Within the nucleus of the cell, DNA is packaged with proteins into chromatin, a highly organized and compacted structure that makes up our chromosomes. Within this structure, genes that are frequently used in the cells are organized together in active domains, which are more readily accessible. Those genes used less often are similarly organized together in inactive domains.

The researchers analyzed whether mutations are distributed more frequently in these active or inactive domains in cancer by studying publicly available whole-genome sequencing data of 3,000 paired samples of normal tissue and tumor tissue across 42 cancer types.

Across every cancer type studied, the inactive domains carried significantly more mutations than the active domains, suggesting that the accumulation of mutations is strongly correlated with the three-dimensional organization of the genome.

As a validation of these findings, the researchers looked specifically at the X chromosome in male and female patients. In females, one of their two X chromosomes is inactivated, so it is essentially itself an inactive domain. When comparing the X chromosome between sexes, females had more mutations than males with a marked distribution difference, largely driven by an abundance of mutations on the inactive chromosome.

Knowing that mutations can be caused by a variety of distinct processes, the researchers also investigated whether external environmental factors resulted in different mutation patterns compared to those caused by internal factors in the cell.

Interestingly, we found that different causes of mutations resulted in distinct accumulation patterns within the cell, senior author Andy Futreal, chair of genomic medicine, said in a statement. Extrinsic factors were associated with an enrichment of mutations in inactive domains, whereas intrinsic factors were correlated with enriched mutations in active domains. This provides us an important foundation going forward to understand the root of cancer mutations when we dont otherwise know the cause.

Knowing the causes and distributions of cancer-related mutations may open up potential therapeutic options, explained Akdemir, such as targeted therapies against a specific signaling pathway or combinations with immunotherapy.

For example, immunotherapy may be able to better recognize a cancer cell if more mutations are present. However, if mutations occur primarily in inactive domains, they would rarely be seen by the immune system. Therapeutic agents that restore activity to these domains, used in combination with immune checkpoint inhibitors, could stimulate a stronger anti-tumor immune response.

This research was supported by the Cancer Prevention & Research Institute of Texas (R1205), The Robert A. Welch Distinguished University Chair in Chemistry, and NIH (P50CA127001, DP5OD023071, Z1AES103266). A full list of authors and their disclosures can be found with the full paper here.

UCSD study: Personalized cancer therapy improves outcomes in advanced disease

Researchers at the University of California San Diego School of Medicine found that patients receiving care for advanced cancer at Moores Cancer Center at UC San Diego Health were more likely to survive or experience a longer period without their disease progressing if they received personalized cancer therapy.

The study was published in Nature Communications.

Led by Razelle Kurzrock, director of the Center for Personalized Cancer Therapy at Moores Cancer Center and senior author of the study, a multidisciplinary molecular tumor board was established to advise treating physicians on course of care using an individual patients molecular tumor makeup to design precision medicine strategies.

Patients who underwent a molecular tumor board-recommended therapy were better matched to genomic alterations in their cancer and had improved outcomes, Kurzrock said in a statement. The three-year survival for patients with the highest degree of matching and who received a personalized cancer therapy was approximately 55% compared to 25% in patients who received therapy that was unmatched or had low degrees of matching.

Of 429 patients evaluated by the molecular tumor board, 62% were matched to at least one drug. Twenty percent of patients matched to all recommended drugs, including combination therapies.

The tumor board acted in an advisory role and treating physicians chose not to use the boards recommended strategy in 38% of cases, opting instead for a standard therapy approach that might have been unmatched to the patients genetic alterations or had a low degree of matching. These patients experienced a lower progression-free survival and overall survival rates.

The use of next-generation sequencing allows for the identification of novel potential targets for patients with cancer to improve outcomes, but there are challenges to using this approach widely, said Shumei Kato, associate professor of medicine at UC San Diego School of Medicine and first author.

One of the hurdles is that every cancer patient appears to be carrying different molecular and genomic patterns despite having the same cancer type, Kato, a Moores Cancer Center medical oncologist specializing in rare and gastrointestinal cancers, said in a statement. This can be challenging since we are customizing therapy based on the unique genomic pattern patients have, and thus it is difficult to predict the response. In addition, this approach requires multidisciplinary expertise as well as access to drugs or clinical trials not always available in smaller practices.

At Moores Cancer Center, the molecular tumor board is composed of experts in basic, transitional and clinical research as well as bioinformatics, genetics, radiology, pathology and physicians in multiple specialties such as medical, surgical and radiation oncology.

This research was funded, in part, by NIH (P30 CA023100) and the Joan and Irwin Jacobs Fund.

Phase III CheckMate-816 trial: Opdivo + chemotherapy demonstrates improvement in pathologic CR in resectable NSCLC

The phase III CheckMate-816 trial met a primary endpoint of pathologic complete response in resectable non-small cell lung cancer.

In the trial, significantly more patients treated with Opdivo (nivolumab) plus chemotherapy before surgery showed no evidence of cancer cells in their resected tissue compared to those treated with chemotherapy alone. CheckMate-816 is the first and only phase III trial to demonstrate a benefit with an immune checkpoint inhibitor in combination with chemotherapy as a neoadjuvant treatment in non-metastatic NSCLC.

Opdivo is sponsored by Bristol Myers Squibb.

Patients in the experimental arm of the trial received up to three doses of Opdivo plus chemotherapy prior to surgery, a standard number of cycles of therapy in the neoadjuvant setting. The safety profile of Opdivo plus chemotherapy was consistent with previously reported studies in NSCLC.

Nivolumab has shown benefit as an adjuvant, or post-surgical, treatment option in other cancer types, and the positive results from CheckMate -816 speak to its potential in the neoadjuvant setting of resectable non-small cell lung cancer, Mark Awad, clinical director of Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said in a statement.

The CheckMate-816 trial is ongoing to assess the other primary endpoint of event-free survival, to which the company remains blinded, as well as key secondary endpoints.

In non-metastatic NSCLC, Bristol Myers Squibb and collaborators are exploring the use of immunotherapy in the neoadjuvant, adjuvant and peri-operative settings, as well as in association with chemoradiation. To date, Opdivo has shown improved efficacy in the neoadjuvant or adjuvant treatment of four tumor types: lung cancer, bladder cancer, esophageal/gastroesophageal junction cancer and melanoma.

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City of Hope leads novel clinical trial to treat cancer patients with COVID-19 - The Cancer Letter

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Global Tooth Regeneration Market: Industry Analysis and Forecast (2020-2027)-by Type, Application, Population Demographics and Region – re:Jerusalem

October 10th, 2020 9:49 am

Global Tooth Regeneration Market was valued US$ XX Mn in 2019 and is expected to reach US$ XX Mn by 2027, at a CAGR of 6.5% during a forecast period 2020-2027.

Market Dynamics

The Research Report gives a comprehensive account of the drivers and restraints in the tooth regeneration.Somatic stem cells are composed and reprogrammed to induced pluripotent stem cells which can be placed in the dental lamina directly or placed in an absorbable biopolymer in the shape of the new tooth, which is a main source of the novel bioengineered teeth. Tooth replacement therapy is pondered to be a greatly attractive concept for the next generation bioengineered organ replacement.The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

REQUEST FOR FREE SAMPLE REPORT: https://www.maximizemarketresearch.com/request-sample/55424

The global tooth regeneration market is mainly compelled by the high occurrence of dental problems with the new research and development activities. According to WHO, the Global Burden of Disease Study 2017 estimated that oral diseases affect close to 3.5 billion people worldwide, with caries of permanent teeth being the most common condition. Globally, it is likely that 2.3 billion people suffer from caries of permanent teeth and more than 530 million children suffer from caries of primary teeth. Additionally, positive refund policies for instance coverage of Medicaid insurance for dental loss treatment and emergence of new technologies like laser tooth generation techniques are projected to enhance the global tooth generation market throughout the estimated period.

Different researches are carried out by several academies and corporations to understand the possibility of stem cell-based regenerative medicines tooth regeneration. Though stem cell is the protuberant technology in research for tooth regeneration, several organizations are also leveraging laser, drug, and gel as mediums to regenerate teeth. For example, the Wyss Institute at Harvard University is engaged in research related to tooth regeneration using lasers. Tooth generation using stem cells is now under research through the globe. There are some key stem cells on which research are carried out such as stem cells from human exfoliated deciduous teeth (SHEDs), dental pulp stem cells, dental follicle progenitor cells (DFPCs), periodontal ligament stem cells (PDLSCs), and stem cells from apical papilla (SCAPs).A 2009 nationwide survey by the Nova South-eastern University in the U.S. publicized that around 96% of dentists expect stem cell regeneration to lead the future of the dentistry industry.However, occurrence rates are growing in low and middle-income countries. Though, some factors like the preference for endodontic treatment over tooth regeneration products in key dental surgeries and local inflammatory activity, which results in chronic complications to dental replacements, is anticipated to hamper the market throughout the forecast period.

Global Tooth Regeneration Market Segment analysis

Based on population demographics, the geriatric segment is expected to grow at a CAGR of XX% during the forecast period. According to NIH, the geriatric population has an average 18.9 remaining teeth. About 23% of the geriatric population has no teeth, making a positive market situation for manufacturing companies. The above 18 million dental procedures are anticipated to be carried out amongst the geriatric population between 2019 and 2027. Commercialization of tooth regeneration is expected to create lucrative market opportunities for industry players.Based on Type, the dentin segment accounted for a projecting share of the global tooth regeneration market in 2019, owing to the growing occurrence of dental surgery and the uprising demand for tooth regeneration in cosmetic surgery, particularly from developing economies like India, China, and Brazil.

Global Tooth Regeneration Market Regional analysis

The Asia Pacific is projected to dominate the global tooth regeneration market throughout the forecast period. Tooth regeneration addressable market is likely to be highest in the Asia Pacific, with China and India located as the major growth engines. The occurrence of tooth regeneration is projected to capture this market. Also, the number of dental procedures is anticipated to grow at the highest CAGR of ~10.8% in the Asia Pacific between 2019 and 2027. Besides, the growing incidence of dental cavities & periodontics, particularly in emerging countries like China and India has led to the rising demand for orthopedic & dental surgery.North America and Europe are estimated to collectively account for the major share of global procedures during the forecast period.

Key Developments

In June 2018, Datum Dental Ltd., the prominent provider of OSSIX brand innovative solutions for bone and tissue regeneration for dentistry, announced clearances for OSSIX Bone with Health Canada and CE Mark approval in Europe. OSSIX Bone received FDA clearance in July 2017 and was launched commercially in the USA. In April 2018, Datum Dental, the leading provider of OSSIX brand innovative solutions for bone and tissue regeneration for dentistry, announced the expansion of its global distribution network. In the USA, Dentsply Sirona Implants is now promoting the full OSSIX line.

The objective of the report is to present a comprehensive analysis of the Global Tooth Regeneration Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers all the aspects of the industry with a dedicated study of key players that includes market leaders, followers and new entrants. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors of the market has been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analysed, which will give a clear futuristic view of the industry to the decision-makers.

DO INQUIRY BEFORE PURCHASING REPORT HERE: https://www.maximizemarketresearch.com/inquiry-before-buying/55424

The report also helps in understanding Global Tooth Regeneration Market dynamics, structure by analysing the market segments and projects the Global Tooth Regeneration Market size. Clear representation of competitive analysis of key players by Application, price, financial position, Product portfolio, growth strategies, and regional presence in the Global Tooth Regeneration Market make the report investors guide.Scope of the Global Tooth Regeneration Market

Global Tooth Regeneration Market, By Type

Dentin Dental Pulp Tooth EnamelGlobal Tooth Regeneration Market, By Applications

Hospitals Dental Clinics OthersGlobal Tooth Regeneration Market, By Population Demographics

Geriatric Middle-aged Adults OthersGlobal Tooth Regeneration Market, By Regions

North America Europe Asia-Pacific South America Middle East and Africa (MEA)Key Players operating the Global Tooth Regeneration Market

Unilever Straumann Dentsply Sirona 3M Zimmer Biomet Ocata Therapeutics Integra LifeSciences Datum Dental CryoLife BioMimetic Therapeutic Cook Medical

MAJOR TOC OF THE REPORT

Chapter One: Tooth Regeneration Market Overview

Chapter Two: Manufacturers Profiles

Chapter Three: Global Tooth Regeneration Market Competition, by Players

Chapter Four: Global Tooth Regeneration Market Size by Regions

Chapter Five: North America Tooth Regeneration Revenue by Countries

Chapter Six: Europe Tooth Regeneration Revenue by Countries

Chapter Seven: Asia-Pacific Tooth Regeneration Revenue by Countries

Chapter Eight: South America Tooth Regeneration Revenue by Countries

Chapter Nine: Middle East and Africa Revenue Tooth Regeneration by Countries

Chapter Ten: Global Tooth Regeneration Market Segment by Type

Chapter Eleven: Global Tooth Regeneration Market Segment by Application

Chapter Twelve: Global Tooth Regeneration Market Size Forecast (2019-2026)

Browse Full Report with Facts and Figures of Tooth Regeneration Market Report at: https://www.maximizemarketresearch.com/market-report/global-tooth-regeneration-market/55424/

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Global Tooth Regeneration Market: Industry Analysis and Forecast (2020-2027)-by Type, Application, Population Demographics and Region - re:Jerusalem

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The global regenerative medicine market is projected to reach USD 17.9 billion by 2025 from USD 8.5 billion in 2020, at a CAGR of 15.9% – Yahoo…

October 10th, 2020 9:49 am

during the forecast period. Market growth is driven by the rising prevalence of chronic diseases, genetic disorders, and cancer; rising investments in regenerative medicine research; and the growing pipeline of regenerative medicine products.

New York, Oct. 08, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Regenerative Medicine Market by Product, Application, Geography - Global Forecast to 2025" - https://www.reportlinker.com/p04700208/?utm_source=GNW However, the high cost of cell and gene therapies and ethical concerns related to the use of embryonic stem cells in research and development are expected to restrain the growth of this market during the forecast period.The cell therapies segment accounted for the highest growth rate in the regenerative medicine market, by product, during the forecast periodBased on products, the regenerative medicine market is segmented into tissue-engineered products, cell therapies, gene therapies, and progenitor and stem cell therapies.The cell therapies segment accounted for the highest growth rate in the regenerative medicine market in 2019.

The increasing adoption of tissue-engineered products for the treatment of chronic wounds and musculoskeletal disorders and the rising funding for the R&D of regenerative medicine products and therapies are the major factors driving the growth of this segment.

Oncology segment accounted for highest CAGRBased on applications, the regenerative medicine market is segmented into musculoskeletal disorders, wound care, oncology, ocular disorders, dental, and other applications.In 2019, the oncology segment accounted for the highest growth rate.

This can be attributed to the rising prevalence of orthopedic diseases, growing geriatric population, increasing number of stem cell research projects, growing number of clinical researches/trials, and the rich pipeline of stem cell products for the treatment of musculoskeletal disorders.

Europe: The fastest-growing region regenerative medicine marketThe global regenerative medicine market is segmented into North America, Europe, the Asia Pacific, and Rest of the World.The North America region is projected to grow at the highest CAGR during the forecast period in 2019.

The growth in the North American regenerative medicine market can be attributed to rising stem cell banking, tissue engineering, and drug discovery in the region; expansion of the healthcare sector; and the high adoption of stem cell therapy and cell immunotherapies for the treatment of cancer and chronic diseases.

The primary interviews conducted for this report can be categorized as follows: By Company Type: Tier 1 - 20%, Tier 2 - 45%, and Tier 3 - 35% By Designation: C-level - 30%, D-level - 20%, and Others - 50% By Region: North America - 36%, Europe - 25%, Asia Pacific - 27%, and Rest of the World 12%

Lits of companies Profiled in the Report: 3M (US) Allergan plc (Ireland) Amgen, Inc. (US) Aspect Biosystems (Canada) bluebird bio (US) Kite Pharma (US) Integra LifeSciences Holdings Corporation (US) MEDIPOST Co., Ltd. (South Korea) Medtronic plc (Ireland) Anterogen Co., Ltd. (South Korea) MiMedx Group (US) Misonix (US) Novartis AG (Switzerland) Organogenesis Inc. (US) Orthocell Limited (Australia) Corestem, Inc. (South Korea) Spark Therapeutics (US) APAC Biotech (India) Shenzhen Sibiono GeneTech Co., Ltd. (China) Smith & Nephew plc (UK) Stryker Corporation (US) Takeda Pharmaceutical Company Limited (Japan) Tego Science (South Korea) Vericel Corporation (US) Zimmer Biomet (US)

Research Coverage:This report provides a detailed picture of the global regenerative medicine market.It aims at estimating the size and future growth potential of the market across different segments, such as product, application, and region.

The report also includes an in-depth competitive analysis of the key market players, along with their company profiles, recent developments, and key market strategies.

Key Benefits of Buying the Report:The report will help market leaders/new entrants by providing them with the closest approximations of the revenue numbers for the overall regenerative medicine market and its subsegments.It will also help stakeholders better understand the competitive landscape and gain more insights to position their business better and make suitable go-to-market strategies.

This report will enable stakeholders to understand the pulse of the market and provide them with information on the key market drivers, restraints, opportunities, and trends.

Read the full report: https://www.reportlinker.com/p04700208/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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The global regenerative medicine market is projected to reach USD 17.9 billion by 2025 from USD 8.5 billion in 2020, at a CAGR of 15.9% - Yahoo...

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COVID Drug Given to Trump Developed From Aborted Fetus Cells – Quint Fit

October 10th, 2020 9:48 am

Embryonic stem cell research has been always disputed by the 2020 Republican party. In 2019, Trumps administration paused funding for government scientists to work on studies involving embryonic stem cells, affecting about $31m in research, according to Science Magazine.

Regeneron, on the other hand, doesnt consider these cells fetal tissue because the HEK-293T line of cells has been immortalized and they divide and regenerate themselves in the laboratory.

The investigational drug has been in clinical trials since June. Even though early results from a trial with around 300 non-hospitalised COVID patients showed the drug was safe and could reduce viral levels and improve symptoms, the data is yet to be peer-reviewed.

According to CNN, the treatment is not yet approved for any use from the US FDA. The company, however, is in talks for an emergency approval. Regeneron has also confirmed that it had provided the drug under a compassionate use request for President Trump from the doctors.

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COVID Drug Given to Trump Developed From Aborted Fetus Cells - Quint Fit

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Laid off from ImmunoGen, an ex-Genzyme and Shire exec heads to an ARCH upstart – Endpoints News

October 10th, 2020 9:48 am

ImmunoGen CBO Blaine McKee got laid off after the company had a big Phase III failure last March, but by the time his official exit came around in December, he already landed a plum new gig. ARCH Venture Partners had tapped the longtime executive to run a biotech willing to spend a lot of cash in an area that had gone under-invested: kidney disease.

Now that biotech is emerging from stealth mode with 12 employees, $51 million in Series A funding from ARCH and UCB Venture and two new methods of directly attacking a disease and an organ that drug developers have long only tried to mitigate from the side. Theyve also got a new name: Walden Biosciences.

Its horribly served, poorly served, there hasnt been much innovation for years, McKee told Endpoints News. Were not looking to slow the progression of renal diseases, were not looking to make a modest impact on renal disease, we want to full on stop or reverse the progression of renal disease.

Although a couple recent upstarts have altered the picture, for years the majority of drugs in biotech pipelines have treated the chronic conditions that often trigger kidney diseases, CSO Alex Duncan noted. Thats been on particularly acute display over the past year, as AstraZeneca gradually rolled out what theyve billed as unprecedented data on their SGLT2 diabetes drug Farxiga. Those data showed a 40% reduction in risk of kidney progression or cardiovascular death, but that was in patients regardless of diabetes status and in some ways an outlier.

Pharma has tended to focus on, well, lets treat the diabetes and we should be able to treat the kidney disease, Duncan, a Medimmune and AstraZeneca vet who last worked at the cancer biotech Agenus, told Endpoints. Well, that hasnt happened.

McKee, a longtime Genzyme executive who ran corporate development for Shire before the Takeda buyout, will direct a platform culled from the labs of Jochen Reiser and Sanja Sever at Massachusetts General Hospital and Harvard. Although they have yet to nominate lead candidates, their approach can be split into two different biological mechanisms.

In one path, theyll look to target a protein known as soluble urokinase plasminogen activator receptor, or simply: suPAR. Researchers have known for years that the protein, when overproduced elsewhere in the body, can flow through the blood and cause harmful inflammation in the kidney. Theyve subsequently largely used it as a biomarker. But Walden says they can use antibodies to basically neutralize suPARs before they reach the kidney, returning it to normal levels an approach akin to the antibodies now being developed to neutralize SARS-CoV-2 before it enters cells.

In the second path, theyll look to activate a protein called dynamin. The protein helps support the physical structure of the kidney itself, and in a 2015 Nature Medicine paper, Sever and Reiser describe how a small molecule that continually activates the receptor can help maintain the kidneys structure and ameliorate disease in animals. The approach, Duncan said, could allow patients to keep on meds they would have discontinued because of renal side effects.

Even with the damage that might be being caused from conditions outside of the kidney, we can make the proper filtration apparatus inside, Duncan said.

As they look to push the two programs, Walden will be boosted by a key regulatory change, McKee said. The FDA in 2018 changed their guidelines to allow companies to use the reduction of protein in the urine as an acceptable endpoint for accelerated approval. That, he said, could shave off years of development time.

He said thats what helped other VCs enter the field over the last 5 years, including Third Rock with GoldFinch in 2016 and Versant with Chinook in 2019.

Theyll be looking to put their first drug into the clinic in 2022.

Continued here:
Laid off from ImmunoGen, an ex-Genzyme and Shire exec heads to an ARCH upstart - Endpoints News

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Lars Jaeger: The Future is Veggie, With 3D Printing – finews.asia

October 10th, 2020 9:48 am

The energy market as well as political have changed strongly in recent years. In many countries around the world, the cards on the energy mix are being reshuffled. Lars Jaeger writes in an essay for finews.first.

This article is published on finews.first, a forum for authors specialized in economic and financial topics.

The latest example is China, where President Xi Jinping announced a few days ago that his country aims to be CO2-neutral by 2060. Political decision-makers seem to have finally started on their mission to stop climate change. But is enough when politicians pay lip service?

What about our individual responsibilities for greenhouse gas emissions? What have we personally done to curb those? Many residents of industrialized countries still drive around in large cars as a matter of course, eat large quantities of meat, eat avocados from Thailand and wear T-shirts from Bangladesh. Even the corona crisis has done little to change us from wanting to take airplanes not only for our summer vacations but increasingly also for our spring and fall vacation.

Animal husbandry accounts for a particularly large proportion of the emissions

A significant amount of greenhouse gases emission is also caused by our food consumption. What we eat is cultivated, harvested, transported, stored, processed, before it finally ends up on the market and is then consumed by us, again after storage, cooling, and preparation.

Animal husbandry accounts for a particularly large proportion of the emissions. According to the Food and Agriculture Organization of the United Nations (FAO) the keeping and processing of animals account for almost 15 percent of greenhouse gas emissions worldwide. Estimates for total food production go up to 30 percent.

To produce one kilogram of beef (approx. 2,500 kcal nutritional value) the greenhouse effective equivalent of approx. 13 kilograms of CO2 is emitted, one kilo of butter (approx. 7,000 kcal nutritional value) even comes to 24 kilograms of CO2, one kilo of lamb (approx. 3,000 kcal nutritional value) to no less than 39 kg CO2, cheese (approx. 3,000 kcal nutritional value) to an average of 8.5 kilograms of CO2 per kilo. For potatoes (approx. 860 kcal nutritional value) this value stands at just 0.4 kilograms of CO2, and the production of one kilo of fresh vegetables (approx. 400 kcal nutritional value) produces on average only 0.15 kilo CO2. Vegetables, therefore, have the best CO2 balance among the basic foodstuffs.

Transportation and packaging of the finished food products play a rather minor role in the environment

Here, methods of genetic engineering, even if they are controversial in Europe, could bring further improvements. For example, there is genetically modified rice, the production of which emits fewer greenhouse gases and which at the same time yields more. The prerequisite for this is that behind these methods stands not only the greed of companies for profit, but that they are also proven by nutritional scientists to be perfectly beneficial to our health and by environmental experts to be not harmful to the biosphere.

Transportation and packaging of the finished food products play a rather minor role in the environment (as long as they are not transported by air). Relying on regional products alone only improves the food footprint by about 4 percent (some products can even be produced overseas at lower CO2 emissions). It is more important to pay attention to seasonal foods: Apples that are stored for months in cold stores are far from being as good as fresh apples in terms of their climate balance. After six months, the energy required for cooling amounts to about 22 percent of the total energy input.

According to the WWF, the CO2 footprint of a Central Europeans diet is reduced by around 25 percent if he or she switches to a vegetarian diet. With a vegan diet, it is even 40 percent. No wonder that the Intergovernmental Panel on Climate Change (IPCC) in its Special Report on Climate Change and Land Systems of August 2019 calls for a radical change in human meat consumption. In order to feed the growing world population, we need further improved methods of food production. We simply can no longer afford to keep animals for 10 billion people.

Will we there have to do without our steak or chops in the future?

In addition, it has been well-known for a long time that meat consumption, in particular that of processed meat, is not necessarily health-promoting. It significantly increases the risk of developing colon cancer (because of the proliferation of potentially aggressive bacteria in the microbiome, the bacterial intestinal flora, which causes inflammation and cells to mutate), as well as pancreatic and prostate cancer. Further consequences of heavy meat-eating are diabetes, cardiovascular diseases, kidney failure, chronic inflammation, arthrosis and rheumatism, doctors, therefore, advise reduced meat consumption.

Will we there have to do without our steak or chops in the future? No, because also in food production we will experience dramatic technological changes. They will enable us to eat healthier and more ecological food which will at the same time be tastier than what we eat today.

The production of artificial meat in the laboratory reduces greenhouse gas emissions by up to 95 percent

Food is really just a combination of protein, fat and carbohydrates plus vitamins and trace elements. These can also be put together technically with suitable processes, and this even more efficient and nutritionally more valuable than nature does. In addition, its creation in sterile cell cultures is much more suitable for industrial meat production, because it is easier to control pathogens and toxins. In addition, the time-consuming and appetizing removal of offal, hair and bones is no longer necessary. The fat content of the meat can also be controlled. And last but not least: The production of artificial meat in the laboratory reduces greenhouse gas emissions by up to 95 percent.

As early as 2013 scientists at Maastricht University produced an artificial meatball. They took muscle stem cells from cattle, mixed those with nutrients, salts, pH buffers and growth factors and left them to reproduce. The cells became cell strands, about 20,000 of which were needed for a 140-gram meatball. Almost like meat, not quite as juicy, but the consistency is perfect, test eaters commented. The effort for this prototype was immense, however, the meatball cost 250,000 euros.

Seven years later, in-vitro meat is almost ready for the market. Appropriate 3D bio-printers serially assemble the cultured cell strands into muscle tissue. In 2020, prices were around 8 to 10 euros per burger (about 140 grams). Today, a number of start-ups are striving to bring their products to market soon at competitive prices.

Farms are also significant virus spinners

Anyone who thinks that artificially produced in-vitro meat is not very appetizing or that a diet of artificially produced meat would take people too far away from nature should spend a few hours in a large slaughterhouse or watch a large agricultural producer.

In the summer of 2020 with the Tnnies crisis in Germany, we became involuntary witnesses of the terrible conditions of todays industrial meat production. The mass production of animals in todays large farms is hardly more appetizing.

Next to wild animals, farms are also significant virus spinners. And the monocultures of todays plant food production, including those for animal feed, are coming with such massive damage to nature (soil compaction, soil erosion, fertilizers and pesticides in the groundwater, bee deaths due to pesticides) that the call for an agricultural turnaround is becoming ever louder. Instead of being a step away from nature, artificial meat production is a powerful step for its protection, i.e. a step towards nature!

Diet becomes healthier without having to sacrifice taste

And as far as palatability is concerned, probably the most important criterion for what we eat, apart from health, the alternative meat producers work together with gourmet chefs and butchers, but also with food technicians, taste experts and manufacturers of flavors and fragrances to optimize juiciness, texture and mouthfeel. Their aim is to simulate the taste of the steak deceptively realistically and by adding appropriate flavors even improve it. First testers unanimously certify that the printed steaks taste like real meat, tasty, firm to the bite and fibrous like the original.

The food market is facing a revolution. Plant food stands up quite favorably in terms of climate balance, in contrast to meat from animal production. Meat and seafood grown from cells and printed by 3D printers will dramatically reduce industrial animal husbandry and even increase our gourmet pleasure. It is estimated that by 2040 35 percent of all meat will be produced in this way.

The popular German philosopher Richard David Precht already paints the picture of a society without livestock farming, but with meat that we print out ourselves instead of it coming from pasture. In this way, we ensure the nutrition of the growing world population and reduce the ecological footprint of our diet. At the same time, our diet becomes healthier without having to sacrifice taste.

Lars Jaeger is a Swiss-German author and investment manager. He writes on the history and philosophy of science and technology and has in the past been an author on hedge funds, quantitative investing, and risk management.

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5 Deadly Pre-existing Conditions You Could Have Due To COVID-19 – Brumpost – Brumpost

October 10th, 2020 9:48 am

The COVID-19 is a respiratory disease caused by SARS-COV-2 virus which is a strain of virus that came from Wuhan in China late December of the year 2019 and has caused a devastating effect on almost everyone on earth forcing businesses to be closed, events to be canceled and economies to be completely shattered since its spread earlier this year 2020.

This is a very new disease and because of that, there is much to learn about the disease which scientists ae constantly working on in order to understand more about it so as to be able to fight it even much more efficiently. Meanwhile in their researches, scientists have been able to realize the roles played by pre-existing conditions in determining the severity of the disease on patients who contracts the coronavirus.

In order to assess the situations which can determine the fatality of the coronavirus infection, scientists have been able to further carry out much more researchers on pre-existing conditions which can cause serious complications.

The research was recently carried out by Penn State University which published in the journal PLOS One took a look at a variety of pre-existing conditions.

A team of researchers reviewed data on almost 500 COVID-19 cases and determined the following five cases are the deadliest pre-existing conditions when it comes to the coronavirus disease.

While an early diagnose of cancer might mean catching the malignant cells when theyre still fresh out, the American Cancer Society writes that doctors are still learning about the possible risks of COVID-19 infection for cancer patients.

The body further warned that all patients who are undergoing chemotherapy or stem cell (bone marrow) treatments should be extra careful and avoid infections at all cost because their immune system can be severely weakened by the treatment.

And for more specific information on cancer and coronavirus, be aware thatThis Type of Cancer Increases Your Risk of Severe COVID by 60 Percent.

While some diabetes can be lifelong, having the illness doesnt mean youre susceptible to catching the COVID-19 but the problem people with diabetes face is primarily a problem of worse outcomes stated the American Diabetes Association.

If your diabetes is being manage safely and regularly that puts you in a much better position but if the blood sugar level are constantly fluctuating or other diabetes-related complications can happen.

Since COVID-19 is a viral disease, this makes it also risky for diabetic patients as it can cause inflammation or internal swelling which is an already risky situation of above-target blood sugars.

Viruses also make patients more likely to experiencediabetic ketoacidosis(DKA). And if youre concerned about this condition,This Quick Trick Can Determine Your Diabetes Risk, Study Says.

Having a high blood pressure can be risky to your lifestyle causing stress and doctors have described this as the silent killer because it can often be present with no symptoms at all.

Meanwhile, early analysis of data from the outbreak of COVID-19 both in the US and China showed that having high blood pressure is the most commonly shared pre-existing condition among those hospitalized with 3- to 50 percent of patients havign it.

Hypertension is very deadly as it can weaken the patients immune system and because of this, patients hit by the COVID-19 are likely to exhibit more severe symptoms.

Patients with congestive heart failure which is a progressive, chronic weakening of the heart which causes the ventricles to lose their strength and their ability to pump sufficient blood throughout the body are 2.03 times more likely to die from COVID-19.

Studies carried out in China suggested that about 20% of the COVID-19 patients in Wuhan which is the epicenter of the original outbreak in December demonstrated a cardiac effect called myocardial injury.

However, analysis by the University of Oxford also stresses that its important thatheart failure patientsare not written off. For patients with known heart failure, continuation of current therapy is crucial, the experts warn.

Those who are constant smokers as well as older people or those living with obesity and diabetes are at a much more higher risk for chronic kidney disease and this disease also runs as an heredity which is more common in African-Americans, Native Americans and Asian-Americans.

COVID aside, chronic kidney disease is especially dangerous as it doesnt cause any symptoms untilmost of your kidney is destroyed.

As many cases of COVID-19 is being reported, patients with this disease are much more vulnerable and can lead to fatal severity if they contract the COVID-19.

Patients with chronic kidney disease (CKD) have ahigher rate of all-type infectionsand cardiovascular disease than the general population, a June paper in theClinical Kidney Journalsums up. A markedly altered immune system and immunosuppressed state may predispose CKD patients to infectious complications. Likewise, they have a state of chronic systemic inflammation that may increase their morbidity and mortality. This research found that the risk for severe COVID-19 is three times higher in those with CKD than those without it.

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Coronavirus Tracker: Bexar Co. cases surpass 59,000; Texas hospitalizations trending in the wrong direction – KENS5.com

October 10th, 2020 9:48 am

Facts, not fear: KENS 5 is tracking the latest numbers from the coronavirus (COVID-19) pandemic in San Antonio and across Texas.

SAN ANTONIO We're tracking the latest numbers from the coronavirus pandemic in San Antonio and across Texas. Here are the latest numbers reported by Bexar and surrounding counties:

How Bexar County is trending

We've tracked how many coronavirus cases have been confirmed in Bexar County from the time officials began reporting cases in March 2020. The graphic below shows the number of cases since June and charts those daily case numbers along a 7-day moving average to provide a more accurate picture of the overall coronavirus case curve in our area and the direction we're trending amid the pandemic.

On Wednesday, San Antonio Mayor Ron Nirenberg announced 214 additional coronavirus cases in Bexar County, sending the local total over 59,000. In all, 59,153 residents have been diagnosed with COVID-19.

Nirenberg also said there were no additional virus-related deaths in the county. In all, 1,168 county residents have died from coronavirus complications.

Hospitalizations in the county dropped ever so slightly on Wednesday. 203 residents were receiving treatment for coronavirus symptoms, which is three fewer than on Tuesday. And the number of patients using ventilators (39) and in ICU (84) are also slight drops from Tuesday's numbers.

Coronavirus in Texas

The number of Texans who have tested positive for the coronavirus since the pandemic began grew by 4,121 cases on Wednesday, according to the Texas Department of State Health Services.

3,776 of those are new diagnoses over the last 24 hours, while the other 345 cases stem from a number of backlogs in several counties and groups of previously unreported cases in some areas. More details can be found at the top of this page.

In total, 777,556 coronavirus cases have been confirmed in Texas.

State health authorities, meanwhile, reported an additional 119 virus-related deaths on Wednesday. At least 16,230 Texans have passed away from COVID-19 complications.

The state also saw a sharp uptick in hospitalizations on Wednesday. There were 125 more Texans receiving treatment for coronavirus symptoms in the last 24 hours, for a total of 3,519 currently hospitalized; it's been nearly a month since the figure was that high.

The state estimates that 692,123 Texans have recovered, while 70,813 Texans remain ill with COVID-19.

Meanwhile, the Texas Education Agency updated its online coronavirus database to show that there have been 9,857 cumulative cases among staff and students across the state as of Sept. 27. More information can be found here.

Latest Coronavirus Headlines

Coronavirus symptoms

The symptoms of coronavirus can be similar to the flu or a bad cold. Symptoms include fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell sore throat, congestion or runny nose, nausea or vomiting and diarrhea, according to the Centers for Disease Control.

Most healthy people will have mild symptoms. A study of more than 72,000 patients by the Centers for Disease Control in China showed 80 percent of the cases there were mild.

But infections can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death, according to the World Health Organization. Older people with underlying health conditions are most at risk.

But infections can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death, according to the World Health Organization. Older people with underlying health conditions are most at risk.

Experts determined there was consistent evidence these conditions increase a person's risk, regardless of age:

The CDC believes symptoms may appear anywhere from two to 14 days after being exposed.

Human coronaviruses are usually spread...

Help stop the spread of coronavirus

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Coronavirus Tracker: Bexar Co. cases surpass 59,000; Texas hospitalizations trending in the wrong direction - KENS5.com

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