StemCell Therapy

CAMBRIDGE, Mass.--(BUSINESS WIRE)--AlloVir (Nasdaq: ALVR), a late clinical-stage cell therapy company, today announced results of a subgroup analysis from a Phase 2, proof-of-concept study (CHARMS) evaluating the companys lead product candidate, Viralym-M (ALVR105), an allogeneic, off-the-shelf, multi-virus specific investigational T-cell therapy (VST), in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients with virus-associated hemorrhagic cystitis (V-HC). These data are being presented in an oral presentation during the Transplantation & Cellular Therapy (TCT) Meeting of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR). Additionally, two separate oral presentations characterize the high economic and clinical burden of V-HC and double-stranded (ds) DNA viral infections in allo-HSCT recipients. Preclinical data was also presented in a poster presentation on ALVR109, AlloVirs virus-specific T-cell therapy targeting SARS-CoV-2, the virus responsible for COVID-19.

The data from the Phase 2 CHARMS study highlight Viralym-M's potential to treat and possibly prevent multiple viral infections and viral diseases. The findings presented at TCT show that this novel virus-specific T cell therapy has the potential to rapidly and effectively resolve macroscopic hematuria in allo-HSCT recipients with virus-associated hemorrhagic cystitis a disease that currently has no effective treatment options and causes significant morbidity and increased risk of mortality, said Agustin Melian, MD, Chief Medical Officer and Head of Global Medical Sciences of AlloVir. We have recently initiated our Phase 3, pivotal study of Viralym-M for the treatment of virus-associated hemorrhagic cystitis and look forward to advancing this therapy through development for patients in need.

Data of Viralym-M in fifty-eight allo-HSCT recipients with at least one treatment-refractory viral infection caused by BK virus (BKV), cytomegalovirus (CMV), adenovirus (AdV), Epstein Barr virus (EBV), human herpesvirus 6 (HHV-6), and/or JC virus (JCV) were evaluated in the CHARMS Phase 2 study. The subgroup analysis presented at TCT included 26 patients who received intravenous VST infusions for the treatment of V-HC due to infection with BKV (n=23), AdV (n=2) and BKV and AdV (n=1). Infusions were well tolerated with mild, grade 1, de novo skin rash from graft-versus-host disease (GVHD) occurring in 15% of patients (n=4). In the 20 patients with available V-HC grading, resolution of macroscopic hematuria was observed in 60% and 80% of patients at two- and six-weeks post-infusion, respectively. In comparison, resolution of macroscopic hematuria was observed in <10% and 30% of patients at weeks two and six, respectively, in a contemporary cohort of allo-HSCT recipients (n=33) with V-HC who were not treated with Viralym-M.

Health economic outcomes data was also presented in two separate oral presentations at the conference. The two presentations analyzed U.S. claims data to compare health care reimbursement, health resource utilization, and clinical outcomes in pediatric and adult allo-HSCT recipients with V-HC and those without V-HC, and allo-HSCT recipients with or without dsDNA infections, respectively. Both studies found that allo-HSCT recipients with V-HC and those with any dsDNA infection had higher reimbursement costs, increased hospital and ICU length of stay, and increased hospital readmission rates. The presence of V-HC or any dsDNA viral infection was associated with a higher risk of mortality.

In addition, a poster presentation at the conference demonstrated the in vitro effector and safety profile of ALVR109, an allogeneic, off-the-shelf investigational VST therapy designed to target SARS-CoV-2, the virus that causes the severe and life-threatening viral disease, COVID-19. These data suggest the potential for using these VSTs to treat COVID-19 in hospitalized high-risk patients to prevent the development of severe disease. A clinical trial evaluating these banked, off-the-shelf SARS-CoV-2 specific T cells has been initiated at the Center for Cell and Gene Therapy, Baylor College of Medicine (BCM), Texas Children's Hospital, and Houston Methodist Hospital.

Viral Infections in Immunocompromised Patients

In healthy individuals, virus-specific T cells (VSTs) from the bodys natural defense system provide protection against numerous disease-causing viruses. However, in patients with a weakened immune system these viruses may be uncontrolled. Viral diseases are common and can cause potentially devastating and life-threatening consequences in immunocompromised patients. For example, up to 90% of patients will reactivate at least one virus following an allogeneic stem cell transplant and two-thirds of these patients reactivate more than one virus, resulting in significant and prolonged morbidity, hospitalization, and premature death. Typically, when viruses infect immunocompromised patients, standard antiviral treatment does not address the underlying problem of a weakened immune system and therefore many patients suffer with life-threatening outcomes such as multi-organ damage and failure, and even death.

Viralym-M

Viralym-M (ALVR105) is an allogeneic, off-the-shelf, multi-virus specific investigational T-cell therapy targeting five devastating viral pathogens: BK virus, cytomegalovirus, adenovirus, Epstein-Barr virus, and human herpesvirus 6. Viralym-M has the potential to transform care for transplant recipients as well as individuals who are at high risk for opportunistic viral infections by reducing or preventing disease morbidity and dramatically improving patient outcomes. Three pivotal and proof-of-concept clinical (POC) trials are ongoing and actively recruiting patients in indications such as treatment of virus-associated hemorrhagic cystitis and multi-virus prevention following allo-HSCT, and preemptive treatment of BK viremia in adult kidney transplant recipients. Additional pivotal and POC trials are expected to initiate for the treatment of CMV and the treatment of AdV in allo-HSCT recipients and in CMV for solid organ transplant recipients, respectively. For more information on the ongoing clinical trials visit clinicaltrials.gov.

Viralym-M has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA), as well as PRIority MEdicines (PRIME) and Orphan Drug Designations (ODD) from the European Medicines Agency.

About AlloVir

AlloVir is a leading late clinical-stage cell therapy company with a focus on restoring natural immunity against life-threatening viral diseases in pediatric and adult patients with weakened immune systems. The companys innovative and proprietary technology platforms leverage off-the-shelf, allogeneic, multi-virus specific T-cells targeting devastating viruses for patients with T-cell deficiencies who are at risk from the life-threatening consequences of viral diseases. AlloVirs technology and manufacturing process enables the potential for the treatment and prevention of a spectrum of devastating viruses with each single allogeneic cell therapy. The company is advancing multiple mid- and late-stage clinical trials across its product portfolio. For more information visit http://www.allovir.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding AlloVirs development and regulatory status of our product candidates, the planned conduct of its preclinical studies and clinical trials and its prospects for success in those studies and trials, and its strategy, business plans and focus. The words may, will, could, would, should, expect, plan, anticipate, intend, believe, estimate, predict, project, potential, continue, target and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on managements current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, those related to AlloVirs financial results, the timing for the initiation and successful completion of AlloVirs clinical trials of its product candidates, whether and when, if at all, AlloVirs product candidates will receive approval from the U.S. Food and Drug Administration, or FDA, or other foreign regulatory authorities, competition from other biopharmaceutical companies, the impact of the COVID-19 pandemic on AlloVirs product development plans, supply chain, and business operations and other risks identified in AlloVirs SEC filings. AlloVir cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. AlloVir disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent AlloVirs views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date.

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AlloVir Research Presented at the 2021 Transplantation & Cellular Therapy Meeting Digital Experience - Business Wire

PRINCETON, N.J., & ALAMEDA, Calif.(BUSINESS WIRE)Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc.(NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of OPDIVO (nivolumab) and CABOMETYX (cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. 9:45 a.m. EST.

Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.)

With a median follow-up of two years (23.5 months), OPDIVO in combination with CABOMETYX continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of OPDIVO and CABOMETYX showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).

Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.)

In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of OPDIVO and CABOMETYX reported statistically significant health-related quality of life benefits. Treatment with OPDIVO in combination with CABOMETYX was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.

There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma, said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.

These additional data from CheckMate -9ER provide strong evidence that OPDIVO in combination with CABOMETYXmay help patients achieve and maintain control of their disease, said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with OPDIVO-based combinations across a wide range of tumor types.

The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of CABOMETYX and OPDIVO after an extended follow-up of two years, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of CABOMETYX in combination with immunotherapies to help more patients with difficult-to-treat tumor types.

OPDIVO in combination with CABOMETYX was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally.

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L11%) were randomized to receive OPDIVO plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Photo courtesy of Bristol Myers Squibb

About OPDIVO

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivotrials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

OPDIVO INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune):conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma

CABOMETYX INDICATIONS

Read the original post:
Opdivo in Combination with Cabometyx Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for Patients with Advanced RCC -...

TOKYO and BOTHELL, Wash., Feb. 12, 2021 /PRNewswire/ --Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced results from the second cohort (cohort 2) of patients in the pivotal phase 2 single-arm EV-201 trial. In the trial, 52 percent of patients who received PADCEV (enfortumab vedotin-ejfv) had an objective response (95 percent Confidence Interval [CI]: 40.8, 62.4) and the median duration of response was 10.9 months (95 percent CI: 5.8, NR). Twenty percent of patients had a complete response, the absence of detectable cancer, after PADCEV treatment, and 31 percent had a partial response. Adverse events were consistent with those observed in previous trial data, with the most common all-grade treatment-related adverse events (AEs) being alopecia (51 percent), peripheral sensory neuropathy (47 percent), and fatigue (34 percent).

Cohort 2 of the EV-201 trial evaluated PADCEV in patients with locally advanced or metastatic urothelial cancer who had been previously treated with a PD-1/L1 inhibitor, had not received a platinum-containing chemotherapy in this setting, and were ineligible for cisplatin. Urothelial cancer is the most common type of bladder cancer and can also be found in the renal pelvis, ureter and urethra.1

Thefindings were presented today in an oral presentation as part of the virtual scientific program of the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (Abstract 394).

"Roughly half of all patients with locally advanced or metastatic urothelial cancer have comorbidities that make them ineligible for cisplatin-based chemotherapy and after progression on first-line immunotherapy, there are few effective treatment options," said Arjun Balar, M.D., Associate Professor of Medicine, Director Genitourinary Medical Oncology Program, NYU Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and an investigator for the trial. "Results from EV-201 cohort 2 indicate that enfortumab vedotin may be an important therapeutic option for these patients."

"Fifty-two percent of patients in this study cohort responded to PADCEV including some patients who showed no detectable cancer following treatment an important result for people with this difficult-to-treat form of urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"We're pleased that PADCEV provided meaningful clinical benefit to a group of patients who historically have very few options and may choose not to pursue further treatment for the disease," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

The results are expected to be submitted to the U.S. Food and Drug Administration by the end of March as part of a supplemental biologics licensing application. EV-201 results will also be included in submissions to some global health authorities.

EV-201 Cohort 2 Trial ResultsIn cohort 2 of the dual-cohort trial, 52 percent of patients who received PADCEV had an objective response (46/89); (95 percent CI: 40.8, 62.4) per blinded independent central review (the primary endpoint), with 20percent of patients (18/89) experiencing a complete response and 31 percent of patients experiencing a partial response (28/89).

In the trial's secondary endpoints, duration of response lasted a median of 10.9 months (95 percent CI: 5.8, NR).Patients lived a median of 5.8 months without cancer progression (progression-free survival) (95 percent CI: 5.0, 8.3), and had a median overall survival of 14.7 months(95 percent CI: 10.5,18.2).

Grade 3 or greater treatment-related AEs of interest included skin reactions (17 percent), peripheral neuropathy (8 percent) and hyperglycemia (6 percent). Four deaths were reported as treatment-related by investigators in patients age 75 years and older with multiple comorbidities.

About Urothelial CancerUrothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.2

About the EV-201 TrialThe EV-201 trial (NCT03219333) is a single-arm, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2). The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally.

The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

About PADCEV (enfortumab vedotin-ejfv)PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information Warnings and Precautions

Adverse ReactionsSerious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab AbnormalitiesIn one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website athttps://www.astellas.com/en.

About Seagen Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit http://www.seagen.com and follow @SeagenGlobal on Twitter.

About the Astellas and Seagen CollaborationAstellas and Seagen are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seagen Forward Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the submission of data from cohort 2 of the EV-201 trial for presentation at an upcoming scientific congress; intended regulatory actions, including plans to submit a supplemental biologics licensing application to the FDA and to make submissions to global health authorities; and the therapeutic potential of PADCEV, including its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibilities that we may experience delays in the submission of results to the FDA; that the results from cohort 2 of the EV-201 trial may not be support any approvals by regulatory authorities; that, even if PADCEV receives an additional approval in the U.S. or an approval in any global registrations, the product labeling may not be as broad or desirable as anticipated; that ongoing and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

References

1

American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed January 27, 2021.

2

Cancer today: data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/home. Accessed January 27, 2021.

3

PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.

4

Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

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Astellas and Seagen Announce Presentation of Results from PADCEV (enfortumab vedotin-ejfv) Pivotal Trial in Patients with Previously Treated Advanced...

Introduction

Sepsis, a destructive inflammatory response syndrome in clinical practice, is principally caused by multi-factors, such as toxins, pathogenic bacteria, and their metabolic products entering in the blood stream.1,2 As a terrible generalized hyperinflammatory condition, sepsis patients suffer a variety of tissue injuries and organ dysfunctions involving in lung, kidney, and heart.35 Despite many efforts have been made to reduce mortality and improve the cure rate of sepsis worldwide, sepsis remains a terrible disease that seriously threatens the patients. Only 30% septic patients survive according to statistics, besides, at least 6 million patients die from septic infection annually according to the statistics of the World Health Organization (WHO).6,7 Among the complications of sepsis, acute kidney injury (AKI) is the most common and serious with high mortality. It is considered that over 60% septic cases occur with AKI and approximately 50% AKI cases are associated with sepsis.8,9 Dreadfully, although the standard treatments are used, the mortality of severe AKI is as high as 45 to 70%.10 Hence, it is extremely urgent to study the accurate mechanisms and develop effective methods to alleviate sepsis-related AKI.

Several studies have revealed the mechanisms related to AKI are controversial, uncontrolled inflammatory response, severe oxidative stress, maladaptive apoptosis, and aberrant endoplasmic reticulum stress are all involved in the pathological process of AKI.11 As known, except for inflammation, oxidative stress is frequently prescribed for AKI pathogenesis. Oxidative stress referring to a state of imbalance between oxidation and anti-oxidation is a negative effect produced by free radicals, which is considered to be an important factor leading to multiple diseases, including retinopathy.12 Under various pathologic conditions, the strong correlation between oxidative stress injury and nuclear factor E2-related factor 2 (Nrf2) has been previously proved.1315 The preceding study has pointed out that Nrf2/HO-1 pathway is one of the most recognized signaling closely associated with oxidative and anti-oxidative balance.16,17 Under normal circumstances, the cap n collar subfamily of basic region-leucine zipper transcription factor Nrf2 is restricted in the cytoplasm by binding to its ligand Kelch-like ECH associating protein 1 (Keap1).18 Once exposed to oxidative stress stimulation, Nrf2-Keap1 complexes can be dissociated, the detached Nrf2 translocates into the nucleus to promote heme-oxygenase 1 (HO-1) expression, which involves in the balance of molecules associated with oxidative stress, such as superoxide dismutase (SOD), malonaldehyde (MDA), reactive oxygen species (ROS), and glutathione peroxidase (GSH-Px).19,20 Previously, regulating Nrf2 and its downstream genes could decrease inflammatory factor release, reduce oxidative stress, and maintain anti-apoptotic and survival abilities in the injured kidney.21 Therefore, restraining oxidative stress through activating Nrf2 pathway might be a possible therapeutic strategy targeting sepsis-related AKI.

The evolving evidence indicates that ROS accumulation resulting from abnormal oxidative stress promotes macromolecule peroxidation, and thereby causing cytochrome c-mediated mitochondrial apoptosis.22 Oxidative-stress-related excessive ROS generation contributes to cardiolipin oxidation, and thereby resulting in cytochrome c binding reduction.23 The free cytochrome c in the mitochondria migrates from inter-membrane side to the cytoplasm and touches off apoptotic cascade at the molecular level.24 Therefore, reducing oxidative stress and thus mitochondrial apoptosis induced by oxidative stress may be a potential therapeutic strategy for septic AKI.

Loganin (iridoid glycoside) is the main active ingredient of Corni fructus, which is the fruit of Cornus officinalis Sieb. and has been used to nourish the liver and kidney in the East for fairly long time.25 Loganin has been reported to possess the property of anti-inflammation, antioxidant, anti-diabetes, neuroprotection, and sedation.2630 Liu et al reported that Loganin alleviated diabetic nephropathy by down-regulating MDA level while up-regulating SOD activity in serum and kidney tissues, indicating the antioxidant capacity of Loganin in renal injury models.29 Moreover, Loganin could also play a hepatoprotective role in type 2 diabetic db/db mice by suppressing inflammatory reaction, oxidative stress, and apoptosis, which are the pathogenesis of septic AKI.28 However, whether Loganin can serve as a potential treatment for septic AKI is still unknown. Hence, the following study was conducted to investigate the effects of Loganin on septic AKI and preliminarily explore the related mechanism.

Cecal ligation and puncture (CLP) method was used to induce sepsis in mice. Male C57BL/6 mice at the age of 8 weeks (License number: SCXK (Liaoning, China) 20150001) were obtained from Changsheng biotechnology Co., Ltd. and kept in a standard laboratory environment (12-hour day/night cycle, 4555% humidity, 22 1C). After the adaption, the mice were randomly divided into the following five groups: Sham; CLP; III CLP+L-Loganin (20 mg/kg); CLP+M-Loganin (40 mg/kg); CLP+H-Loganin (80 mg/kg). After anesthesia, the abdomen of mice was open to expose the cecum. The cecal puncture point was the midpoint between the end of the cecum and the ligation point. For the mice in sham group, the cecum was found and returned into the abdominal. After the CLP operation, the mice were given Loganin (20, 40, 80 mg/kg) or equal volume of vehicle by gavage for once. A part of the mice were euthanized under deep anesthesia 24 h after the CLP operation to collect serum and renal cortex for follow-up experiments. The remaining mice were used to calculate the survival rate. All the animal treatment was performed in accordance with the Guide for Care and Use of Laboratory Animals (Eighth Edition) published by the Institute of Laboratory Animal Resources Commission on Life Sciences. All laboratory procedures were approved by The First Affiliated Hospital of Harbin Medical University (No.SYDW2019-229).

The collected serum was used to determine the levels of creatinine and blood urea nitrogen in accordance with the manufacturers instruction (Jiancheng Bioengineering Institute, China).

The fixed kidney tissues were embedded in paraffin, sliced into sections at 5 mm thick, subjected to hematoxylin solution (Solarbio, China), and counterstained with eosin (Sangon, China) in accordance with the manufacturer's instruction. The kidney pathological alterations were observed under light microscopy at 200 X magnification and scored to evaluate the degree of renal injury.

Simply, the above-mentioned kidney sections were blocked in goat serum at room temperature for 15 min, incubated in the primary antibody (Rabbit anti-neutrophil gelatinase-associated lipocalin (NGAL), dilution: 1:50, Affinity, China) at 4C overnight, and treated with HRP IgG antibody (dilution: 1:500, Thermo Fisher, USA) at room temperature for 1 hTo visualize renal NGAL expression, diaminobenzidine slide (Solarbio, China) and hematoxylin (Solarbio, China) were applied according to the manufacturers instruction. Finally, the expression of target protein was observed under light microscopy at 400 X magnification.

Briefly, cell apoptosis in the aforementioned kidney section was detected by TUNEL assay by using the In Situ Cell Death Detection Kit (Roche, Switzerland). After all the procedure required by the manufacturer's instruction, apoptosis was observed under light microscopy at 400 X magnification.

Human kidney proximal tubular (HK2) cells were obtained from Procell Life Science & Technology Co., Ltd. (Wuhan, China) and cultured in DMEM medium (Gibco, USA) in a humidified 5% CO2 incubator at 37C. After adhering to the plates, HK2 cells were exposed to 100 ng/mL lipopolysaccharides (LPS) with or without Loganin (5, 10, 20 M) for 48 h. The treated HK2 cells were collected for the future experiments.

To inhibit the function of AKT or Nrf2, HK2 cells were grown in 10 M LY294002 (a broad-spectrum inhibitor of PI3K) or 10 M ML385 (a specific Nrf2 inhibitor) for 48 h in the presence of 100ng/mL LPS and 20 M Loganin.

Oxidative stress markers, including SOD and GSH-Px activity as well as MDA production in the kidney tissues or HK2 cells, were, respectively, measured by corresponding assay kits (Nanjing Jiancheng Biological Engineering Institute, China). The microplate reader (BioTek, USA) was used to read the optical density (OD) value at 570 nm. ROS production in the kidney tissues or HK2 cells was measured by a ROS assay kit (Nanjing Jiancheng Biological Engineering Institute, China) and flow cytometry (NovoCyte, Aceabio, USA) was used for its quantitative analysis.

Mitochondrial membrane potential detection kit obtained from Beyotime Institute of Biotechnology (Shanghai, China) was used to detect the changes in mitochondrial membrane potential of kidney tissue homogenates or HK2 cells. All the procedures were according to the manufacturers instructions and flow cytometry (NovoCyte, Aceabio, USA) was used for the quantitative analysis.

Fluo-4 AM fluorescent probe was used to detect intracellular calcium mobilization. Briefly, kidney tissue homogenates or HK2 cells were incubated in 4 M Fluo-4 AM (Beyotime Institute of Biotechnology, China) at 37C for 30 min. After washing by PBS for three times, flow cytometry (NovoCyte, Aceabio, USA) was used for quantitative analysis.

Kidney tissues and treated HK2 cells were used to extract total, cytoplasmic, or nuclear protein, and the protein concentration was quantified by the BCA kit (Solarbio, China). The isolated protein was separated by sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE), transferred onto polyvinylidene difluoride (PVDF) membranes and blocked by 5% skimmed milk. Next, the PVDF membranes were subjected to the primary antibodies and horseradish peroxidase (HRP) labelled secondary antibody. Finally, chemiluminescence (ECL) kit was used to visualize the protein, which integrated intensity was calculated by Gel-Pro-Analyzer. The protein levels were presented as relative expression, which was calculated by comparing with the sham or control group. The primary antibodies were as follows: Rabbit anti-cytochrome c; anti-Bax; anti-Bcl-2; anti-AKT, anti-p-AKT (Ser473); anti-Nrf2; anti-HO-1 (dilution: 1:1000, Abclonal, China); anti-cleaved caspase-3 (dilution: 1:1000, Affinity, China).

Data were represented as means standard derivations (SD). The data from three or more groups were analyzed by one-way ANOVA followed by Tukeys multiple comparison tests. P value less than 0.05 was considered statistically significant.

First of all, we detected the survival rate in septic mice with Loganin administration. As shown in Figure 1A, the survival rate was observably elevated in the Loganin-treated septic mice when compared with the model ones (20, 40, 80 mg/kg). The concentrations of serum creatinine and blood urea nitrogen (Figure 1B and C) as well as the expressions of acute kidney injury marker NGAL (Figure 1E) were down-regulated with Loganin treatment (20, 40, 80 mg/kg, p < 0.05). Besides, compared with the septic group, the renal injury score calculated by HE staining was also decreased with Loganin treatment (20, 40, 80 mg/kg, Figure 1D and F, p < 0.05). The above results indicated that Loganin not only possessed the feature of down-regulating mortality but also could relieve AKI in septic mice.

Figure 1 Effects of Loganin on the survival rate, renal function and renal pathological changes in septic mice. (A) The survival rate in septic mice after Loganin treatment. The levels of serum (B) creatinine and (C) blood urea nitrogen in septic mice after Loganin treatment. (D) HE staining (at 200magnification) and (E) immunohistochemistry targeting NGAL (at 400magnification) in kidney tissue of septic mice after Loganin treatment. (F) HE staining score. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ###p < 0.001 vs the sham group and **p < 0.01, ***p < 0.001 vs the CLP group.

Since oxidative stress is considered to be one of the principal elements mediating AKI, we measured the changes in oxidative stress status of kidney tissues after Loganin treatment. As exhibited in Figure 2AD, the activities of SOD and GSH-Px were up-regulated, while the productions of MDA and ROS were down-regulated in the kidney tissue of septic mice after Loganin treatment (20, 40, 80 mg/kg, p < 0.05), indicating Loganin prevented oxidative stress damage. To investigate whether Loganin was involved in mitochondrial dysfunction associated with renal impairment, we detected mitochondrial function in the kidney tissue of septic mice after Loganin treatment. As described in Figure 2E and F, the mitochondrial membrane potential loss and calcium overload were obvious in the kidney tissues after CLP procedure, which could be remitted by Loganin treatment (20, 40, 80 mg/kg, p < 0.05). With the restoration of mitochondrial function after Loganin treatment, the release of cytochrome c from mitochondria to cytoplasm was also decreased (20, 40, 80 mg/kg, Figure 2G and H, p < 0.05). Afterwards, the possible molecular mechanism related oxidative stress status was preliminarily studied. As shown in Figure 2IK, the nuclear translocation of Nrf2 was accelerated in Loganin-treated group (20, 40, 80 mg/kg, p < 0.05). Accompanied by Nrf2 nuclear translocation, HO-1 expression was also increased in kidney tissue of septic mice (20, 40, 80 mg/kg, p < 0.05). The above results indicated that Loganin reduced oxidative stress injury and promoted mitochondrial function recovery in kidney tissue of septic mice, which might be regulated by Nfr2/HO-1 signaling pathway.

Figure 2 Effects of Loganin on oxidative stress and mitochondrial function in kidney tissue of septic mice. (A) SOD activity in kidney tissue of septic mice after Loganin treatment. (B) MDA levels in kidney tissue of septic mice after Loganin treatment. (C) GSH-Px activity in kidney tissue of septic mice after Loganin treatment. (D) ROS production in kidney tissue of septic mice after Loganin treatment. (E) Flow cytometry was used to analyze JC-1 staining in kidney tissue of septic mice after Loganin treatment. (F) Flow cytometry was used to analyze calcium overload in kidney tissue of septic mice after Loganin treatment. Representative Western blot for (G) mitochondrial cytochrome c, (H) cytoplasmic cytochrome c (I) nuclear Nrf2, (J) cytoplasmic Nrf2 and (K) HO-1 in kidney tissues of septic mice after Loganin treatment. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. #p< 0.05, ###p < 0.001 vs the sham group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the CLP group.

Subsequently, apoptosis in kidney tissues was also studied in our work. As suggested by TUNEL staining of the kidney tissue, apoptosis was distinctly increased after CLP procedure, which could be inhibited by Loganin administration (Figure 3A, 20, 40, 80 mg/kg). Consistent with TUNEL staining results, the levels of cleaved caspase-3 and Bax were decreased, whereas Bcl-2 levels were increased in the kidney of septic mice treated with Loganin (Figure 3BD, 20, 40, 80 mg/kg, p < 0.05). Simultaneously, AKT phosphorylation was down-regulated by CLP procedure compared with the sham operation, which was restored by Loganin administration (Figure 3E, 20, 40, 80 mg/kg, p < 0.05). The above results indicated that Loganin inhibited apoptosis in kidney tissue of septic mice, which might be regulated by AKT signaling pathway.

Figure 3 Effects of Loganin on apoptosis in kidney tissue of septic mice. (A) TUNEL staining in kidney tissue of septic mice. Representative Western blot for (B) cleaved caspase-3, (C) Bax, (D) Bcl-2 and (E) p-AKT in kidney tissue of septic mice after Loganin treatment. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ###p < 0.001 vs the sham group and ***p < 0.001 vs the CLP group.

Since the in vivo experiments suggested Loganin could alleviate oxidative stress injury and promoted mitochondrial function recovery in septic kidney tissues, we should prove the beneficial effects of Loganin in vitro. As described in Figure 4AD, SOD and GSH-Px activities were decreased, while MDA and ROS productions were increased in LPS-incubated HK2 cells (p < 0.05). The incubation of Loganin could eliminate this phenomenon (5, 10, 20 M, p < 0.05). In addition, the loss of mitochondrial membrane potential and the overload of calcium, accompanied by cytochrome c release to cytoplasm, were almost reversed by Loganin incubation (Figure 4EJ, 5, 10, 20 M, p < 0.05). Similar to the in vivo results, the abnormal activation of Nrf2/HO-1 signaling pathway was also reversed with Loganin treatment (Figure 4KM, 20 M, p < 0.05), indicating Loganin mitigated oxidative stress and facilitated mitochondrial function recovery possibly via activating Nrf2/HO-1 signaling pathway in LPS-stimulated HK2 cells.

Figure 4 Effects of Loganin on oxidative stress and mitochondrial function in LPS-treated HK2 cells. (A) SOD activity in LPS-stimulated HK2 cells after Loganin treatment. (B) MDA levels in LPS-stimulated HK2 cells after Loganin treatment. (C) GSH-Px activity in LPS-stimulated HK2 cells after Loganin treatment. (D) ROS production in LPS-stimulated HK2 cells after Loganin treatment. (E) and (G) Flow cytometry was used to analyze JC-1 staining in LPS-stimulated HK2 cells after Loganin treatment. (F) and (H) Flow cytometry was used to analyze calcium overload in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (I) mitochondrial cytochrome c, (J) cytoplasmic cytochrome c, (K) nuclear Nrf2, (L) cytoplasmic Nrf2 and (M) HO-1 in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ##p < 0.01, ###p < 0.001 vs the control group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the LPS group.

As shown in Figure 5A, the apoptosis rate of LPS-treated HK2 cells was distinctly increased compared with the control (p < 0.05), which could be lessened by Loganin incubation (5, 10, 20 M, p < 0.05). The incubation of Loganin inhibited caspase-3 splitting and Bax expression, whereas elevated Bcl-2 levels in LPS-stimulated HK2 cells (Figure 5BD, 5, 10, 20 M, p < 0.05). In addition, the aberrant phosphorylation of AKT was also reversed by Loganin treatment in LPS-stimulated HK2 cells (Figure 5E, 20 M, p < 0.05), which was consistent with the results of in vivo experiments, indicating Loganin inhibited LPS-induced HK2 cell apoptosis potentially by regulating AKT signaling pathway.

Figure 5 Effects of Loganin on apoptosis in LPS-treated HK2 cells. (A) Flow cytometry was used to analyze apoptosis in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (B) cleaved caspase-3, (C) Bax, (D) Bcl-2 and (E) p-AKT in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. #p< 0.05, ##p < 0.01, ###p < 0.001 vs the control group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the LPS group.

The aforementioned data suggested both Nrf2/HO-1 and AKT pathway might involve in the protective effects of Loganin on septic AKI. Finally, antagonist targeting the activity of Nrf2 and AKT, ML385 and LY294002 was used to verify the regulating effects of Loganin on Nrf2/HO-1 and AKT signaling pathway in LPS-induced HK2 cells. As shown in Figure 6AD, the antioxidant properties of Loganin were diminished by ML385 or LY294002 application in LPS-treated HK2 cells as indicated by SOD and GSH-Px activities as well as MDA and ROS productions (p < 0.05). Besides, the protective effects of mitochondrial function of Loganin were offset by Nrf2 or AKT suppression (Figure 6EH and J, p < 0.05). Similarly, as indicated by flow cytometry results, its antiapoptotic effects were also weakened by ML385 or LY294002 (Figure 6I, p < 0.05). The above results proved that the protective effects of Loganin were mediated by regulating Nrf2/HO-1 and AKT signaling pathway, but the direct target of Loganin was left to be explored in the future.

Figure 6 Verifying the effects of Loganin on AKT and Nrf2/HO-1 signaling. (A) SOD activity in LPS-stimulated HK2 cells after Loganin treatment. (B) MDA levels in LPS-stimulated HK2 cells after Loganin treatment. (C) GSH-Px activity in LPS-stimulated HK2 cells after Loganin treatment. (D) ROS production in LPS-stimulated HK2 cells after Loganin treatment. (E) and (G) Flow cytometry was used to analyze JC-1 staining in LPS-stimulated HK2 cells after Loganin treatment. (F) and (H) Flow cytometry was used to analyze calcium overload in LPS-stimulated HK2 cells after Loganin treatment. (I) Flow cytometry was used to analyze apoptosis in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (J) mitochondrial cytochrome c and cytoplasmic cytochrome c in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. *p< 0.05 **p < 0.01, ***p < 0.001 vs the indicated group.

Sepsis is a complex inflammatory condition that responded to infection. The complications of sepsis are varied. Acute lung injury (ALI) is the first to appear, whereas AKI is the most serious one resulting in a mortality of 4570% in septic patients.10 In the present work, we aimed to study whether Loganin possessed the nephroprotective effect in septic mice and investigated the underlying mechanisms. Firstly, we found Loganin administration improved the survival rate in septic mice. Meanwhile, AKI was also relieved Loganin administration reflected by reduced oxidative stress, restored mitochondrial function, and inhibited apoptosis in the kidney tissue of septic mice. Besides, Loganin treatment promoted Nrf2 nuclear translocation, activated its downstream molecules, and simultaneously facilitated AKT phosphorylation in the kidney of septic mice and LPS-treated HK2 cells. Meanwhile, the beneficial effects of Loganin could be crippled by Nrf2 antagonist ML385 or PI3K inhibitor LY294002, indicating Nrf2/HO-1 and AKT signaling pathway activation is essential for the nephroprotective effects of Loganin in septic models. Above all, the present work suggested that Loganin treatment acquired protective effects in septic AKI through reducing oxidative stress and apoptosis via regulating Nrf2/HO-1 and AKT signaling pathway.

The sepsis model was established by using the CLP method, which was supposed to be the gold in vivo model for the experimental sepsis.31 It is well accepted that CLP method can simulate clinical symptoms of sepsis more practically than endotoxin or bacteria injection method.32 Hence, CLP method was adopted in our work to evaluate the therapeutic effect of Loganin on septic AKI and its underlying mechanisms. In the present study, the degree of kidney injury was analyzed after CLP procedure in mice. Consistent with previous research,33 we found the levels of serum creatinine, blood urea nitrogen, and AKI marker NGAL expression were significantly increased, indicating the septic AKI models were successfully imitated. As the exhibited results, the survival rate in septic mice with Loganin treatment was distinctly increased, indicating the potential protection of Loganin in sepsis. Afterwards, the reduction in serum creatinine concentration, blood urea nitrogen level, and renal NGAL expression was observed in septic mice with Loganin treatment, suggesting the palliative effects of Loganin on sepsis-related AKI. The in vivo data preliminarily confirmed the renal protective effects of Loganin in septic mice.

It is well understood that excessive oxidative stress is appeared to participate in the process of kidney injury resulting from multiple factors, including diabetes and sepsis.34,35 The influence of abnormal oxidative stress in the kidney tissue of CLP-treated mice should not be belittled. The previous studies have reported that Loganin possesses the ability to restore the balance of oxidative stress in diabetic nephropathy animal models by down-regulating MDA level while up-regulating SOD activity.29 Besides, Loganin also could remit inflammatory reaction, oxidative stress, and apoptosis in the livers of type 2 diabetic db/db mice models.28 Based on these backgrounds, we preliminarily inferred that Loganin might play the protective role of renal injury in septic mice by alleviating oxidative stress and experiments were carried out. In our study, we found that the CLP procedure induced SOD and GSH-Px activity decline while MDA and ROS production rise in the kidney tissue, which could be restored by the single gavage of Loganin. Similar to previous studies, the results reminded that the anti-oxidant effect of Loganin might be the basis of its renal protection.36,37 The evidence presented supported the strong relationship between mitochondrial dysfunction and abundant oxidative stress.38 In the work, we found the mitochondrial membrane potential loss and calcium overload were obvious in the kidney tissue after CLP procedure, indicating mitochondrial dysfunction occurred in the septic kidney. Not surprisingly, improved mitochondrial function reflected by elevated mitochondrial membrane potential and decreased calcium overload in the septic kidney was concurrently remitted by Loganin. The above results indicated that the anti-oxidation and mitochondrial function protection might be the basis for nephroprotective effects of Loganin.

Except for providing energy for cells, mitochondria are also involved in differentiation information transmission and apoptosis.39 Given that apoptosis, an important factor contributing to AKI progression, is worthy to be studied. Under the pathological conditions, cytochrome c in the inter-membrane space of mitochondria was released to cytoplasm, recruited apoptosome formation, and thereby inducing pathological apoptosis.40 Our data showed CLP surgery caused cytochrome c migration from mitochondrial inter-membrane space to the cytoplasm, which could be reversed by Loganin treatment. To evaluate apoptosis occurrence in the kidney, TUNEL staining and apoptosis-related protein expressions (cleaved caspase-3, Bax, and Bcl-2) were detected. Fortunately, apoptosis could be inhibited by Loganin treatment in vivo and in vitro in a dose-dependent form, indicating the anti-apoptosis effects of Loganin.

Several lines of evidence showed that Nrf2 is a redox-sensitive transcription factor modulating the transcription of oxidative stress-associated genes.41 Meanwhile, the salutary effects of Loganin in type 2 diabetic db/db might be mediated by Nrf2 introduction to the nuclei.28 Therefore, we speculated that Loganin might also alleviate septic AKI by activating Nrf2-related signalling pathway. Fortunately, we found that Loganin administration promoted Nrf2 nuclear translocation and HO-1 activation. Next, the in vitro studies were implemented to confirm whether Nrf2/HO-1 signaling was involved in the beneficial effect of Loganin in LPS-treated HK2 cells. Similar to the experimental results in vivo, Loganin alleviated oxidative stress injury, restored mitochondrial function, and inhibited apoptosis in LPS-stimulated HK2 cells, which could be diminished by the specific Nrf2 inhibitor ML385. Although it has not been confirmed that Nrf2 is a direct target of Loganin, our experimental results show that Nrf2/HO-1 signaling pathway is closely related to its protective effect. The key point regulating apoptosis, AKT phosphorylation, was also measured in our work. Analogously, Loganin increased the phosphorylation of AKT in the injured kidney and LPS-stimulated HK2 cells. Besides, the salutary effects also diminished in vitro by LY294002, the broad-spectrum inhibitor of PI3K, indicating AKT pathway is associated with the property of Loganin. According to the validating results of in vitro experiments, our study suggested that Loganin alleviated septic AKI through regulating oxidative stress injury, mitochondrial function, and apoptosis in tubular epithelial cells, which might attribute to the involvement of AKT and Nrf2/HO-1 signaling. However, the direct target of Loganin remained to be explored, which was the focus of our future work.

Above all, our work suggested that Loganin possessed the property to remit AKI in septic mice by regulation of oxidative stress mitochondrial function and apoptosis tubular epithelial cells via AKT and Nrf2/HO-1 signaling, which might provide a new therapeutic strategy for septic AKI.

AKI, acute kidney injury; CLP, cecal ligation and puncture; GSH-Px, glutathione peroxidase; LPS, lipopolysaccharides; HO-1, heme-oxygenase 1; Keap1, Kelch-like ECH associating protein 1; MDA, malonaldehyde; Nrf2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase.

This research was supported by grants from the National Natural Science Foundation of China (No. 81571871 and 81770276) and Nn10 program of Harbin Medical University Cancer Hospital.

The authors declared no conflicts of interest for this work.

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11. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest. 2011;121(11):42104221. doi:10.1172/JCI45161

12. Opatrilova R, Kubatka P, Caprnda M, et al. Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches. Acta Ophthalmol. 2018;96(3):222231. doi:10.1111/aos.13384

13. Fei L, Jingyuan X, Fangte L, et al. Preconditioning with rHMGB1 ameliorates lung ischemia-reperfusion injury by inhibiting alveolar macrophage pyroptosis via the Keap1/Nrf2/HO-1 signaling pathway. J Transl Med. 2020;18(1):301. doi:10.1186/s12967-020-02467-w

14. Garrido-Pascual P, Alonso-Varona A, Castro B, Burn M, Palomares T. H2O2-preconditioned human adipose-derived stem cells (HC016) increase their resistance to oxidative stress by overexpressing Nrf2 and bioenergetic adaptation. Stem Cell Res Ther. 2020;11(1):335. doi:10.1186/s13287-020-01851-z

15. Yifan Z, Benxiang N, Zheng X, et al. Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury. Oxid Med Cell Longev. 2020;2020:6428498. doi:10.1155/2020/6428498

16. Luo J, Li X, Li X, et al. Selenium-Rich Yeast protects against aluminum-induced peroxidation of lipide and inflammation in mice liver. BioMetals. 2018;31(6):10511059. doi:10.1007/s10534-018-0150-2

17. Diao C, Chen Z, Qiu T, et al. Inhibition of PRMT5 Attenuates Oxidative Stress-Induced Pyroptosis via Activation of the Nrf2/HO-1 Signal Pathway in a Mouse Model of Renal Ischemia-Reperfusion Injury. Oxid Med Cell Longev. 2019;2019:2345658. doi:10.1155/2019/2345658

18. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89116. doi:10.1146/annurev.pharmtox.46.120604.141046

19. Zhou X, Liu Z, Ying K, et al. WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling. Oxid Med Cell Longev. 2020;2020:7950457. doi:10.1155/2020/7950457

20. Irazabal MV, Torres VE. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 2020;9(6):1342. doi:10.3390/cells9061342

21. Zhang X, Zhu Y, Zhou Y, Fei B. Activation of Nrf2 Signaling by Apelin Attenuates Renal Ischemia Reperfusion Injury in Diabetic Rats. Diabetes Metab Syn Obesity. 2020;13:21692177. doi:10.2147/DMSO.S246743

22. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913922. doi:10.1007/s10495-007-0756-2

23. Dodd-O JM, Welsh LE, Salazar JD, et al. Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. Am J Physiol. 2004;287(2):H92736.

24. Ruffolo SC, Breckenridge DG, Nguyen M, et al. BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ. 2000;7(11):11011108. doi:10.1038/sj.cdd.4400739

25. Lee KY, Sung SH, Kim SH, Jang YP, Oh TH, Kim YC. Cognitive-enhancing activity of loganin isolated from Cornus officinalis in scopolamine-induced amnesic mice. Arch Pharm Res. 2009;32(5):677683. doi:10.1007/s12272-009-1505-6

26. Shi R, Han Y, Yan Y, et al. Loganin exerts sedative and hypnotic effects via modulation of the serotonergic system and GABAergic neurons. Fron Pharmacol. 2019;10:409. doi:10.3389/fphar.2019.00409

27. Li Y, Li Z, Shi L, et al. Loganin inhibits the inflammatory response in mouse 3T3L1 adipocytes and mouse model. Int Immunopharmacol. 2016;36:173179. doi:10.1016/j.intimp.2016.04.026

28. Park CH, Tanaka T, Kim JH, et al. Hepato-protective effects of loganin, iridoid glycoside from Corni Fructus, against hyperglycemia-activated signaling pathway in liver of type 2 diabetic db/db mice. Toxicology. 2011;290(1):1421. doi:10.1016/j.tox.2011.08.004

29. Liu K, Xu H, Lv G, et al. Loganin attenuates diabetic nephropathy in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of advanced glycation end products. Life Sci. 2015;123:7885. doi:10.1016/j.lfs.2014.12.028

30. Kim H, Youn K, Ahn M-R, et al. Neuroprotective effect of loganin against A 2535 -induced injury via the NF-B-dependent signaling pathway in PC12 cells. Food Funct. 2015;6(4):11081116. doi:10.1039/C5FO00055F

31. Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011;19(4):198208. doi:10.1016/j.tim.2011.01.001

32. Doi K, Leelahavanichkul A, Yuen PST, Star RA. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest. 2009;119(10):28682878. doi:10.1172/JCI39421

33. Sung P-H, Lo Chang C, Tsai T-H, et al. Apoptotic adipose-derived mesenchymal stem cell therapy protects against lung and kidney injury in sepsis syndrome caused by cecal ligation puncture in rats. Stem Cell Res Therapy. 2013;4(6):155. doi:10.1186/scrt385

34. Kim JY, Leem J, Hong HL. Protective effects of spa0355, a thiourea analogue, against lipopolysaccharide-induced acute kidney injury in mice. Antioxidants. 2020;9:113.

35. Chen X, Liu W, Xiao J, et al. FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury. FASEB J. 2020;34(10):1330013316. doi:10.1096/fj.202000783R.

36. Xia S, Lin H, Liu H, et al. Honokiol Attenuates Sepsis-Associated Acute Kidney Injury via the Inhibition of Oxidative Stress and Inflammation. Inflammation. 2019;42(3):826834. doi:10.1007/s10753-018-0937-x

37. Zhao H, Liu Z, Shen H, Jin S, Zhang S. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress. Eur J Pharm. 2019;2019:9299. doi:10.1016/j.ejphar.2016.04.006

38. Ge M, Fontanesi F, Merscher S, Fornoni A. The Vicious Cycle of Renal Lipotoxicity and Mitochondrial Dysfunction. Front Physiol. 2020;11:732.

39. Clavier A, Rincheval-Arnold A, Colin J, Mignotte B, Gunal I. Apoptosis in Drosophila: which role for mitochondria? Apoptosis. 2016;21:239251.

40. Liang S, Sun K, Wang Y, et al. Role of Cyt-C/caspases-9,3, Bax/Bcl-2 and the FAS death receptor pathway in apoptosis induced by zinc oxide nanoparticles in human aortic endothelial cells and the protective effect by alpha-lipoic acid. Chem Biol Interact. 2016;258:4051.

41. Feng X, Guan W, Zhao Y, et al. Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3/Nrf2 signaling pathway. J Cell Physiol. 2019;234:1899419009.

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[Full text] Loganin Attenuates Septic Acute Renal Injury with the Participation of | DDDT - Dove Medical Press

Introduction

Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.13 Hallucinations are also common.13 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5

Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8

We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.

Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.531.02 mg/dL) and 8 mL/min (normal range: 80180 mL/min), respectively. He was diagnosed with BenceJones protein -type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and BenceJones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of BenceJones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patients renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.

Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification 200). (B) Periodic acid-Schiff stain (magnification 400).

On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patients blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysiscell counts 1/L, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dLrevealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, 9 points indicate high probability for adverse reactions and 58 points indicate probability for adverse reactions.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.

Table 1 Results of the Patients Admission Blood Tests

Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.

The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 45 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.

We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.

In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited BenceJones proteinuria. Increased excretion of BenceJones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.

In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with BenceJones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.

In conclusion, among patients with multiple myeloma with BenceJones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.

ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.

There is no funding to report.

The authors declare that they have no conflicts of interest.

1. Rashiq S, Briewa L, Mooney M, Giancarlo T, Khatib R, Wilson FM. Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med. 1993;234:507511. doi:10.1111/j.1365-2796.1993.tb00785.x

2. Asahi T, Tsutsui M, Wakasugi M, et al. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009;16:457460. doi:10.1111/j.1468-1331.2008.02527.x

3. Adair JC, Gold M, Bond RE. Acyclovir neurotoxicity: clinical experience and review of the literature. South Med J. 1994;87:12271231. doi:10.1097/00007611-199412000-00006

4. Chowdhury MA, Derar N, Hasan S, Hinch B, Ratnam S, Assaly R. Acyclovir-induced neurotoxicity: a case report and review of literature. Am J Ther. 2016;23:e941e943. doi:10.1097/MJT.0000000000000093

5. Das V, Peraldi MN, Legendre C. Adverse neuropsychiatric effects of cytomegalovirus prophylaxis with valaciclovir in renal transplant recipients. Nephrol Dial Transplant. 2006;21:13951401. doi:10.1093/ndt/gfk031

6. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 Phase III trial. J Clin Oncol. 2010;28:46214629. doi:10.1200/JCO.2009.27.9158

7. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:47844790. doi:10.1200/JCO.2007.14.9641

8. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906917. doi:10.1056/NEJMoa0801479

9. UpToDate. Valaciclovir: drug information. Available from: https://www.uptodate.com/contents/valacyclovir-drug-information?search=valacyclovir&topicRef=8337&source=see_link#F50991799. Accessed January 17, 2021.

10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239245. doi:10.1038/clpt.1981.154

11. Sacchetti D, Alawadhi A, Albakour M, Rapose A. Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma. BMJ Case Rep. 2014;2014:bcr2013201941. doi:10.1136/bcr-2013-201941

12. Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2011;8:4351. doi:10.1038/nrneph.2011.168

13. Leung N, Rajkumar SV. Renal manifestations of plasma cell disorders. Am J Kidney Dis. 2007;50:155165. doi:10.1053/j.ajkd.2007.05.007

14. Izumo A, Sakai K, Tamura Y. Acyclovir-induced neurotoxicity in an elderly patient: report of a case. J Japan Soc Emerg Med. 2017;20:763768.

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[Full text] Encephalopathy Induced by Preventive Administration of Acyclovir in a | IJGM - Dove Medical Press

Joint inflammation can lead to swollen, painful joints. Depending on the cause, it can affect one particular joint or be more widespread, affecting multiple joints throughout the body.

Inflammation is the bodys normal immune response to an injury, infection, or irritant. Allergies, wounds, and diseases can all cause inflammation. The most common causes of joint inflammation are injuries and inflammatory arthritis.

Pain and inflammation resulting from injuries usually resolve, but inflammatory arthritis is a chronic condition that may get worse with time. Keep reading to learn more.

Joint inflammation occurs when the immune system or damaged tissue releases chemicals that cause swelling and other symptoms in a joint. It can affect just one joint, such as when a person sustains an injury. However, certain medical conditions can lead to multiple instances of joint inflammation throughout the body.

When a joint is inflamed, the blood vessels around it dilate to allow more blood to reach it. White blood cells, which play a crucial role in the bodys immune response, rush to the inflamed site, where they work to fight any infection or irritant.

This response leads to inflammation in this area. The joint may feel hot or painful, and the inflammation may intensify the pain of an underlying injury or infection.

In the short term, inflammation helps the body fight off dangerous invaders. However, chronic inflammation can damage the joint.

The most common causes of joint inflammation are:

An injury to a joint usually causes localized inflammation. However, it can sometimes cause inflammation in several joints if they are very close together. For example, if a person injures their foot, they might have joint inflammation in several toes.

Swelling is the bodys natural response to an injury. Inflammation helps the body deliver nutrients and white blood cells to an injured joint to fight off infection and promote healing.

However, inflammation is painful, and intense swelling may actually slow healing. Anyone who experiences inflammation that is serious enough to interfere with everyday functioning should see a doctor.

Arthritis is a group of conditions that affect joint health. Inflammatory forms of arthritis cause inflammation in the joints. Most types of inflammatory arthritis are chronic, progressive conditions. They may begin in one joint but eventually progress to other joints.

Some examples of inflammatory arthritis include:

Many types of inflammatory arthritis are autoimmune diseases, which means that they appear when the bodys immune system mistakenly attacks healthy tissue.

However, some infections can also cause inflammatory arthritis. Septic arthritis happens when a joint becomes infected. Sometimes, an infection in another area of the body travels through the bloodstream to a joint.

This type of inflammation is not chronic and usually gets better with treatment. Without quick treatment, though, there is a risk of permanent damage to the joints and bones.

Learn more about inflammatory arthritis here.

Some symptoms of joint inflammation include:

When the symptoms appear following an injury, inflammation is usually just a short-term response to the injury.

People who notice ongoing inflammation or pain may have arthritis. Joint pain that occurs with a fever or following an infection may signal a joint infection that requires immediate medical treatment.

The right treatment for inflammation depends on the cause. Some minor injuries will improve on their own with rest and time. More serious injuries may require medical treatment or even surgery.

People with a bacterial infection often need antibiotics. In severe cases, they may need to stay in the hospital.

For serious injuries and chronic inflammation, these medical treatments may help:

Several home remedies can help with most types of inflammation, regardless of the cause:

A person should contact a doctor or healthcare provider if:

It is necessary to go to the emergency room or call 911 if:

Inflammation comes in many forms, and it can affect a single joint or many joints throughout the body.

Short-term joint inflammation from an injury usually goes away on its own.

While chronic inflammation can be difficult to treat and may get worse with time, various medications can help. A person can contact a doctor for help managing all forms of inflammation.

Originally posted here:
Joint inflammation: Causes, treatment, and symptoms - Medical News Today

New smart stem cells show a promising power to heal.

Researchers have reprogrammed human fat cells into adaptive smart stem cells that can lie dormant in the body until they are needed to heal various tissues. They demonstrated the cells' effectiveness at healing damaged tissue in a mouse study.

To create the smart stem cells, the team from UNSW Sydney exposed human fat cells to a compound mixture. After about three and a half weeks, the cells lost their original identity and began acting like stem cells, or iMS (induced multipotent stem cells).

"The stem cells acted like chameleons. They followed local cues to blend into the tissue that required healing."

"The stem cells we've developed can adapt to their surroundings and repair a range of damaged tissues," said UNSW hematologist John Pimanda, and co-author of the study, which they published in Science Advances.

"To my knowledge, no one has made an adaptive human multipotent stem cell before. This is uncharted territory."

Next, they injected the experimental iMS cells into healthy mice to see how the cells would respond. The cells remained dormant for some time, but they activated when the mouse was injured. Because of the cells' regenerative ability to act as "smart stem cells," they transformed themselves into whatever tissue was needed to heal the injured mouse --- like bone tissue, heart, or skin.

"The stem cells acted like chameleons," said Avani Yeola, lead author on the study at UNSW Medicine & Health. "They followed local cues to blend into the tissue that required healing."

All cells in a human body contain the same DNA. To differentiate between tissues, like a skin cell versus a bone cell, the cells only use a small portion of their total DNA. The rest of the DNA is shut down naturally by local modifications.

"The idea behind our approach was to reverse these modifications," said Pimanda. "We wanted the cells to have the option of using that part of the DNA if there was a signal from outside the cell."

Tissue-specific stem cells, like those that are restricted to becoming parts of the liver or lung, are limiting. But smart stem cells that can respond to their environment and become any tissue, like multipotent stem cells, will have many uses.

In the future, doctors could take a patient's fat cells, incubate them with the compound, and inject them into the patient to heal heart damage or trauma injuries.

But applications like this could be a long way off. The team needs to do much more research to prove this is safe in humans for different kinds of trauma before it becomes a real therapy.

We'd love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at [emailprotected]

Continued here:
Smart Stem Cells Made From Fat Have the Power to Heal - Freethink

Machine learning for medicine

Small-molecule screens aimed at identifying therapeutic candidates traditionally search for molecules that affect one to several outputs at most, limiting discovery of true disease-modifying drugs. Theodoris et al. developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell disease model of a common form of heart disease involving the aortic valve. Gene network correction by the most efficacious therapeutic candidate generalized to primary aortic valve cells derived from more than 20 patients with sporadic aortic valve disease and prevented aortic valve disease in vivo in a mouse model.

Science, this issue p. eabd0724

Determining the gene-regulatory networks that drive human disease allows the design of therapies that target the core disease mechanism rather than merely managing symptoms. However, small molecules used as therapeutic agents are traditionally screened for their effects on only one to several outputs at most, from which their predicted efficacy on the disease as a whole is extrapolated. In silico correlation of disease network dysregulation with pathways affected by molecules in surrogate cell types is limited by the relevance of the cell types used and by not directly testing compounds in patient cells.

In principle, mapping the architecture of the dysregulated network in disease-relevant cells differentiated from patient-derived induced pluripotent stem cells (iPSCs) and subsequent screening for small molecules that broadly correct the abnormal gene network could overcome this obstacle. Specifically, targeting normalization of the core regulatory elements that drive the disease process, rather than correction of peripheral downstream effectors that may not be disease modifying, would have the greatest likelihood of therapeutic success. We previously demonstrated that haploinsufficiency of NOTCH1 can cause calcific aortic valve disease (CAVD), the third most common form of heart disease, and that the underlying mechanism involves derepression of osteoblast-like gene networks in cardiac valve cells. There is no medical therapy for CAVD, and in the United States alone, >100,000 surgical valve replacements are performed annually to relieve obstruction of blood flow from the heart. Many of these occur in the setting of a congenital aortic valve anomaly present in 1 to 2% of the population in which the aortic valve has two leaflets (bicuspid) rather than the normal three leaflets (tricuspid). Bicuspid valves in humans can also be caused by NOTCH1 mutations and predispose to early and more aggressive calcification in adulthood. Given that valve calcification progresses with age, a medical therapy that could slow or even arrest progression would have tremendous impact.

We developed a machine-learning approach to identify small molecules that sufficiently corrected gene network dysregulation in NOTCH1-haploinsufficient human iPSC-derived endothelial cells (ECs) such that they classified similar to NOTCH1+/+ ECs derived from gene-corrected isogenic iPSCs. We screened 1595 small molecules for their effect on a signature of 119 genes representative of key regulatory nodes and peripheral genes from varied regions of the inferred NOTCH1-dependent network, assayed by targeted RNA sequencing (RNA-seq). Overall, eight molecules were validated to sufficiently correct the network signature such that NOTCH1+/ ECs classified as NOTCH1+/+ by the trained machine-learning algorithm. Of these, XCT790, an inverse agonist of estrogen-related receptor (ERR), had the strongest restorative effect on the key regulatory nodes SOX7 and TCF4 and on the network as a whole, as shown by full transcriptome RNA-seq.

Gene network correction by XCT790 generalized to human primary aortic valve ECs derived from explanted valves from >20 patients with nonfamilial CAVD. XCT790 was effective in broadly restoring dysregulated genes toward the normal state in both calcified tricuspid and bicuspid valves, including the key regulatory nodes SOX7 and TCF4.

Furthermore, XCT790 was sufficient to prevent as well as treat already established aortic valve disease in vivo in a mouse model of Notch1 haploinsufficiency on a telomere-shortened background. XCT790 significantly reduced aortic valve thickness, the extent of calcification, and echocardiographic signs of valve stenosis in vivo. XCT790 also reduced the percentage of aortic valve cells expressing the osteoblast transcriptional regulator RUNX2, indicating a reduction in the osteogenic cell fate switch underlying CAVD. Whole-transcriptome RNA-seq in treated aortic valves showed that XCT790 broadly corrected the genes dysregulated in Notch1-haploinsufficient mice with shortened telomeres, and that treatment of diseased aortic valves promoted clustering of the transcriptome with that of healthy aortic valves.

Network-based screening that leverages iPSC and machine-learning technologies is an effective strategy to discover molecules with broadly restorative effects on gene networks dysregulated in human disease that can be validated in vivo. XCT790 represents an entry point for developing a much-needed medical therapy for calcification of the aortic valve, which may also affect the highly related and associated calcification of blood vessels. Given the efficacy of XCT790 in limiting valve thickening, the potential for XCT790 to alter the progression of childhood, and perhaps even fetal, valve stenosis also warrants further study. Application of this strategy to other human models of disease may increase the likelihood of identifying disease-modifying candidate therapies that are successful in vivo.

A gene networkbased screening approach leveraging human disease-specific iPSCs and machine learning identified a therapeutic candidate, XCT790, which corrected the network dysregulation in genetically defined iPSC-derived endothelial cells and primary aortic valve endothelial cells from >20 patients with sporadic aortic valve disease. XCT790 was also effective in preventing and treating a mouse model of aortic valve disease.

Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

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Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease - Science

Opthalmology Pacs Market Scenario 2021: Latest AnalysisThis detailed market study covers Opthalmology Pacs Market growth potentials which can assist the stakeholders to understand key trends and prospects in the Opthalmology Pacs market identifying the growth opportunities and competitive scenarios. The report also focuses on data from different primary and secondary sources and is analyzed using various tools. It helps to gain insights into the markets growth potential, which can help investors identify scope and opportunities. The analysis also provides details of each segment in the global Opthalmology Pacs market

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The current trends in the Opthalmology Pacs market combined with a variety of growth opportunities, key drivers, restraints, challenges, and other critical aspects have been clearly set out in the Opthalmology Pacs market report. Additionally, the report takes into account various market dynamics, which in turn creates a variety of development prospects for the major players in the Opthalmology Pacs industry.

The global Opthalmology Pacs market is illustrated by key results:1.The overview, scope, definition and the factors driving or impaling the market discussed strategically.2.Opthalmology Pacs full analysis, DROCs analysis, Competitor analysis with the key players introduction and revenue generated.3.Segments and Sub-segments full analysis with correct market estimations that will help diversify the market with ease.4.Global Opthalmology Pacs market report advices on the report values and the details that are focused to grow in the industry and reviews the challenges faced in the market during the pandemic.

Some of the Important and Key Players of the Global Opthalmology Pacs Market:

Topcon Corporation, IBM corporation, Carl Zeiss Meditec AG, EyePACS, Heidelberg Engineering and more.

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Detailed SWOT analysis of these players has also been included in the Opthalmology Pacs market report to determine the threats and opportunities faced by them while operating in the Opthalmology Pacs industry. The Opthalmology Pacs market 2021 industry research study further analyzes the global Opthalmology Pacs industry in terms of revenue and has presented the historical data and forecast figures with the help of tables, charts, and infographics. The Opthalmology Pacs report also provides a comprehensive analysis of the global Opthalmology Pacs market with the help of several analytical tools and helps in determining the growth prospects and opportunities of the Opthalmology Pacs industry. It also helps in understanding the major factors that affect the structure and profitability of the global Opthalmology Pacs industry.

Opthalmology Pacs Market SegmentationType Analysis of Opthalmology Pacs Market:

By End-Use, market is segmented into:

HospitalsAmbulatory Surgical Center (ASCS) & Specialty ClinicsOthersBy Type, market is segmented into:

Standalone PACSIntegrated PACSBy Delivery Model, market is segmented into:

Cloud/ web based modelsOn-premise modelsOthers

Table of Contents1.Opthalmology Pacs Market Overview: Market Segment, Market Size, Sales and Growth, Price by Type2.Global Opthalmology Pacs Market Competition by Company/Manufacturers: Market Share, Price, Base Distribution, Sales Area, Product by Company and Opthalmology Pacs Market Competitive Situation and Trends, Opthalmology Pacs Market Share of Top 5 and Top 10 Players3.Opthalmology Pacs Company Profiles and Sales Data: Company/Manufacturers Basic Information, Manufacturing Base and Competitors, Opthalmology Pacs Product Category, Application and Specification, Opthalmology Pacs Manufacturers Sales, Revenue, Price and Gross Margin(2018-2021) and Main Business Overview4.Opthalmology Pacs Market Status and Outlook by Regions (North America, Europe, Asia-Pacific, South America, Middle East, and Africa): Market Size and CAGR, Sales and Revenue, Sales Market Share by Regions5.Opthalmology Pacs Application: Opthalmology Pacs Product Segment, Sales and Market Share by Application6.Global Opthalmology Pacs Market Forecast: Sales, Revenue, Growth Rate Forecast (2021-2027) and Forecast by Regions, by Type, by Application7.Opthalmology Pacs Upstream Raw Materials8.Marketing Strategy Analysis, Distributors9.Research Findings and Conclusion10.Methodology/Research Approach

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New Jersey, United States,- Verified Market Reports has recently published a market research report titled, Connective Tissue Growth Factor Market Size, Status and Forecast 2021-2027. Analysts have used primary and secondary research methodologies to determine the path of the market. The data includes historic and forecast values for a well-rounded understanding. It is a phenomenal compilation of important studies that explore the competitive landscape, segmentation, geographical expansion, and revenue, production, and consumption growth of the Connective Tissue Growth Factor market. Players can use the accurate market facts and figures and statistical studies provided in the report to understand the current and future growth of the Connective Tissue Growth Factor market.

This report includes the assessment of various drivers, government policies, technological innovations, upcoming technologies, opportunities, market risks, restraints, market barriers, challenges, trends, competitive landscape, and segments which gives an exact picture of the growth of the Connective Tissue Growth Factor market.

Competitive analysis:

Competitor analysis is one of the best sections of the report that compares the progress of leading players based on crucial parameters, including market share, new developments, global reach, local competition, price, and production. From the nature of competition to future changes in the vendor landscape, the report provides an in-depth analysis of the competition in the Connective Tissue Growth Factor market.

The report covers the following key players in the Connective Tissue Growth Factor Market:

Segmentation of Connective Tissue Growth Factor Market:

The Connective Tissue Growth Factor market report has been segmented into Types, Applications, and End-users. It provides the market share of each segment participating in the Connective Tissue Growth Factor market. Companies operating in this market have a thorough understanding of the fastest-growing segment. That way, they can identify their target customers and allocate their resources wisely. Segment analysis helps create the perfect environment for engagement, customer loyalty, and acquisition. This section will help companies operating in the Connective Tissue Growth Factor market identify key areas of intervention while making their strategic investments.

By the product type, the market is primarily split into:

BLR-200 IB-DMD OLX-201 PBI-4050s Hypertrophic Scars Opthalmology Genetic Disorders Liver Fibrosiss Regional and Country-level Analysis The Connective Tis

By the application, this report covers the following segments:

BLR-200 IB-DMD OLX-201 PBI-4050s Segment by Application the Connective Tissue Growth Factor market is segmented into Hypertrophic Scars Opthalmology Genetic Disorders

Connective Tissue Growth Factor Market Report Scope

Regional analysis:

The Connective Tissue Growth Factor market report covers the analysis of various regions such as North America, Europe, Asia-Pacific, Latin America, Middle East, and Africa. Market trends change by region and result in changes due to their physical environment. The report, therefore, covers key regions with sales, revenue, market share and growth rate of Connective Tissue Growth Factor in these regions from 2020 to 2027. It analyzes the region with the highest market share as well as the fastest growing region of the Connective Tissue Growth Factor market. The report by region is then broken down into analyzes at the country level. For example, North America is divided into the United States and Canada. Europe includes the UK, France, and Germany, followed by APAC, which includes countries like China, India, and Japan. Latin America is made up of countries like Mexico and Brazil, and the MEA countries included in the Connective Tissue Growth Factor market are the GCC countries and South Africa.

Research methodology:

The research methodology used to aggregate the Connective Tissue Growth Factor market report involves a combination of primary and secondary research approaches. The research team starts desk research from various sources to collect data on the Connective Tissue Growth Factor market. The report combined its data from reliable secondary sources such as company annual reports, industry publications, news, government websites and more. In addition, the primary research includes interviews to get first-hand market intelligence. Our analysts interviewed several C-level executives, decision-makers, board members, key opinion leaders, industry veterans and other stakeholders in the Connective Tissue Growth Factor market. All of the data is then combined and presented in a report to enable a deep understanding and analysis of the Connective Tissue Growth Factor market.

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In the field of medical science, lasers are used in specific wavelengths of light, from red to near infrared, in order to create beneficial and therapeutic effects. Such kind of results include improved time of healing, reduction in pain, increased blood circulation and a reduction in swelling. A trend in the laser therapy devices market includes a shift towards pain-free and non-invasive procedures. The procedures related to medical aesthetics, both invasive and non-invasive, are becoming increasingly popular amongst the younger population. These procedures using lasers have replaced the traditional surgery and they give superior results with minimum complications. Moreover, non-invasive laser procedures like removal of scars, resurfacing of the skin, facelifts, laser hair removal and liposuction are becoming increasingly popular as they promote a younger looking appearance with minimal side effects.

Global Market Research Report Overview on Laser Therapy Devices @https://www.futuremarketinsights.com/reports/laser-therapy-devices-market

The global laser therapy devices market is slated to touch a value of about US$ 1,900 Mn in the year 2022 and display a moderate CAGR during the assessment period.

4 Forecast Highlights on Global Laser therapy devices Market

As per the forecast of Future Market Insights, the gas laser segment is slated to touch a value of more than US$ 470 Mn in the year 2022. This represents a robust CAGR during the assessment period of 2017-2022. The gas laser segment is estimated to account for nearly one-fourth of the revenue share of the device type segment by the year 2017 and is forecasted to gain market share by 2022 over 2017.

As per the forecast of Future Market Insights, the specialized clinics segment will reach a value of about US$ 825 Mn in the year 2017. This represents a moderate CAGR growth during the forecast period. The specialized clinics segment is forecasted to account for more than half of the total revenue share of the end user segment by the end of the year 2017 and is expected to gain in market share by 2022 as compared with the year 2017.

As per the forecast of Future Market Insights, the ophthalmology segment is slated to reach a value of more than US$ 560 Mn in 2022. The ophthalmology segment is expected to gain market share by the end of the year 2022. The largest share is contributed by the North America region in the ophthalmology segment.

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Future Market Insights forecasts the United States laser therapy devices market to exhibit a compound annual growth rate (CAGR) of more than 4% from 2017 to 2022.

The report has also included the profiles of some of the leading companies in the laser therapy devices market like Thermo Fisher Scientific, Inc., Lumenis Ltd., Boston Scientific Corporation, Danaher Corporation, IPG Photonics Corporation, Alma Lasers, Ltd., Coherent, Inc., Fotona d.d., Biolitec AG and Hologic Inc.

1. Global Laser Therapy Devices Market Executive Summary

2. Global Laser Therapy Devices Market Overview

2.1. Introduction

2.1.1. Global Laser Therapy Devices Market Taxonomy

2.1.2. Global Laser Therapy Devices Market Definition

2.2. Global Laser Therapy Devices Market Size (US$ Mn) and Forecast, 2012-2022

2.2.1. Global Laser Therapy Devices Market Y-o-Y Growth

2.3. Global Laser Therapy Devices Market Dynamics

View Report Table of Contents, Figures, and Tables@https://www.futuremarketinsights.com/reports/laser-therapy-devices-market/toc

2.4. Supply Chain

2.5. Cost Structure

2.6. Regulations

2.7. Procedure Numbers By Region

2.8. Pricing Analysis

2.9. Key Participants Market Presence (Intensity Map) By Region

3. Global Laser Therapy Devices Market Analysis and Forecast By Device Type

3.1. Global Laser Therapy Devices Market Size and Forecast By Device Type, 2012-2022

3.1.1. Solid-state Laser Market Size and Forecast, 2012-2022

3.1.1.1. Revenue (US$ Mn) Comparison, By Region

3.1.1.2. Market Share Comparison, By Region

3.1.1.3. Y-o-Y growth Comparison, By Region

3.1.2. Gas Laser Market Size and Forecast, 2012-2022

3.1.2.1. Revenue (US$ Mn) Comparison, By Region

3.1.2.2. Market Share Comparison, By Region

3.1.2.3. Y-o-Y growth Comparison, By Region

3.1.3. Liquid Laser Market Size and Forecast, 2012-2022

3.1.3.1. Revenue (US$ Mn) Comparison, By Region

3.1.3.2. Market Share Comparison, By Region

3.1.3.3. Y-o-Y growth Comparison, By Region

3.1.4. Semiconductor Laser Market Size and Forecast, 2012-2022

3.1.4.1. Revenue (US$ Mn) Comparison, By Region

3.1.4.2. Market Share Comparison, By Region

3.1.4.3. Y-o-Y growth Comparison, By Region

4. Global Laser Therapy Devices Market Analysis and Forecast By End User

4.1. Global Laser Therapy Devices Market Size and Forecast By End User, 2012-2022

4.1.1. Hospitals Market Size and Forecast, 2012-2022

4.1.1.1. Revenue (US$ Mn) Comparison, By Region

4.1.1.2. Market Share Comparison, By Region

4.1.1.3. Y-o-Y growth Comparison, By Region

4.1.2. Specialized Clinics Market Size and Forecast, 2012-2022

4.1.2.1. Revenue (US$ Mn) Comparison, By Region

4.1.2.2. Market Share Comparison, By Region

4.1.2.3. Y-o-Y growth Comparison, By Region

4.1.3. Ambulatory Surgical Centers Market Size and Forecast, 2012-2022

4.1.3.1. Revenue (US$ Mn) Comparison, By Region

4.1.3.2. Market Share Comparison, By Region

4.1.3.3. Y-o-Y growth Comparison, By Region

4.1.4. Other End users Market Size and Forecast, 2012-2022

4.1.4.1. Revenue (US$ Mn) Comparison, By Region

4.1.4.2. Market Share Comparison, By Region

4.1.4.3. Y-o-Y growth Comparison, By Region

5. Global Laser Therapy Devices Market Analysis and Forecast By Application

5.1. Global Laser Therapy Devices Market Size and Forecast By Application, 2012-2022

5.1.1. Opthalmology Market Size and Forecast, 2012-2022

5.1.1.1. Revenue (US$ Mn) Comparison, By Region

5.1.1.2. Market Share Comparison, By Region

5.1.1.3. Y-o-Y growth Comparison, By Region

5.1.2. Dermatology Market Size and Forecast, 2012-2022

And So On

Explore Wide-ranging Coverage of FMIsHealthcareMarket Insights Landscape

Rib Fracture Repair Systems Market FMIs analysis gives an insight into key market trends, strategies, regional players and various segments on the basis of form, type, application and region.

Ovulation Test Kit Market Find insights into global market scenario and segmentation on the basis of ingredients, application, source and region.

Radiometric Detectors Market FMIs report highlights parent market trends and strategies in the market with segments and dynamics through the forecast period.

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Regenerative medicine is a segment of translational research in molecular biology and tissue engineering. It involves the process of regeneration of human cells, tissues, or organs to re-establish their normal functions through stimulation of bodys repair system. They are widely used in the treatment of many degenerative disorders occurring in the areas of dermatology, orthopedic, cardiovascular and neurodegenerative diseases. Stem cell therapy is the available tool in the field of translational regenerative medicine. It has gained importance in the past few years as it is a bio-based alternative to synthetic options. Stem cells have high power of regeneration. Hence, these enable production of other cells in the body. This has increased demand for stem cell therapy in the treatment of degenerative diseases. Currently, stem cell therapy has applications in the treatment of diseases such as autism, cancer, retinal diseases, heart failure, diabetes, rheumatoid arthritis, Alzheimers. Extensive research is being carried out on stem cell therapy. The Centre for Commercialization of Regenerative Medicine (CCRM) has reported around 1900 active clinical trials undergoing currently. It also reported 574 active industry-sponsored cell therapy clinical studies, 50 of these are in phase 3 development. Hence, stem cell therapy is projected to contribute to the growth of the translational regenerative medicine market. However, ethical issues in the use of embryonic stem cells is likely to restrain the market.

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Rising prevalence of degenerative diseases, aging population, rapid growth of emerging countries, and technical advancements in developed countries are the major factors fueling the growth of the translational regenerative medicine market.

The global translational regenerative medicine market has been segmented based on product type, therapy, application, and region. In terms of product type, the market has been categorized into cellular and acellular. The cellular segment dominated the global market in 2016. Based on therapy, the global translational regenerative market has been segmented into cell therapy, gene therapy, immunotherapy, and tissue engineering. Immunotherapy is projected to be the fastest growing segment during the forecast period. In terms of application, the market has been segmented into orthopedic & musculoskeletal, cardiology, diabetes, central nervous system diseases, dermatology, and others. Cardiology and orthopedic & musculoskeletal are anticipated to be the fastest growing segments of the global translational regenerative medicine market.In terms of region, the global translational regenerative medicine market has been segmented into North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. North America dominated the global regenerative medicine market owing to a large number of leading companies and expansion of research and development activities in the U.S. Increased medical reimbursement and advanced health care also drive the market in the region. Orthopedic is the leading application segment contributing to the growth of the market in the region. Asia Pacific is forecasted the huge growth because of large consumer pool, rising income, and health care expenditure. However, the market in Asia Pacific could face challenges such as high cost of bio-based medicines and stringent regulatory policies.

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The global translational regenerative medicine market is dominated by key players such as CONMED Corporation, Arthrex, Inc., Organogenesis, Inc., Nuvasive, Inc., Osiris Therapeutics, Inc., Celgene Corporation, Brainstorm Cell Therapeutics Inc. and Medtronic.

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The following regional segments are covered comprehensively:

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Translational Regenerative Medicine Market: Immunotherapy is projected to be the fastest growing segment during the forecast period - BioSpace

Scientists in the field of regenerative medicine have long been interested in using muscle stem cells to repair injuries, but growing the cells in the lab has proven to be challenging. Now, a team of Australian researchers is suggesting an alternative: a naturally occurring protein that regenerates muscle.

A team from the Australian Regenerative Medicine Institute at Monash University discovered that a protein called NAMPT (nicotinamide phosphoribosyltransferase) stimulates the growth of muscle stem cells and healing in zebrafish and mice. They published their findings in the journal Nature.

The researchers started by studying the cells that migrated to injury sites in zebrafish. They discovered that a particular group of immune cells called macrophages stimulated the regeneration of muscle stem cells.

Macrophages are known to migrate to injury sites, where some remove debris that appears immediately and others stay for long-term cleaning. But the Australian scientists discovered eight genetically distinct macrophagesonly one of which seemed to be involved in the regeneration of muscle stem cells.

They went on to discover that the macrophages with those regenerative abilities released NAMPT. So they tried removing the macrophages from the fish and then adding NAMPT to the aquarium water. It worked: Muscle stem cells started to grow and promote healing, showing that the protein took over for the missing macrophages, the researchers said.

RELATED: Stem cells don't repair injured hearts, but inflammation might, study finds

Several regenerative medicine research teams are focused on harnessing the healing power of macrophages. Researchers from the Cincinnati Children's Hospital Medical Center, for example, discovered that the inflammatory response to stem-cell injections into the heart activated macrophages, which in turn promoted healing.

The Monash-led research team did further studies with NAMPT, which included placing patches that contained the protein into mouse models of muscle-wasting disease. They observed significant muscle healing and are now in discussions with biotech companies about taking the technique into clinical trials, they said in a statement.

They believe NAMPT-based therapies could prove useful in treating a range of conditions including muscular dystrophy, limb injuries and muscle wasting due to aging.

Continue reading here:
Zebrafish reveal regenerative protein that could inspire new treatments for muscle-wasting diseases and aging - FierceBiotech

Bloomberg

(Bloomberg) -- Crown Resorts Ltd. Chief Executive Officer Ken Barton stepped down, bowing to days of pressure after a scathing regulatory report found the Australian casino operator facilitated money laundering and wasnt fit to hold a license in Sydney.Barton will leave immediately, Melbourne-based Crown said in a statement Monday. Helen Coonan will lead the company as executive chairman while the board oversees a search for a new CEO.The report last week by former judge Patricia Bergin was particularly critical of Barton, saying he didnt have the skills for the job. His departure leaves Coonan to find a path out of a crisis that has left Australias largest casino company also facing regulatory pressure at its main operations in Melbourne and Perth.The board is determined to maintain the momentum as Crown takes significant steps to improve our governance, compliance and culture, Coonan said. I will continue to lead on implementation of Crowns ambitious reform program.Crown shares rose 1.1% to A$10.00 in early trading in Sydney, valuing the company at A$6.8 billion ($5.3 billion).After a year-long inquiry for the state gaming watchdog in New South Wales, Bergin recommended an overhaul of Crown before the company could start gaming operations at its new A$2.2 billion Sydney casino. The New South Wales gaming regulator, the Independent Liquor and Gaming Authority, is due to consider the report at a board meeting on Feb. 17.Barton is no match for what is needed at the helm of a casino licensee, Bergin wrote. Barton clung on and as recently as Friday was still assessing his position. He became CEO of Crown in early 2020 after a decade as chief financial officer.Both board nominees of Crowns biggest shareholder, James Packer, left the day after the report was released. Director Andrew Demetriou also resigned last week.Barton disclosed last year during Bergins investigation that Crown hadnt yet analyzed the accounts that were reportedly used by money launderers. He was also unaware for years that a major junket operator had a cash desk at Crowns Melbourne casino, even though the setup posed a money-laundering risk.Packers Casino Dream Dashed as Crown Seen Unfit for LicenseBartons evidence during the inquiry demonstrated a serious lack of judgment, Bergin wrote. His problems will not be cured by the appointment of people expert in the field who report to him, she said.Philip Crawford, chair of the Independent Liquor and Gaming Authority, said Feb. 11 there was a certain obviousness to the notion that Barton should step down.(Adds share price, regulatory pressure on Crown in third paragraph.)For more articles like this, please visit us at bloomberg.comSubscribe now to stay ahead with the most trusted business news source.2021 Bloomberg L.P.

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Global Regenerative Medicine Partnering Deals, Terms and Agreements Directory 2014-2020: Analysis of the Structure of Regenerative Medicine Agreements...

The globalREGENERATIVE MEDICINE marketis constantly evolving and presenting new avenues to stakeholders. The study on the REGENERATIVE MEDICINE market presents a comprehensive assessment of economic, social, and policy factors shaping the changing dynamic. The research offers data-validated insights into current opportunities in various segments and possible avenues during forecast period of 2020 20xy. The trends shaping the value chain assessment, degree of control by incumbent players, intensity of competition are analysed in the study with succinct recommendations and opinionsby market analysts.

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The study offers strategic scenario planning for the recent disruptions caused by Covid-19, a pandemicthatis still emerging. Further, the report has come out with popular strategic moves being made by players to regain agility and come on the growth trajectory as in the pre-Covid era. The research hasgleaned over the change in perspectives of governments and investors and the changing demand dynamic in various end-use industries for evaluating the growth dynamics on the REGENERATIVE MEDICINE market.

The factors that shaped high value-grab opportunities in various regions and consumer segments in the REGENERATIVE MEDICINE market are scrutinized, along with the inherent possibilities in the allied industries.The REGENERATIVE MEDICINE market was pegged at US$ xy mn/Bn and is projected to touch the mark of ab Mn/cd Bn by the end of the forecast period.The researchanalysts also point outsegments that emergedas data outliers,and attribute reasons for the same to offera holistic understatingofgrowth dynamics.

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11 February 2021

An exciting discovery by Monash University scientists may lead to faster recovery from muscle injury and wasting diseases.

When we tear a muscle stem cells within it repair the problem. We can see this occurring not only in severe muscle wasting diseases such as muscular dystrophy and in war veterans who survive catastrophic limb injuries, but also in our day to day lives when we pull a muscle. Also when we age and become frail we lose much of our muscle and our stem cells dont seem to be able to work as well as we age.

These muscle stem cells are invisible engines that drive the tissue's growth and repair after such injuries. But growing these cells in the lab and then using them to therapeutically replace damaged muscle has been frustratingly difficult.

Researchers at the Australian Regenerative Medicine Institute at Monash University in Melbourne, Australia have discovered a factor that triggers these muscle stem cells to proliferate and heal. In a mouse model of severe muscle damage, injections of this naturally occurring protein led to the complete regeneration of muscle and the return of normal movement after severe muscle trauma.

The research led by Professor Peter Currie, Director of Monash Universitys Australian Regenerative Medicine Institute, is published today in Nature.

The scientists studied the regeneration of skeletal muscle in zebrafish, fast becoming the go-to animal model for the study of stem cell regeneration because the fish are quick to reproduce, easier to experimentally manipulate, and share at least 70 percent of their genes with humans. It is also transparent which allows the scientists to witness the actual regeneration in living muscle.

By studying the cells that migrated to a muscle injury in these fish the scientists identified a group of immune cells, called macrophages, which appeared to have a role in triggering the muscle stem cells to regenerate. What we saw were macrophages literally cuddling the muscle stem cells, which then started to divide and proliferate. Once they started this process, the macrophage would move on and cuddle the next muscle stem cell, and pretty soon the wound would heal, Professor Currie said

Macrophages are the cells that flock to any injury or infection site in the body, removing debris and promoting healing. They are the clean up crew of the immune system, Professor Currie said.

It has long been thought that two types of macrophages exist in the body: those that move to the injury rapidly and remove debris, and those that come in slower and stick around doing the longer term clean-up.

The research team, however, found that there were in fact eight genetically different types of macrophages in the injury site, and that one type, in particular, was the cuddler. Further investigation revealed that this affectionate macrophage released a substance called NAMPT. By removing these macrophages from the zebrafish and adding the NAMPT to the aquarium water the scientists found they could stimulate the muscle stem cells to grow and heal effectively replacing the need for the macrophages.

Importantly recent experiments placing a hydrogel patch containing NAMPT into a mouse model of severe muscle wasting led to what Professor Currie called significant replacement of the damaged muscle.

The researchers are now in discussions with a number of biotech companies about taking NAMPT to clinical trials for the use of this compound in the treatment of muscle disease and injury.

Read the full paper in Nature titled:Macrophages provide a transient muscle stem cell miche via NAMPT secretion.

DOI: 10.1038/s41586-021-03199-7

Read more from Professor Peter Currie onMonash Lens.

About The Australian Regenerative Medicine Institute at Monash University

The Australian Regenerative Medicine Institute is one of the largest regenerative medicine and stem cell research organisations in the world and Australias only research institute specialising in regeneration and stem cells.Located on the Clayton campus of Monash University, researchers at ARMI focus on understanding the basic mechanisms of the regenerative process, aiming to eventually enable doctors to prevent, halt and reverse damage to vital organs due to disease, injury or genetic conditions.

Link:
Reversing severe muscle wasting in disease, aging and trauma - Monash University

PHOENIX, Feb. 8, 2021 /PRNewswire/ --(OTC-CELZ) Creative Medical Technology Holdings Inc. announced today recruitment of Dr. Caigan Du, Associate Professor at the University of British Columbia to the Company's Scientific Advisory Board.

Dr. Du is a top researcher in the area of molecular and immunological understanding of kidney failure and transplant rejection. Dr. Du is funded by numerous national and international organizations including the Kidney Foundation and the Canadian Institutes of Health Research.

"I am honored to work with Creative Medical Technology Holdings in this fascinating field of leveraging reprogrammed immune cells for regenerating injured kidneys." Said Dr. Du. "To date people think about regenerative medicine and immunology as separate fields. It is very exciting to consider the possibility that immune cells can act as a catalyst for regenerative processes: this is the basis of the ImmCelz product."

ImmCelz is a personalized cell therapy generated by incubation of patient cells with allogeneic JadiCell stem cells under proprietary conditions. The JadiCell possess potent ability to reprogram the immune system, as exemplified in part by their ability to significantly extend survival of COVID patients in an FDA double blind, placebo controlled, clinical trial1. ImmCelz has been demonstrated effective in animal models of rheumatoid arthritis2, liver failure3, stroke4, type 1 diabetes5 and kidney failure6. Scientific studies suggest ImmCelz functions through secretion of a fundamentally important molecule called Hepatocyte Growth Factor7, as well as stimulation of T regulatory cells, a type of immune system cell that suppresses pathological immunity8.

"As a clinical-stage biotechnology company, having already commercialized other stem cell products, we understand the key to any success is based on the ability to attract scientific key opinion leaders." Said Timothy Warbington, President and CEO of Creative Medical Technology Holdings. "Dr. Du is a visionary and pioneer in understanding of kidney diseases and we wholeheartedly look forward to him joining our scientific advisory board."

The Advisory Board of Creative Medical Technology Holdings includes internationally renowned neurologist Santosh Kesari MD, Ph.D, the former head of cardiology at Cedar Sinai Medical Center Timothy Henry, MD and our Director Dr. Amit Patel, inventor of the JadiCell and the first physician to have implanted stem cells into the human heart.

About Creative Medical Technology HoldingsCreative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in regenerative medicine/stem cell technology in the fields of immunotherapy, urology, neurology and orthopedics and is listed on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking StatementsOTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Creativemedicaltechnology.comwww.StemSpine.comwww.Caverstem.comwww.Femcelz.com ImmCelz.com

1 Umbilical cord mesenchymal stem cells for COVID19 acute respiratory distress syndrome: A doubleblind, phase 1/2a, randomized controlled trial - Lanzoni - - STEM CELLS Translational Medicine - Wiley Online Library2 Creative Medical Technology Holdings Reports Positive Preclinical Data on ImmCelz Immunotherapy Product in Rheumatoid Arthritis Model | BioSpace3 Creative Medical Technology Holdings Announces Reversion of Liver Failure Using ImmCelz Personalized Cellular Immunotherapy in Preclinical Model | Nasdaq4 Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com)5 Creative Medical Technology Holdings Announces Positive Data and Patent Filing Using ImmCelz to Treat Type 1 Diabetes (prnewswire.com)6 Creative Medical Technology Holdings Files Patent based on Positive Data on Renal Failure using ImmCelz Regenerative Immunotherapy (prnewswire.com)7 Creative Medical Technology Holdings Identifies and Files Patent on Novel Mechanism of ImmCelz Therapeutic Activity (apnews.com)8 Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com)

SOURCE Creative Medical Technology Holdings, Inc.

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Creative Medical Technology Holdings Recruits Internationally Renowned Kidney Expert to Scientific Advisory Board - PRNewswire

VANCOUVER, BC, Feb. 10, 2021 /PRNewswire/ --Notch Therapeutics, Inc., a biotechnology company developing renewable, induced pluripotent stem cell (iPSC)-derived cell therapies for cancer, announced today the closing of an oversubscribed U.S. $85 million Series A financing. The financing was led by an exclusively healthcare-focused investment fund, with participation by existing investors Allogene Therapeutics, Inc. (NASDAQ: ALLO), Lumira Ventures, and CCRM Enterprises Holdings Ltd., an affiliate of Centre for Commercialization of Regenerative Medicine (CCRM); along with new investors EcoR1 Capital, a undisclosed leading global investment firm, Casdin Capital, Samsara BioCapital, and Amplitude Ventures. Proceeds from the financing will support the continuing development of Notch's portfolio of iPSC-derived T cell therapeutic product candidates and clinical readiness of the company's proprietary Engineered Thymic Niche (ETN) platform. The financing will also enable Notch to expand its team to support the company's future growth, including establishing operations in Seattle, in addition to the company's existing operations in Vancouver and Toronto.

"We are gratified to have the confidence of this exceptional group of investors and have them share in our vision that our platform can be game-changing for cell therapies by easing cell manufacturing and broadening their clinical and commercial potential," said David Main, President and Chief Executive Officer of Notch. "The level of interest in this financing round enabled us to far exceed our original capital-raising goals. With this support, Notch is well positioned to support our partners and advance development of our initial cell therapy products for patients with cancer."

Notch is applying its scalable Engineered Thymic Niche (ETN) technology platform to develop homogeneous and universally compatible, stem cell-derived cell therapies. To date, Notch has assembled a world-class scientific team and built a fully integrated, tightly controlled platform for generating and editing immune cells from clonal stem cells to enable development of a broad range of T cell therapeutics. Notch has an existing partnership with Allogene Therapeutics to apply Notch's proprietary ETN platform to develop CAR-targeted, iPSC-derived, off-the-shelf T cell or natural killer (NK) cell therapies for hematologic cancer indications.

"We have great confidence in Notch's high-caliber management team and the rigorous science underlying its research programs," said David Chang, M.D., Ph.D., President, Chief Executive Officer, and Co-Founder of Allogene and a member of the Notch Board of Directors. "We are impressed by the company's innovation and accomplishments and pleased to continue our support of Notch as the company advances the development of a new generation of cell therapies for cancer and other immune disorders."

About Notch Therapeutics (www.notchtx.com)Notch is developing a pipeline of cellular immunotherapies originating from pluripotent stem cells that are specifically engineered to address the underlying biology of complex disease systems. The company has unlocked the ability for large-quantity production of T cells and other cells from any source of stem cells to bring best-in-class cell therapies for cancer and other immune disorders to thousands of patients. The core of the Notch platform is the Engineered Thymic Niche (ETN), which enables precision control of cell fate during the differentiation and expansion of stem cells in suspension bioreactors without the need for feeder cells or serum. The ETN has the potential to generate immunotherapies with decreased variability, increased potency, and engineered improvements. The technology was invented in the laboratories of Juan-Carlos Ziga-Pflcker, Ph.D. at Sunnybrook Research Institute and Peter Zandstra, Ph.D., FRSC at the University of Toronto. Notch was founded by these two institutions, in conjunction with MaRS Innovation (now Toronto Innovation Acceleration Partners) and the Centre for Commercialization of Regenerative Medicine (CCRM), which initially incubated the company.

Contact:Mary MoynihanM2Friend Biocommunications802-951-9600[emailprotected]

SOURCE Notch Therapeutics

Notch Therapeutics

Link:
Notch Therapeutics Closes $85 Million Series A Financing to Develop Pipeline of Renewable Stem Cell-Derived Cancer Immunotherapies - PRNewswire

WAALRE, Netherlands, Feb. 10, 2021 /PRNewswire/ -- IME Medical Electrospinning, a global leader in electrospun medical devices, today announced that it has entered into a collaboration with Dutch medical device company STENTiT, to join forces in the further development and production of regenerative endovascular support grafts(see video).These resorbable fibrous implants hold the promise to rebuild a new blood vessel inside the existing artery, by exploiting the natural healing response of the body.

IME's technological solutions enable the manufacturing of innovative devices like STENTiT's endovascular support grafts, which are aimed to mimic the natural human extracellular matrix for implants in the human body in nanometer and micrometer format. Human cells rebuild these matrices leading to new body tissue. This is in contrast to implants of traditional structures, which are seen as foreign and therefore can lead to scar tissue formation or rejection phenomena.

STENTiT is an emerging player in the field of regenerative medical devices, offering a breakthrough solution for cardiovascular interventions developing first-of-its-kind regenerative endovascular blood vessel implants. Using a catheter-based approach, it provides the ability to restore the artery without the need for an invasive surgical intervention. The aim is to ultimately restore the affected artery from the inside-out to provide a life-lasting solution.

Bart Sanders, CEO of STENTiT, says:

"We are thrilled to join forces with IME Medical Electrospinning to further optimize our fibrillated endovascular implants. IME is a highly innovative and leading company in the field of Medical Electrospinning, for which I'm confident that together we will spur the development of a superior and reproducible product, while getting STENTiT ready to scale."

Judith Heikoop, CEO of IME Medical Electrospinning, adds:

"We are extremely proud to have been able to expandourcollaborations with such a promising company like STENTiT. IME Medical Electrospinning develops medical devices in close collaboration with an ever-growing portfolio of customers and partners worldwide within the industry, the scientific environment, hospitals and medical institutes. This collaboration is testimony to our strategic goal to become a trusted partner worldwide in co-developing electrospun medical devices that will cause a revolution in the industry and will enable tissue rebuilding."

IME has set the worldwide standard in the co-development and production of scalable and reproducible nanometer and micrometer scaffolds that enable scientists to develop medical implants helping the human body to repair itself, such as heart valves, blood vessels, nerves, tendons, skin and bone. IME operates a brand new high-end GMP Laboratory and set of cleanrooms. With this the company is able to not only develop and manufacture its top-end proprietary electrospinning machines, but to also produce the actual scaffolds for the intended medical implants for their customers. The cleanroom facilities enable the production of Class I, II and III medical devices.

About Medical Electrospinning

Applying specific polymers, IME's advanced equipment creates fiber-based medical device solutions that mimic the natural human extracellular matrix in nanometer and micrometer format for implants and membranes in the human body. Human cells recognize these artificial matrices (scaffolds) as the body's own, facilitating the repair of the damaged tissue for heart valves, blood vessels, nerves, tendons, skin and bone etc. This is in contrast to implants and membranes of traditional structures, which are seen as foreign and therefore can lead to scar tissue or rejection phenomena. The MediSpinXL platform has been developed specifically for MedTech industrial manufacturing of medical devices and is now also suitable for pharmaceutical drug delivery applications and ensures firm control over the crucial parameters of the electrospinning process, leading to reproducible and consistent end-products.

About STENTiT

STENTiT is a medical device spin-off company from Dutch Eindhoven University of Technology, focusing on the development of regenerative endovascular implants. These devices trigger a natural healing response by the circulating blood cells, in which the implant is being rebuilt with new vascular tissue while safely dissolving over time.

Since the establishment of the company in 2017, STENTiT has received broad international recognition and awards for its high-potential approach, covering world leading stages. As the company is currently going through the next translational phases, STENTiT is on its way to fulfill its ambition to become the new standard in endovascular treatment, providing a life-lasting solution for millions of patients around the world.

For more info, please visit http://www.stentit.com

About IME Medical Electrospinning

For over ten years, IME Medical Electrospinning has been a leading player in the field of developing and implementing electrospinning processes and equipment for the manufacturing of medical devices for (regenerative) medicine and drug delivery. Electrospinning is a flexible process for producing extremely thin fibers and structures that have excellent properties to help regenerate human tissue. IME Medical Electrospinning has developed a unique set of innovations in electrospinning technology for the reproducible and scalable production of electrospun material under tightly controlled conditions required for the MedTech and Pharma market. Customers and scientific partners include the MedTech and Pharma industry, scientists and health institutions.

More information available atwww.ime-electrospinning.com

For further inquiries:

IME Medical Electrospinning, Waalre, The NetherlandsJudith Heikoop M.Sc. Ph.D.T: +31 40 28 27 956E: [emailprotected]

STENTiT, Eindhoven, The NetherlandsBart Sanders M.Sc. Ph.D.T: +31 40 24 72 445E: [emailprotected]

For media:

LifeSpring Life Sciences Communication, AmsterdamLon MelensT: +31 6 538 16 427E: [emailprotected]

Logo: https://mma.prnewswire.com/media/1248580/IME_Medical_Electrospinning_Logo.jpg

SOURCE IME Medical Electrospinning

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IME Medical Electrospinning and STENTiT enter into development cooperation on resorbable endovascular support grafts to regenerate vascular tissue -...

(Feb 2021 trend research report )The newly added report titledGlobal Regenerative Medicine Market Report 2020, Forecast to 2030to the database ofinsightSLICEreveals existing trends and tendencies in the industry. The report contains vital insights on the market and a thorough overview of the market where it identifies industry trends, determines industry insights, and offers competitive intelligence. The report helps to figure out and study the market needs, market size, and competition. The report includes noteworthy information alongside future conjecture and point by point market scanning on a worldwide, regional, and local level for the global Regenerative Medicine industry. The research document is designed with correctness and in-depth knowledge which helps the business to grow and henceforth results in revenue growth.

The report analyzes the current market trends, consumer demands, and preferences, market situations, opportunities, and market status. Other principles studied in terms of the market report include market definition, market segmentation, competitive analysis, and research methodology. The report offers an in-depth analysis of the global Regenerative Medicine markets historical data and estimated projections about the market size and share in the forecast period from 2020 to 2030. It also includes market trends, revenue growth patterns market shares, and demand and supply. The report is segmented on the basis of types, end-users, applications, and regional markets.

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Development policies and plans are discussed and manufacturing processes and industry chain structures are analyzed. This report also provides data on import / export, supply and consumption, as well as manufacturing costs and global revenues, and gross margin by region. The numerical data are copied with statistical tools, such as SWOT analysis, BCG matrix, SCOT analysis and PESTLE analysis. Statistics are presented in graphical form to provide a clear understanding of the facts and figures.

The main manufacturers covered in this report:

3M Group, Novartis AG and Integra Lifesciences Holdings Corporation.

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The ongoing pandemic has changed several facets of the market. This research report provides financial impacts and market disruption to the Regenerative Medicine market. It also includes analyzing potential opportunities and challenges in the foreseeable future. insightSLICEinterviewed several industry delegates and engaged in primary and secondary research to provide customers with information and strategies to address market challenges during and after the COVID-19 pandemic.

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