Stem Cell Clinic

Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy – Nature.com

By Stem Cell Treatment

Human samples

Rapid harvesting of cadaveric pancreatic tissues was obtained with informed consent from next of kin, from heart-beating, brain-dead donors, with research approval from the Human Research Ethics Committee at St Vincents Hospital, Melbourne. Pancreas from individuals without and with diabetes, islet, acinar and ductal samples were obtained as part of the research consented tissues through the National Islet Transplantation Programme (at Westmead Hospital, Sydney and the St Vincents Institute, Melbourne, Australia), HREC Protocol number: 011/04. The donor characteristics of islet cell donor isolations are presented in Table 1.

Islets were purified by intraductal perfusion and digestion of the pancreases with collagenase AF-1.24 (SERVA/Nordmark, Germany) followed by purification using Ficoll density gradients.25 Purified islets, from low-density gradient fractions and acinar/ductal tissue, from high-density fractions, were cultured in Miami Media 1A (Mediatech/Corning 98021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a 37C, 5% CO2 incubator.

Total RNA from human ex vivo pancreatic cells was isolated using TRIzol (Invitrogen) and RNeasy Kit (QIAGEN) including a DNase treatment. First-strand cDNA synthesis was performed using a high-capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to the manufacturers instructions. cDNA primers were designed using oligoperfect designer (Thermo Fisher Scientific), as shown in Table 2. Briefly, quantitative RT-PCR analyses were undertaken using the PrecisionFast 2 qPCR Master Mix (Primerdesign) and primers using Applied Biosystems 7500 Fast Real-Time PCR System. Each qPCR reaction contained: 6.5l qPCR Master Mix, 0.5l of forward and reverse primers, 3.5l H2O and 2l of previously synthesised cDNA, diluted 1/20. Expression levels of specific genes were tested and normalised to 18s ribosomal RNA housekeeping gene.

Modification of Histone H3 and histone-associated Ezh2 protein signals were quantified in human pancreatic ductal epithelial cells (AddexBio) by the LI-COR Odyssey assay. The cells were treated with 5 or 10M of GSK 126 (S7061, Selleckchem) for 48h. Histones and their associated proteins were examined using an acid extraction and immunoblotting as described previously.18 Protein concentrations were determined using Coomassie Reagent (Sigma) with BSA as a standard. Equal amounts (3g) of acid extract were separated by Nu-PAGE (Invitrogen), transferred to a PVDF membrane (Immobilon-FL; Millipore) and then probed with antibodies against H3K27me3 (07449, Millipore), H3K27ac (ab4729, Abcam), H3K9me3 (ab8898, Abcam), H3K9me2 (ab1220, Abcam), H3K4me3 (39159, Active Motif), Ezh2 (#4905, Cell Signaling Technology), and total histone H3 (#14269, Cell Signaling Technology). Protein blotting signals were quantified by an infra-red imaging system (Odyssey; LI-COR). Modification of Histone H3 and histone-associated Ezh2 signals were quantified using total histone H3 signal as a loading control.

Chromatin immunoprecipitation assays in human exocrine cells were performed previously described.26,27 Cells were fixed for 10min with 1% formaldehyde and quenched for 10min with glycine (0.125M) solution. Fixed cells were resuspended in sodium dodecyl (lauryl) sulfate (SDS) lysis buffer (1% SDS, 10mM EDTA, 50mM Tris-HCl pH 8.1) including a protease inhibitor cocktail (Roche Diagnostics GmBH, Mannheim, Germany) and homogenised followed by incubation on ice for 5min. Soluble samples were sonicated to 200600bp and chromatin was resuspended in ChIP Dilution Buffer (0.01% SDS, 1.1% Triton X-100, 1.2mM EDTA, 16.7mM Tris-HCl pH 8.0, and 167mM NaCl) and 20l of Dynabeads Protein A (Invitrogen, Carlsbad, CA, USA) was added and pre-cleared. H3K27me3 antibody was used for immunoprecipitation of chromatin and incubated overnight at 4C as previously described.28 Immunoprecipitated DNA were collected by magnetic isolation, washed low salt followed by high salt buffers and eluted with 0.1M NaHCO3 with 1% SDS. Protein-DNA cross-links were reversed by adding Proteinase K (Sigma, St. Louis, MO, USA) and incubation at 62C for 2h. DNA was recovered using a Qiagen MinElute column (Qiagen Inc., Valencia, CA, USA). H3K27me3 content at the promoters of the INS, INS-IGF2, NGN3 and PDX1 genes were assessed by qPCR using primers designed from the integrative ENCODE resource.29 ChIP primers are shown in Table 3.

Insulin and glucagon localisation in human islets were assessed using paraffin sections (5m thickness) of human pancreas tissue fixed in 10% neutral-buffered formalin and stained with hematoxylin and eosin (H&E) or prepared for immunohistochemistry. Insulin and glucagon were detected using Guinea Pig anti-insulin (1/100, DAKO) or mouse anti-glucagon (1/50) mAbs (polyclonal Abs, Sigma-Aldrich).

Pharmacological inhibition of EZH2, human pancreatic exocrine cells were kept untreated or stimulated with 10M GSK-126 (S7061, Selleckchem) at a cell density of 1105 per well for 24h. After 24h of treatment, fresh Miami Media was added to the cells, which were treated again with 10 GSK-126 and cultured for a further 24h. All cell incubations were performed in Miami Media 1A (Mediatech/Corning 98-021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a cell culture incubator at 37C in an atmosphere of 5% CO2 for 48h using non-treated six-well culture plates (Corning).

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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy - Nature.com

Bristol Myers Squibb Receives Positive CHMP Opinion Recommending Approval for LAG-3-Blocking Antibody Combination Opdualag (nivolumab and relatlimab)…

By Stem Cell Treatment

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of the fixed-dose combination of nivolumab and relatlimab for the first-line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older with tumor cell PD-L1 expression < 1%. The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the CHMP opinion.

We are very proud of the role we have played in progressing the treatment of advanced melanoma over the years. As part of our mission to deliver new medicines for patients, we have continued to develop new dual immunotherapy combinations, said Paul Basciano, development lead, relatlimab, Bristol Myers Squibb. This positive CHMP opinion marks the first step toward the potential approval of the first LAG-3 blocking antibody combination and the third distinct checkpoint inhibitor for BMS for advanced melanoma patients in the EU.

The positive opinion is based upon efficacy and safety results from the Phase 2/3 RELATIVITY-047 trial. The trial showed that treatment with the fixed-dose combination of nivolumab and relatlimab more than doubled the median progression-free survival (PFS), including in patients with tumor cell PD-L1 expression < 1%, when compared to nivolumab monotherapy an established standard of care. The proposed indication for the EU is based upon an exploratory analysis of the data in patients with tumor cell PD-L1 expression < 1%. No new safety events were identified with the combination when compared to nivolumab monotherapy.

On March 18, 2022, the U.S. Food and Drug Administration (FDA) approved the fixed-dose combination of nivolumab and relatlimab as Opdualag (nivolumab and relatlimab-rmbw) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Please see important safety information from the U.S. prescribing information below.

Bristol Myers Squibb thanks the patients and investigators involved in the RELATIVITY-047 trial.

About RELATIVITY-047

RELATIVITY-047 is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of nivolumab and relatlimab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. Patients were enrolled regardless of tumor cell PD-L1 expression. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. The primary endpoint of the trial is progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in the all-comer population. The secondary endpoints are overall survival (OS) and objective response rate (ORR) in the all-comer population. A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of nivolumab (480 mg) and relatlimab (160 mg) or nivolumab (480 mg) by intravenous infusion every four weeks until disease progression, unacceptable toxicity or withdrawal of consent.

About LAG-3

Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. Preclinical studies indicate that inhibition of LAG-3 may restore effector function of exhausted T cells and potentially promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.

Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types.

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 106,110 new diagnoses of melanoma and about 7,180 related deaths are estimated for 2021. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses.

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.

OPDUALAG U.S. INDICATION

Opdualag (nivolumab and relatlimab-rmbw) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

OPDUALAG IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

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

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, 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 IMARs 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

Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis

Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus 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.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis

Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies

Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag 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. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

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. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction

Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

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

Immune-Mediated Dermatologic Adverse Reactions

Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

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

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis

Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdualag 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: 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. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including 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, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation

There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions

In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in 1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities

The most common adverse reactions reported in 20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in 20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see U.S. Full Prescribing Information for OPDUALAG.

OPDIVO U.S. INDICATIONS

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

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

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

OPDIVO (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors 4 cm or node positive) non-small cell lung cancer (NSCLC).

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 adult 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 adult 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 adult patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult 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 adult 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 adult 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.

OPDIVO (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

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

OPDIVO (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum- containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

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 patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). 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%). Inpatients 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%).

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 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%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4ALT 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

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Canine Stem Cell Therapy Market to Witness Growth Acceleration | Aratana Therapeutics, Okyanos, Magellan Stem Cells Travel Adventure Cinema – Travel…

By Stem Cell Clinics

New Jersey (United States) A2Z Market Research published new research on Global Canine Stem Cell Therapy covering the micro-level of analysis by competitors and key business segments (2022-2029). The Global Canine Stem Cell Therapy explores a comprehensive study on various segments like opportunities, size, development, innovation, sales, and overall growth of major players. The research is carried out on primary and secondary statistics sources and it consists of both qualitative and quantitative detailing.

Some of the Major Key players profiled in the study are Aratana Therapeutics, Okyanos, Magellan Stem Cells, Stem Cell Vet, VetStem Biopharma, Medrego, Regeneus Ltd, MediVet Biologic, Cell Therapy Sciences

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The global Canine Stem Cell Therapy Market research report delivers a comprehensive analysis of market size, market trends, and market growth prospects. This report also delivers extensive information on the technology expenditure for the forecast period, which gives a unique view of the global Canine Stem Cell Therapy Market across numerous segments. The global Canine Stem Cell Therapy market report also allows consumers recognize market prospects and challenges.

Various factors are responsible for the markets growth trajectory, which are studied at length in the report. In addition, the report lists down the restraints that are posing threat to the global

Global Canine Stem Cell Therapy Market Segmentation:

Market Segmentation: By Type

Allogeneic Stem Cells, Autologous Stem Cells

Market Segmentation: By Application

Veterinary Hospitals, Veterinary Clinics, Veterinary Research Institutes

Key market aspects are illuminated in the report:

Executive Summary: It covers a summary of the most vital studies, the Global Canine Stem Cell Therapy market increasing rate, modest circumstances, market trends, drivers and problems as well as macroscopic pointers.

Study Analysis: Covers major companies, vital market segments, the scope of the products offered in the Global Canine Stem Cell Therapy market, the years measured, and the study points.

Company Profile: Each Firm well-defined in this segment is screened based on a products, value, SWOT analysis, their ability and other significant features.

Manufacture by region: This Global Canine Stem Cell Therapy report offers data on imports and exports, sales, production and key companies in all studied regional markets

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The cost analysis of the Global Canine Stem Cell Therapy Market has been performed while keeping in view manufacturing expenses, labor cost, and raw materials and their market concentration rate, suppliers, and price trend. Other factors such as Supply chain, downstream buyers, and sourcing strategy have been assessed to provide a complete and in-depth view of the market. Buyers of the report will also be exposed to a study on market positioning with factors such as target client, brand strategy, and price strategy taken into consideration.

Highlighting points of Global Canine Stem Cell Therapy Market Report:

Table of Contents

Global Canine Stem Cell Therapy Market Research Report 2022 2029

Chapter 1 Canine Stem Cell Therapy Market Overview

Chapter 2 Global Economic Impact on Industry

Chapter 3 Global Market Competition by Manufacturers

Chapter 4 Global Production, Revenue (Value) by Region

Chapter 5 Global Supply (Production), Consumption, Export, Import by Regions

Chapter 6 Global Production, Revenue (Value), Price Trend by Type

Chapter 7 Global Market Analysis by Application

Chapter 8 Manufacturing Cost Analysis

Chapter 9 Industrial Chain, Sourcing Strategy and Downstream Buyers

Chapter 10 Marketing Strategy Analysis, Distributors/Traders

Chapter 11 Market Effect Factors Analysis

Chapter 12 Global Canine Stem Cell Therapy Market Forecast

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Canine Stem Cell Therapy Market to Witness Growth Acceleration | Aratana Therapeutics, Okyanos, Magellan Stem Cells Travel Adventure Cinema - Travel...

Gov. Whitmer announces more budget vetoes, mostly tied to curbs on abortion rights – Detroit Free Press

By Stem Cell Clinics

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Attorney General Dana Nessel discusses Supreme Court ruling on abortion

Nessel has pledged not to enforce Michigan's highly restrictive 1931 abortion law, should it take effect after Friday's U.S. Supreme Court ruling.

Provided by the Michigan Department of the Attorney General

LANSING Gov. Gretchen Whitmer'soffice on Monday detailed more than $20 million in line-item vetoes she plans to make to the state's main 2023 budget billwhen she signs it into law Wednesday.

Most of the vetoed budget itemsin House Bill 5783 relate to the Department of Health and Human Services and involve restrictions on the use of state funds to pay for abortionsor funding for pregnancy and parenting centers that promote alternatives to abortion.Whitmer also vetoed a $2 million tax credit for adoptive parents, a $10 million marketing program to promote adoption as an alternative to abortion, and a $100,000 legal fund in the Michigan Department of Corrections to pay for efforts to prevent the use of state funds for gender-confirmationsurgery or therapies in state prisons.

The announcement drew swift criticism from Republicans. The governor claims to be a voice for choice, but her actions clearly support only one option for women in a crisis pregnancy the deadly choice of abortion," said State Rep. Thomas Albert, R-Lowell, chairman of the House Appropriations Committee.

Monday's announcement follows Whitmer's vetoes Thursday of $6 million from the education budget. The money funded college and university pregnancy and parenting centers that would be prohibited from making abortion referrals and money for "ethical stem cell/tissue research" that would place restrictions on which stem cells and human embryos could be used.

On Wednesday, Whitmer "is expected to veto funding for centers that often purport to offer comprehensive reproductive health care, including abortion, but dont, preying on women at a vulnerable time in their lives," Whitmer spokesman Bobby Leddy said.

The centers, which Leddy said are sometimes known as fake womens health centers or pregnancy resource centers, frequentlyuse deceptive advertising that target young women and women with low incomes who are seeking abortion care, painting themselves as comprehensive, licensed health care clinics that provide all options, and then lie to women about medical facts," Leddy said.

Whitmer "supports legislation that provides every possible resource to women who are pregnant, seeking to start a family, or those who arent ready yet, but she cannot support aspects of a bill that sends millions in taxpayer dollars to fake health centers that intentionally withhold information from women about their health, bodies, and full reproductive freedom," Leddy said.

The budget, approved overwhelmingly by lawmakers from both parties, was the product of negotiations and a consensus the governor reached with Republican legislative leaders. Still, none of the leaders should be surprised by any of the vetoes, Leddy said.

Gideon D'Assandro, a spokesman for House Speaker Jason Wentworth, R-Farwell, confirmed the vetoes are not a surprise.

More: Whitmer vetoes budget items restricting abortion access, stem cell research

More: Whitmer signs $22.2B budget for Michigan K-12 schools, colleges and universities

Albertsaid it is shocking that"helping pregnant women who might consider adoption instead is now a bridge too far," and the vetoes remove help for "expecting mothers and their babies, including those facing a crisis pregnancy, by denying them access to essential care both before and after giving birth."

Whitmer is usingher line-item veto powers for budget bills as tensions are high between herand the Republican-controlled Legislature after the U.S. Supreme Court struck down Roe v. Wade, which recognized abortion rights.

The toppling of Roe would put into effect a 1931 state law that prohibits abortions except to save the life of the mother, but a Court of Claims judge has temporarily preserved the status quo by issuing an injunction against the 1931 law. Whitmer has asked the Michigan Supreme Court to declare that the law violates the state constitution; Republicans are fighting to preserve the law.

Contact Paul Egan: 517-372-8660 or pegan@freepress.com.Follow him on Twitter @paulegan4. Read more on Michigan politics and sign up for our elections newsletter.

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Gov. Whitmer announces more budget vetoes, mostly tied to curbs on abortion rights - Detroit Free Press

Embryonic Research Could Be the Next Target After Roe – WIRED

By Embryonic Stem Cells

Two weeks after the US Supreme Court overturned the federal right to an abortion, Ye Yuan heard from a woman who wanted to reverse her decision to donate her embryos to scientific research. The womanwho contacted Yuan anonymously through a fertility counselorwas fearful that if the law in Colorado changed to make it illegal to discard or experiment on human embryos, then she would be forced to have hers frozen indefinitely. In a year, or five years, might a law change to stop her from having the final say over what happened to them?

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In states where human embryonic research is legal, people undergoing IVF are often given the choice to donate any excess fertilized embryos to scientific research. These are sometimes used to search for potential treatments for diseases such as diabetes or, as in Yuans case, to research ways to make IVF more successful. Those discarded embryos are really one of the key pieces for us to maintain the high quality of our platform here, says Yuan, who is research director at the Colorado Center for Reproductive Medicine (CCRM). But in the wake of the Dobbs verdict, he is worried that people will be less likely to donate their spare embryos for research and, down the line, that embryonic research could become the next target of antiabortion campaigners.

Its like youre a little girl living in a dark room. You know there are bad guys outside but youre not too worried because the door has been locked, says Yuan. But then somebody tells you that the door has been unlocked. Yuan fears that anything that slows down access to human embryos will ultimately end up slowing progress in IVF, which is responsible for between 1 and 2 percent of all US births annually.

The majority opinion written by Justice Samuel Alito doesnt single out IVF or human embryonic research, but his choice of words to describe abortion could be seen as also being applicable to embryos outside the body, says Glenn Cohen, a bioethicist and professor of law at Harvard Law School. The right to an abortion is distinct from other rights, Alito notes in the opinion, because it destroys potential life and the life of an unborn human being.

The same thing that he uses to distinguish abortion seems to me completely applicable to distinguishing embryos, says Cohen. To me it makes it very, very clear after Dobbs that any state that wants to prohibit the destruction of embryos as part of research is free to do so.

The wording that legislators use to describe the beginning of human life is also important. In at least nine states, trigger lawspieces of legislation designed to restrict abortion quickly after the fall of Roeinclude language that implies an egg cell becomes an unborn child or unborn human being at the precise moment of fertilization. In other words, according to these definitions, every single human embryoincluding donated embryos that might be used in scientific researchis an unborn child. Although most of these trigger laws apply specifically to pregnancy, and so do not regulate embryos outside of the human body, the idea that life begins at the very moment of fertilization could be used to target embryonic research, says Cohen. If you have that view, its not clear to me why you would exempt the destruction of embryos if you prohibit abortion. To me, that wrong is the same.

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Embryonic Research Could Be the Next Target After Roe - WIRED

Cell Culture Media Market: Competitive Approach, Breakdown And Forecast by 2027 – Digital Journal

By Embryonic Stem Cells

Market Overview

Thecell culture media marketis expected to cross USD 4.33 billion by 2027 at a CAGR of8.33%.

Market Dynamics

The markets growth is being fueled by a diverse range of cell culture media applications, increased research and development in the pharmaceutical industry, an increase in the prevalence of chronic diseases, and increased expansion and product launches by major players. Over the last few decades, advancements in cell culture technology have accelerated. It is widely regarded as one of the most dependable, robust, and mature technologies for biotherapeutic product development.

The high cost of cell culture media and the risk of contamination, on the other hand, are impeding the markets growth. However, the growing emphasis on regenerative and personalized medicine is likely to spur growth in the global cell culture media market.

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Competitive Dynamics

The notable players are the Merck KGaA (Germany), Bio-Rad Laboratories, Inc. (US), Thermo Fisher Scientific Inc. (US), Lonza (Switzerland), GE Healthcare (US), Becton, Dickinson and Company (US), HiMedia Laboratories (India), Corning Incorporated (US), PromoCell (Germany), Sera Scandia A/S (Denmark), The Sartorius Group (Germany), and Fujifilm Holdings Corporation (Japan).

Segmental Analysis

The global market for cell culture media has been segmented according to product type, application, and end user.

The market has been segmented by product type into classical media, stem cell media, serum-free media, and others.

Further subcategories of stem cell culture media include bone marrow, embryonic stem cells, mesenchymal stem cells, and neural stem cells.

The market is segmented into four application segments: drug discovery and development, cancer research, genetic engineering, and tissue engineering and biochemistry.

The market is segmented by end user into biochemistry and pharmaceutical companies, research laboratories, academic institutions, and pathology laboratories.

Regional Overview

According to region, the global cell culture media market is segmented into the Americas, Europe, Asia-Pacific, and the Middle East & Africa.

The Americas dominated the global cell culture media market. The large share is attributed to the presence of major manufacturers, rising disease prevalence resulting in increased demand for drugs and other medications, technological advancements in the preclinical and clinical segments, growing public awareness, and high disposable income.

Europe ranks second in terms of market size for cell culture media. Factors such as an increase in the biopharmaceutical sector in the European region, increased government initiatives to promote research to find a cure for the growing number of chronic diseases, an increase in the number of pharmaceutical manufacturers, improving economies, a high disposable income per individual, and increased healthcare spending are all contributing to the markets growth in this region. The European market is expected to be driven by expanding R&D activities and a developing biopharmaceutical sector.

Asia-Pacific held the third-largest market share, owing to the presence of numerous research organizations, low manufacturing costs, low labor costs, developing healthcare infrastructure, and increased investment by American and European market giants in Asian countries such as China and India.

The Middle East and Africa, with limited economic development and extremely low income, held the smallest market share in 2019 but is expected to grow due to growing public awareness and demand for improved healthcare facilities in countries, as well as rising disposable income.

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Stem Cell Therapy Market Size, Scope, Growth Opportunities, Trends by Manufacturers And Forecast to 2029 This Is Ardee – This Is Ardee

By Embryonic Stem Cells

New Jersey, United States TheStem Cell TherapyMarket research guides new entrants to obtain precise market data and communicates with customers to know their requirements and preferences. It spots outright business opportunities and helps to bring new products into the market. It identifies opportunities in the marketplace. It aims at doing modifications in the business to make business procedures smooth and make business forward. It helps business players to make sound decision making. Stem Cell Therapy market report helps to reduce business risks and provides ways to deal with upcoming challenges. Market information provided here helps new entrants to take informed decisions making. It emphasizes on major regions of the globe such as Europe, North America, Asia Pacific, Middle East, Africa, and Latin America along with their market size.

Such unique Stem Cell Therapy Market research report offers some extensive strategic plans that help the players to deal with the current market situation and make your position. It helps in strengthening your business position. It offers better understanding of the market and keep perspective to aid one remain ahead in this competitive market. Organizations can gauze and compare their presentation with others in the market on the basis of this prompt market report. This market report offers a clarified picture of the varying market tactics and thereby helps the business organizations gain bigger profits. You get a clear idea about the product launches, trade regulations and expansion of the market place through this market report.

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Key Players Mentioned in the Stem Cell Therapy Market Research Report:

Osiris Therapeutics Medipost Co. Ltd., Anterogen Co. Ltd., Pharmicell Co. Ltd., HolostemTerapieAvanzateSrl, JCR Pharmaceuticals Co. Ltd., Nuvasive RTI Surgical Allosource

Stem Cell TherapyMarket report consists of important data about the entire market environment of products or services offered by different industry players. It enables industries to know the market scenario of a particular product or service including demand, supply, market structure, pricing structure, and trend analysis. It is of great assistance in the product market development. It further depicts essential data regarding customers, products, competition, and market growth factors. Stem Cell Therapy market research benefits greatly to make the proper decision. Future trends are also revealed for particular products or services to help business players in making the right investment and launching products into the market.

Stem Cell TherapyMarket Segmentation:

Stem Cell Therapy Market, By Cell Source

Adipose Tissue-Derived Mesenchymal Stem Cells Bone Marrow-Derived Mesenchymal Stem Cells Cord Blood/Embryonic Stem Cells Other Cell Sources

Stem Cell Therapy Market, By Therapeutic Application

Musculoskeletal Disorders Wounds and Injuries Cardiovascular Diseases Surgeries Gastrointestinal Diseases Other Applications

Stem Cell Therapy Market, By Type

Allogeneic Stem Cell Therapy Autologous Stem Cell Therapy

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For Prepare TOC Our Analyst deep Researched the Following Things:

Report Overview:It includes major players of the Stem Cell Therapy market covered in the research study, research scope, market segments by type, market segments by application, years considered for the research study, and objectives of the report.

Global Growth Trends:This section focuses on industry trends where market drivers and top market trends are shed light upon. It also provides growth rates of key producers operating in the Stem Cell Therapy market. Furthermore, it offers production and capacity analysis where marketing pricing trends, capacity, production, and production value of the Stem Cell Therapy market are discussed.

Market Share by Manufacturers:Here, the report provides details about revenue by manufacturers, production and capacity by manufacturers, price by manufacturers, expansion plans, mergers and acquisitions, and products, market entry dates, distribution, and market areas of key manufacturers.

Market Size by Type:This section concentrates on product type segments where production value market share, price, and production market share by product type are discussed.

Market Size by Application:Besides an overview of the Stem Cell Therapy market by application, it gives a study on the consumption in the Stem Cell Therapy market by application.

Production by Region:Here, the production value growth rate, production growth rate, import and export, and key players of each regional market are provided.

Consumption by Region:This section provides information on the consumption in each regional market studied in the report. The consumption is discussed on the basis of country, application, and product type.

Company Profiles:Almost all leading players of the Stem Cell Therapy market are profiled in this section. The analysts have provided information about their recent developments in the Stem Cell Therapy market, products, revenue, production, business, and company.

Market Forecast by Production:The production and production value forecasts included in this section are for the Stem Cell Therapy market as well as for key regional markets.

Market Forecast by Consumption:The consumption and consumption value forecasts included in this section are for the Stem Cell Therapy market as well as for key regional markets.

Value Chain and Sales Analysis:It deeply analyzes customers, distributors, sales channels, and value chain of the Stem Cell Therapy market.

Key Findings:This section gives a quick look at the important findings of the research study.

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Stem Cell Therapy Market Size, Scope, Growth Opportunities, Trends by Manufacturers And Forecast to 2029 This Is Ardee - This Is Ardee

Human iPSC co-culture model to investigate the interaction between microglia and motor neurons | Scientific Reports – Nature.com

By Induced Pluripotent Stem Cells

Ethics statement

All human material (blood RNA, primary microglia RNA, iPSCs) used in this study was derived after signed informed consent: for blood, according to University of Oxford OHS policy document 1/03; all procedures related to the use of the primary microglia followed established institutional (McGill University, Montreal, QC, Canada) and Canadian Institutes of Health Research guidelines for the use of human cells; for iPSC, with approval from the South Central Berkshire Research Ethics Committee, U.K. (REC 10/H0505/71). The blood RNA and primary microglia RNA samples have been published previously26, as have the iPSC lines (see below).

Four healthy control iPSC lines, SFC840-03-03 (female, 67years old,35), SFC841-03-01 (male, 36,18), SFC856-03-04 (female, 78,36), OX3-06 (male, 49,37), generated from skin biopsy fibroblasts and characterized as described before, were used in this study. Additionally, the previously reported26 line AH016-3 Lenti_IP_RFP (male, 80years old), which constitutively expresses Red Fluorescent Protein (RFP) under continuous puromycin selection, was used for some live-imaging experiments.

iPSCs were cultured in mTeSR1 (StemCell Technologies) or OXE8 medium38 on Geltrex (Thermo Fisher)-coated tissue culture plates with daily medium changes. Passaging was done as clumps using EDTA in PBS (0.5mM). Cells were initially expanded at low passage to create a master stock, which was used for all experiments to ensure consistency. Cells were regularly tested negative for mycoplasma using MycoAlert Mycoplasma Detection Kit (Lonza).

iPSCs were differentiated to MNs according to our previously published protocol18,19,27. Briefly, neural induction of iPSC monolayers was performed using DMEM-F12/Neurobasal 50:50 medium supplemented with N2 (1X), B27 (1X), 2-Mercaptoethanol (1X), AntibioticAntimycotic (1X, all ThermoFisher), Ascorbic Acid (0.5M), Compound C (1M, both Merck), and Chir99021 (3M, R&D Systems). After two days in culture, Retinoic Acid (RA, 1M, Merck) and Smoothened Agonist (SAG, 500nM, R&D Systems) were additionally added to the medium. Two days later, Compound C and Chir99021 were removed from the medium. After another 5days in culture, neural precursors were dissociated using accutase (ThermoFisher), and split 1:3 onto Geltrex-coated tissue culture plates in medium supplemented with Y-27632 dihydrochloride (10M, R&D Systems). After one day, Y-27632 dihydrochloride was removed from the medium, and then the cells were cultured for another 8days with medium changes every other day. For terminal maturation, the cells were dissociated on day in vitro (DIV) 18 using accutase and plated onto coverslips or tissue culture plates coated with polyethylenimine (PEI, 0.07%, Merck) and Geltrex or tissue culture dishes coated with PDL (Sigma-Aldrich)/ Laminin (R&D Systems)/ Fibronectin (Corning). For this step, the medium was additionally supplemented with BDNF (10ng/mL), GDNF (10ng/mL), Laminin (0.5g/mL, all ThermoFisher), Y-27632 dihydrochloride (10M), and DAPT (10M, R&D Systems). Three days later, Y-27632 dihydrochloride was removed from the medium. After another three days, DAPT was removed from the medium. Full medium changes were then performed every three days.

For MNs differentiated in co-culture medium alone, all steps were performed similarly until three days after the terminal re-plating (D21). MNs were then cultured in co-culture medium as described below.

iPSCs were differentiated to macrophage/microglia precursors as described previously20,21. Briefly, embryoid body (EB) formation was induced by seeding iPSCs into Aggrewell 800 wells (STEMCELL Technologies) in OXE838 or mTeSR1 medium supplemented with Bone Morphogenetic Protein 4 (BMP4, 50ng/mL), Vascular Endothelial Growth Factor (VEGF, 50ng/mL, both Peprotech), and Stem Cell Factor (SCF, 20ng/mL, Miltenyi Biotec). After four days with daily medium changes, EBs were transferred to T175 flasks (~150 EBs each) and differentiated in X-VIVO15 (Lonza), supplemented with Interleukin-3 (IL-3, 25ng/mL, R&D Systems), Macrophage Colony-Stimulating Factor (M-CSF, 100ng/mL), GlutaMAX (1X, both ThermoFisher), and 2-Mercaptoethanol (1X). Fresh medium was added weekly. After approximately one month, precursors emerged into the supernatant and could be harvested weekly. Harvested cells were passed through a cell strainer (40M, Falcon) and either lysed directly for RNA extraction or differentiated to microglia in monoculture or co-culture as described below.

Three days after the final re-plating of differentiating MNs (DIV21), macrophage/microglia precursors were harvested as described above and resuspended in co-culture medium comprised of Advanced DMEM-F12 (ThermoFisher) supplemented with GlutaMAX (1X), N2 (1X), AntibioticAntimycotic (1X), 2-Mercaptoethanol (1X), Interleukin-34 (IL-34, 100ng/mL, Peprotech), BDNF (10ng/mL), GDNF (10ng/mL), and Laminin (0.5g/mL). MNs were quickly rinsed with PBS, and macrophage/microglia precursors re-suspended in co-culture medium were added to each well. Co-cultures were then maintained for at least 14days before assays were conducted as described below. Half medium changes were performed every 23days.

For comparisons between co-cultures and monocultures, MNs and monocultured microglia were also differentiated alone in co-culture medium.

Cells cultured on coverslips were pre-fixed with 2% paraformaldehyde in PBS for 2min and then fixed with 4% paraformaldehyde in PBS for 15min at room temperature (RT). After permeabilization and blocking with 5% donkey/goat serum and 0.2% Triton X-100 in PBS for 1h at RT, the coverslips were incubated with primary antibodies diluted in 1% donkey/goat serum and 0.1% Triton X-100 in PBS at 4C ON. The following primary antibodies were used: rabbit anti-cleaved caspase 3 (1:400, 9661S, Cell Signaling), mouse anti-ISLET1 (1:50, 40.2D6, Developmental Studies Hybridoma Bank), mouse anti-TUJ1 (1:500, 801201, BioLegend), rabbit anti-TUJ1 (1:500, 802001, BioLegend), chicken anti-TUJ1 (1:500, GTX85469, GeneTex), rabbit anti-IBA1 (1:500, 019-19741, FUJIFILM Wako Pure Chemical Corporation), goat anti-IBA1 (1:500, ab5076, abcam), rabbit anti-synaptophysin (1:200, ab14692, abcam), goat anti-ChAT (1:100, ab114P, abcam), rat anti-TREM2 (1:100, MAB17291-100, R&D Systems), rabbit anti-TMEM119 (1:100, ab185337, abcam), rat anti-CD11b (1:100, 101202, BioLegend).

After three washes with PBS-0.1% Triton X-100 for 5min each, coverslips were incubated with corresponding fluorescent secondary antibodies Alexa Fluor 488/568/647 donkey anti-mouse/rabbit/rat/goat, goat anti-chicken (all 1:1000, all ThermoFisher). Coverslips were then washed twice with PBS-0.1% Triton X-100 for 5min each and incubated with 4,6-diamidino-2-phenylindole (DAPI, 1g/mL, Sigma-Aldrich) in PBS for 10min. After an additional 5min-washing step with PBS-0.1% Triton X-100, the coverslips were mounted onto microscopy slides using ProLong Diamond Antifade Mountant (ThermoFisher). Confocal microscopy was then performed using an LSM 710 microscope (Zeiss).

For the analysis of neuronal and MN markers after differentiation, three z-stacks (2m intervals) of randomly selected visual fields (425.1425.1m) were taken for each coverslip at 20magnification. The ratios of TUJ1-positive, ChAT-positive, ISLET1-positive, ChAT-positive/ TUJ1-positive, and ISLET1-positive/ TUJ1-positive cells were then quantified using Fiji in a blinded fashion.

For the analysis of microglial markers in monoculture and co-culture, three z-stacks (1m intervals) of randomly selected visual fields (212.55212.55m) were taken for each coverslip at 40magnification. The expression of CD11b, TMEM119, and TREM2 in IBA1-positive cells in monoculture and co-culture was then quantified using Fiji.

For the analysis of apoptosis in neurons, five z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. The ratios of cleaved caspase 3/ TUJ1-positive cells were then quantified for neurons in monoculture and co-culture in a blinded fashion. For the analysis of apoptosis in microglia, three z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. The ratios of cleaved caspase 3/ IBA1-positive cells were then quantified for microglia in monoculture and co-culture.

For the analysis of microglial ramifications, five z-stacks images of randomly selected visual fields (212.55212.55m) were taken at 40magnification for each coverslip. To analyze the branching of IBA1-positive microglia in monoculture and co-culture, the average branch length, number of branch points and number of branch endpoints was determined using 3DMorph39, a Matlab-based script for the automated analysis of microglial morphology.

From the same harvest, macrophage precursors (pMacpre) were either lysed directly or differentiated to microglia in monoculture (pMGL) or microglia in co-culture with MNs (co-pMG) for 14days. pMGL were rinsed with PBS and directly lysed in the dish. For both pMacpre and pMGL, RNA was extracted using an RNAeasy Mini Plus kit (Qiagen) according to the manufacturers instructions. Co-cultures were first dissociated by 15min incubation with papain (P4762, Sigma-Aldrich) diluted in accutase (20 U/mL) and gentle trituration based on a previously published protocol40. The cell suspension was then passed through a cell strainer (70m, Falcon) to remove cell clumps. To extract co-pMG, magnetic-activated cell sorting (MACS) was then performed using CD11b-MACS beads (130093-634, Miltenyi Biotec) according to the manufacturers instructions. The panned cell population was lysed for RNA extraction using an RNAeasy Micro kit (Qiagen) according to the manufacturers instructions. In addition, RNA from human fetal microglia and blood monocytes from three different healthy genetic backgrounds wasre-used from our previous study26.

RNA from the four different healthy control lines (listed earlier) per condition (pMacpre, pMGL, co-pMG) was used for RNA sequencing analysis. Material was quantified using RiboGreen (Invitrogen) on the FLUOstar OPTIMA plate reader (BMG Labtech) and the size profile and integrity analysed on the 2200 or 4200 TapeStation (Agilent, RNA ScreenTape). RIN estimates for all samples were between 9.2 and 9.9. Input material was normalised to 100ng prior to library preparation. Polyadenylated transcript enrichment and strand specific library preparation was completed using NEBNext Ultra II mRNA kit (NEB) following manufacturers instructions. Libraries were amplified (14 cycles) on a Tetrad (Bio-Rad) using in-house unique dual indexing primers (based on41). Individual libraries were normalised using Qubit, and the size profile was analysed on the 2200 or 4200 TapeStation. Individual libraries were normalised and pooled together accordingly. The pooled library was diluted to~10nM for storage. The 10nM library was denatured and further diluted prior to loading on the sequencer. Paired end sequencing was performed using a NovaSeq6000 platform (Illumina, NovaSeq 6000 S2/S4 reagent kit, v1.5, 300 cycles), generating a raw read count of a minimum of 34M reads per sample.

Further processing of the raw data was then performed using an in-house pipeline. For comparison, the RNA sequencing data (GSE89189) fromAbud et al.28 and the dataset (GSE85839) fromMuffat et al.29 were downloaded and processed in parallel. Quality control of fastq files was performed using FastQC (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and MultiQC42. Paired-end reads were mapped to the human GRCh38.p13 reference genome (https://www.gencodegenes.org) using HISAT2 v2.2.143. Mapping quality control was done using SAMtools44 and Picard (http://broadinstitute.github.io/picard/) metrics. The counts table was obtained using FeatureCounts v2.0.145. Normalization of counts and differential expression analysis for the comparison of pMGL and co-pMG was performed using DESeq2 v1.28.146 in RStudio 1.4.1103, including the biological gender in the model and with the BenjaminiHochberg method for multiple testing correction. Exploratory data analysis was performed following variance-stabilizing transformation of the counts table, using heat maps and hierarchical clustering with the pheatmap 1.0.12 package (https://github.com/raivokolde/pheatmap) and principal component analysis. Log2 fold change (log2 fc) shrinkage for the comparison of pMGL and co-pMG was performed using the ashr package v2.2-4747. Genes with |log2 fc|>2 and adjusted p value<0.01 were defined as differentially expressed and interpreted with annotations from the Gene Ontology database using clusterProfiler v3.16.148 to perform over-representation analyses.

Equal amounts of RNA (30ng) were reverse-transcribed to cDNA using the High-Capacity cDNA Reverse Transcription Kit (ThermoFisher) according to the manufacturers instructions. Quantitative real-time PCR was performed with Fast SYBR Green Master Mix (ThermoFisher) according to the manufacturers instructions using a LightCycler 480 PCR System (Roche). The following primers (ChAT from Eurofins Genomics, all others from ThermoFisher) were used:

Quantification of the relative fold gene expression of samples was performed using the 2Ct method with normalization to the GAPDH reference gene.

AH016-3 Lenti-IP-RFP-microglia were co-cultured with healthy control motor neurons in PEI- and Geltrex-coated glass bottom dishes for confocal microscopy (VWR). The RFP signal was used to identify microglia in co-culture. To visualize microglial movement, images of the RFP signal and brightfield were taken every~30s for 1h (22 stitched images, 20magnification) using a Cell Observer spinning disc confocal microscope (Zeiss) equipped with an incubation system (37C, 5% CO2). To image phagocytic activity, co-cultures were rinsed with Live Cell Imaging Solution (1X, ThermoFisher), and pHrodo Green Zymosan Bioparticles Conjugates (P35365, ThermoFisher) diluted in Live Cell Imaging Solution (50g/mL), which become fluorescent upon phagocytic uptake, were added. The dish was immediately transferred to the spinning disc confocal microscope, and stitched images (33, 20magnification) were acquired every 5min for 2h.

To induce pro-inflammatory (M1) or anti-inflammatory (M2) microglial phenotypes, cells were treated with Lipopolysaccharides (LPS, 100ng/mL, Sigma) and Interferon- (IFN-, 100ng/mL, ThermoFisher), or Interleukin-4 (IL-4, 40ng/mL, R&D Systems) and Interleukin-13 (IL-13, 20ng/mL, Peprotech), respectively, for 18h. Vehicle-treated (co-culture medium) cells were used as an unstimulated (M0) control.

To analyze the clustering of microglia upon pro-inflammatory and anti-inflammatory stimulation, RFP-positive microglia were imaged directly before the addition of M1/M2 inducing agents, and at 9h and 18h post-stimulation using the Cell Observer spinning disc confocal microscope (55 stitched images, 10magnification). The number of individual microglial cells and size of microglial clusters was quantified using the analyze particle function in Fiji.

After stimulation with M1/M2-inducing agents, culture supernatants were collected and spun down at 1200g for 10min at 4C. Pooled samples from three different healthy control lines for each cell type were analyzed using the Proteome Profiler Human XL Cytokine Array Kit (R&D Systems) according to the manufacturers instructions. The signal was visualized on a ChemiDoc MP imaging system (Bio-Rad) and analyzed using ImageStudioLite v5.2.5 (LI-COR). Data was then plotted as arbitrary units using the pheatmap 1.0.12 package in RStudio 1.4.1103.

In addition, to confirm the relative expression of Serpin E1 and CHI3L1 in cell culture supernatants, the Human Human Chitinase 3-like 1 Quantikine ELISA Kit (DC3L10) and Human Serpin E1/PAI-1 Quantikine ELISA Kit (DSE100, both R&D Systems) were used according to the manufacturers instructions.

pNeuron, pMGL and co-cultures were plated and maintained in WillCo-dish Glass Bottom Dishes (WillCo Wells) for 14days. Calcium transients were measured using the fluorescent probe Fluo 4-AM according to the manufacturers instructions (ThermoFisher). Cells were incubated with 20M Fluo 4-AM resuspended in 0.2% dimethyl sulfoxide for 30min at RT in Live Imaging Solution (ThermoFisher). After a washing step with Live Imaging Solution, cells were allowed to calibrate at RT for 1520min before imaging. Ca2+ images were taken by fluorescence microscopy at RT. The dye was excited at 488nm and images were taken continuously with a baseline recorded for 30s before stimulation. The stimuli used for calcium release were 50mM KCl (Sigma-Aldrich) for 30s, followed by a washing step for one minute. Microglial calcium release was stimulated by 50M ADP (Merck) under continuous perfusion for 1min, followed by a 1-min wash. Analysis of fluorescence intensity was performed using Fiji. Fluorescence measurements are expressed as a ratio (F/Fo) of the mean change in fluorescence (F) at a pixel relative to the resting fluorescence at that pixel before stimulation (Fo). The responses were analysed in 2040 cells per culture.

MNs on DIV 3345 were maintained in a bath temperature of 25C in a solution containing 167mM NaCl, 2.4mM KCl, 1mM MgCl2, 10mM glucose, 10mM HEPES, and 2mM CaCl2 adjusted to a pH of 7.4 and 300mOsm. Electrodes with tip resistances between 3 and 7M were produced from borosilicate glass (0.86mm inner diameter; 1.5mm outer diameter). The electrode was filled with intracellular solution containing 140mMK-Gluconate, 6mM NaCl, 1mM EGTA, 10mM HEPES, 4mM MgATP, 0.5mM Na3GTP, adjusted to pH 7.3 and 290mOsm. Data acquisition was performed using a Multiclamp 700B amplifier, digidata 1550A and clampEx 6 software (pCLAMP Software suite, Molecular Devices). Data was filtered at 2kHz and digitized at 10kHz. Series resistance (Rs) was continuously monitored and only recordings with stable<50 M and Rs<20% were included in the analysis. Voltage gated channel currents were measured on voltage clamp, neurons were pre-pulsed for 250ms with 140mV and subsequently a 10mV-step voltage was applied from 70 to+70mV. Induced action potentials were recorded on current clamp, neurons were held at 70mV and 8 voltage steps of 10mV, from 10 to 60mV, were applied. Data was analyzed using Clampfit 10.7 (pCLAMP Software suite).

Statistical analyses were conducted using GraphPad Prism 9 (GraphPad Software, San Diego, California USA, http://www.graphpad.com). Comparisons of two groups were performed by two-tailed unpaired t-tests and multiple group comparisons by one-way or two-way analysis of variance (ANOVA) with appropriate post-hoc tests as indicated in the figure legends. The statistical test and number of independent experiments used for each analysis are indicated in each figure legend. Data are presented as single data points and meansSEM. Differences were considered significant when P<0.05 (*P<0.05; **P<0.01; ***P<0.001; ns: not significant). GraphPad Prism 9 or RStudio 1.4.1103 were used to plot data. Final assembly and preparation of all figures was done using Adobe Illustrator 25.4.1.

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Human iPSC co-culture model to investigate the interaction between microglia and motor neurons | Scientific Reports - Nature.com

What lab-grown cerebral organoids are revealing about the brain – New Scientist

By Induced Pluripotent Stem Cells

Blobs of human brain cells cultivated in the lab, known as brain organoids or mini-brains, are transforming our understanding of neural development and disease. Now, researchers are working to make them more like the real thing

By Clare Wilson

Neil Webb

A DOZEN tiny, creamy balls are suspended in a dish of clear, pink liquid. Seen with the naked eye, they are amorphous blobs. But under a powerful microscope, and with some clever staining, their internal complexity is revealed: intricate whorls and layers of red, blue and green.

These are human brain cells, complete with branching outgrowths that have connected with one other, sparking electrical impulses. This is the stuff that thoughts are made of. And yet, these collections of cells were made in a laboratory in this case, in the lab of Madeline Lancaster at the University of Cambridge.

The structures, known as brain organoids or sometimes mini-brains, hold immense promise for helping us understand the brain. They have already produced fresh insights into how this most mysterious organ functions, how it differs in people with autism and how it goes awry in conditions such as dementia and motor neurone disease. They have even been made to grow primitive eyes.

To truly fulfill the potential of mini-brains, however, neuroscientists want to make them bigger and more complex. Some are attempting to grow them with blood vessels. Others are fusing two organoids, each mimicking a different part of the brain. Should they succeed, their lab-grown brains could model development and disease in the real thing in greater detail than ever before, paving the way to new insights and treatments.

But as researchers seek to make mini-brains genuinely worthy of the name, they move ever closer to a crucial question: at what point will their creations approach sentience?

The key to developing organoids was the discovery of stem cells,

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What lab-grown cerebral organoids are revealing about the brain - New Scientist

Dean Kamen on the power of celebrating your own obsoletion – TechCrunch

By Induced Pluripotent Stem Cells

More than 40 years and 1,000 or so patents after selling his first company, AutoSyringe, to healthcare giant Baxter, Dean Kamen still gets a charge describing breakthrough innovation. Its been five years since his organ fabricating project ARMI (Advanced Regenerative Manufacturing Institute) divided critics.

The project made more waves early last month, at the CNN-hosted conference Life Itself. Kamen paints the picture appearing on a panel at TC Sessions: Robotics today:

Doris Taylor, who moved up here from where she spent more than a decade in Texas, at the Texas Heart Institute, she gets on stage with a beaker. In the beaker is a miniature, pediatric-scale beating heart that was manufactured with induced pluripotent stem cells were put into a scaffold of preexisting organ. Within an hour of that presentation, Martine Rothblatt, the founder and chairman of United Therapeutics, is on stage and they roll out from backstage an almost surrealistic, lit from the top of the box. A panel opens, and what emerges out of the top of this platform is a scaffold of a human lung, that was printed, entirely printed at the smallest scale any printer has ever operated.

Inventor Dean Kamen looks on as over 110,000 pounds of personal protective equipment (PPE), shipped from Shanghai, China, is unloaded from a cargo plane at Manchester-Boston Regional Airport in Manchester, New Hampshire, Thursday, April 30, 2020. The equipment will be used for medical workers and first responders in their fight against the virus outbreak. (AP Photo/Charles Krupa)

Kamen is first to admit, however, that the path to all success is paved with failure. The trick is learning the right lesson.

What Ive learned from failure is go back and decide was the fundamental goal wrong thats why it failed, you succeeded, but nobody needs this or did the available technology and your systems integration and application have it wrong, in which case, youve now learned enough, go try again, go use a different approach, Kamen explains. Pick yourself up, try again, using a different approach. And it really doesnt matter how many times you fall down. If you fall down five times, but you stand up six, its okay. And in the end, you only need a win every once in a while to keep your confidence up. And hopefully, to give you the resources to keep going even though inevitably youll have failures, let the projects fail, dont let the people fail.

These are among the fundamentals Kamen has attempted to infuse into FIRST, the education program he co-founded in 1989, with MIT professor Woodie Flowers. It is best known for its robotics competitions, which center around competitive builds of robots and other projects, bringing the teamwork and enthusiasm of sports to STEM education subjects that might otherwise turn off students who traditionally encounter them in more formal and staid settings.

Kids wont go to class, or theyll take math for 45 minutes between phonics and spelling, one day a week. But theyll go after school for three hourse, every single day to get better at football or get better at basketball. So I said, look, were not competing for the hearts and minds of kids with the science fair and the spelling bee, were competing with the things that they invest all of their time, energy and passion in. So lets use that model make it aspirational, make it after school. Dont give them quizzes and tests, give them letters and trophies. Bring the school band and the mascots.

U.S. Sen. Jeanne Shaheen (D-NH), right, looks toward inventor Dean Kamen as over 110,000 pounds of personal protective equipment (PPE) from Shanghai, China, delivered to protect medical workers and first responders fighting the COVID-19 virus outbreak, is unloaded from a cargo plane at Manchester-Boston Regional Airport in Manchester, New Hampshire, Thursday, April 30, 2020. (AP Photo/Charles Krupa)

Perhaps the hardest-fought lesson of all, however, is understanding, accepting and even welcoming the fact that progress in technology and sciences means that one day your best work will be eclipsed.

You have to be more than prepared for it. You have to be confident it will happen, and you have to celebrate it. I celebrate it more when its me that obsoleted the last thing I did, but if somebody else can obsolete it and if I get to a point where I need a better clinical solution than a dialysis machine or an insulin pump, if I can get to a place with somebody elses technology to gave me a new organ or a prosthetic limb or something, I need to have a better quality of life, I will thank that person. And I hope I will return that favor by giving them something of value that we invented.

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Dean Kamen on the power of celebrating your own obsoletion - TechCrunch

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