Update: Todos Medical Reports Fourth-Quarter and Full-Year 2021 Financial Results and Corporate Updates
By Dr. Matthew Watson
New York, NY, and Tel Aviv, ISRAEL, April 01, 2022 (GLOBE NEWSWIRE) -- via NewMediaWire -- Todos Medical, Ltd. (OTCQB: TOMDF), a comprehensive medical diagnostics and related solutions company, today reported financial results for the fourth quarter and full-year ended December 31, 2021 and provided corporate updates.
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Update: Todos Medical Reports Fourth-Quarter and Full-Year 2021 Financial Results and Corporate Updates
TCR² Therapeutics Reports Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)
By Dr. Matthew Watson
CAMBRIDGE, Mass., April 01, 2022 (GLOBE NEWSWIRE) -- TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage cell therapy company with a pipeline of novel T cell therapies for patients suffering from solid tumors, today announced that on March 31, 2022 (the “Grant Date”), the Compensation Committee of the Board of Directors of TCR2’s approved the grant of inducement stock options covering an aggregate of 73,000 shares of TCR2’s common stock to 9 new non-executive employees. The stock options were granted as an inducement material to the employees’ acceptance of employment with TCR2 in accordance with Nasdaq Listing Rule 5635(c)(4).
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TCR² Therapeutics Reports Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)
ASLAN Pharmaceuticals Announces Receipt of Nasdaq Deficiency Notice Regarding Minimum Bid Price Requirement
By Dr. Matthew Watson
MENLO PARK, Calif. and SINGAPORE, April 01, 2022 (GLOBE NEWSWIRE) -- ASLAN Pharmaceuticals (NASDAQ: ASLN) ("ASLAN" or the "Company"), announced today that on March 28, 2022, it received a written notice (the "Notice") from the Listing Qualifications Department of The Nasdaq Stock Market LLC ("Nasdaq") indicating that the Company is not in compliance with the US$1.00 minimum bid price requirement under the Nasdaq Listing Rules (the "Listing Rules"). Based on the closing bid price of the Company's listed securities for the last 30 consecutive business days from February 11, 2022 to March 25, 2022, the Company has not met the minimum bid price requirement set forth in Listing Rule 5550(a)(2) during that period. The Notice is only a notification of deficiency and has no immediate effect on the listing of the Company’s American Depositary Shares (“ADS”). The Company’s ADSs will continue to trade on the Nasdaq Global Market at this time. The Company’s receipt of the Notice does not impact the Company’s business, operations or reporting requirements with the Securities and Exchange Commission.
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ASLAN Pharmaceuticals Announces Receipt of Nasdaq Deficiency Notice Regarding Minimum Bid Price Requirement
Oncternal Therapeutics Reports Granting of Inducement Award Under Nasdaq Listing Rule 5635(c)(4)
By Dr. Matthew Watson
SAN DIEGO, April 01, 2022 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced that it has granted an inducement award to one new employee, Rachel Monet Kenny, who joined the Company as Associate Director, CMC and Clinical Supply Chain.
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Oncternal Therapeutics Reports Granting of Inducement Award Under Nasdaq Listing Rule 5635(c)(4)
Sotagliflozin Improved Outcomes in Patients With and Without Prior Cardiovascular Disease in New Analysis Presented at the American College of…
By Dr. Matthew Watson
Late-breaking presentation of analysis of SCORED clinical trial data describes significant reduction in cardiovascular death, myocardial infarction and stroke with sotagliflozin treatment as compared to placebo Late-breaking presentation of analysis of SCORED clinical trial data describes significant reduction in cardiovascular death, myocardial infarction and stroke with sotagliflozin treatment as compared to placebo
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Sotagliflozin Improved Outcomes in Patients With and Without Prior Cardiovascular Disease in New Analysis Presented at the American College of...
Are COVID-19-Linked Arrhythmias Caused by Viral Damage to the Heart’s Pacemaker Cells? – Weill Cornell Medicine Newsroom
By daniellenierenberg
The SARS-CoV-2 virus can infect specialized pacemaker cells that maintain the hearts rhythmic beat, setting off a self-destruction process within the cells, according to a preclinical study co-led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and NYU Grossman School of Medicine. The findings offer a possible explanation for the heart arrhythmias that are commonly observed in patients with SARS-CoV-2 infection.
In the study, reported March 8 in Circulation Research, the researchers used an animal model as well as human stem cell-derived pacemaker cells to show that SARS-CoV-2 can readily infect pacemaker cells and trigger a process called ferroptosis, in which the cells self-destruct but also produce reactive oxygen molecules that can impact nearby cells.
This is a surprising and apparently unique vulnerability of these cellswe looked at a variety of other human cell types that can be infected by SARS-CoV-2, including even heart muscle cells, but found signs of ferroptosis only in the pacemaker cells, said study co-senior author Dr. Shuibing Chen, the Kilts Family Professor of Surgery and a professor of chemical biology in surgery and of chemical biology in biochemistry at Weill Cornell Medicine.
Arrhythmias including too-quick (tachycardia) and too-slow (bradycardia) heart rhythms have been noted among many COVID-19 patients, and multiple studies have linked these abnormal rhythms to worse COVID-19 outcomes. How SARS-CoV-2 infection could cause such arrhythmias has been unclear, though.
In the new study, the researchers, including co-senior author Dr. Benjamin tenOever of NYU Grossman School of Medicine, examined golden hamstersone of the only lab animals that reliably develops COVID-19-like signs from SARS-CoV-2 infectionand found evidence that following nasal exposure the virus can infect the cells of the natural cardiac pacemaker unit, known as the sinoatrial node.
To study SARS-CoV-2s effects on pacemaker cells in more detail and with human cells, the researchers used advanced stem cell techniques to induce human embryonic stem cells to mature into cells closely resembling sinoatrial node cells. They showed that these induced human pacemaker cells express the receptor ACE2 and other factors SARS-CoV-2 uses to get into cells and are readily infected by SARS-CoV-2. The researchers also observed large increases in inflammatory immune gene activity in the infected cells.
The teams most surprising finding, however, was that the pacemaker cells, in response to the stress of infection, showed clear signs of a cellular self-destruct process called ferroptosis, which involves accumulation of iron and the runaway production of cell-destroying reactive oxygen molecules. The scientists were able to reverse these signs in the cells using compounds that are known to bind iron and inhibit ferroptosis.
This finding suggests that some of the cardiac arrhythmias detected in COVID-19 patients could be caused by ferroptosis damage to the sinoatrial node, said co-senior author Dr. Robert Schwartz, an associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Although in principle COVID-19 patients could be treated with ferroptosis inhibitors specifically to protect sinoatrial node cells, antiviral drugs that block the effects of SARS-CoV-2 infection in all cell types would be preferable, the researchers said.
The researchers plan to continue to use their cell and animal models to investigate sinoatrial node damage in COVID-19and beyond.
There are other human sinoatrial arrhythmia syndromes we could model with our platform, said co-senior author Dr. Todd Evans, the Peter I. Pressman M.D. Professor of Surgery and associate dean for research at Weill Cornell Medicine. And, although physicians currently can use an artificial electronic pacemaker to replace the function of a damaged sinoatrial node, theres the potential here to use sinoatrial cells such as weve developed as an alternative, cell-based pacemaker therapy.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosurespublic to ensure transparency. For this information, see profiles for Dr. Todd Evans, and Dr. Robert Schwartz.
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Are COVID-19-Linked Arrhythmias Caused by Viral Damage to the Heart's Pacemaker Cells? - Weill Cornell Medicine Newsroom
#VisualAbstract: Cardiosphere-derived cell therapy slows disease progression in Duchenne muscular dystrophy – Physician’s Weekly
By daniellenierenberg
Evidence Rating Level:1 (Excellent)
Study Rundown:Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration leading to significant reduction in life expectancy. Males with DMD have an estimated life expectancy of 22 years with heart and respiratory muscles affected in later disease stages. In this phase 2 trial, a formulation of allogenic cardiosphere-derived cells (CAP-1002) was evaluated against placebo in patients with DMD. CAP-1002 is, in essence, a concentrate of cardiac stem cells with potential disease-modifying properties such as regenerative abilities. Participants (n=20) were randomized 1:1 to receive either CAP-1002 or placebo every three months for four total infusions. Primary outcome was upper limb function measured by a scale of 0-6 (PUL). CAP-1002 was shown to slow PUL decline by 71% compared to placebo or by an absolute difference of 2.6 points. CAP-1002 was generally well-tolerated with only one severe adverse hypersensitivity reaction leading to withdrawal from the trial. Limitations of this study include the small sample size. Nonetheless, this study provides promising preliminary results for a potential disease-modifying therapy in DMD.
Click to read the study in the Lancet
Relevant Reading:Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.
In-Depth [randomized controlled trial]:HOPE-2 was a randomized-controlled phase 2 clinical trial to assess to safety and efficacy of intravenous CAP-1002 for the treatment of Duchenne muscular dystrophy (DMD). The study enrolled patients aged 10 and older with genetically confirmed DMD. Participants had to score between 2-5 on the Performance of Upper Limb (PUL) scale with 0 being no useful function of hands and 6 being maximum overhead reach without compensation. 20 participants were assigned 1:1 to either CAP-1002 (n=8) or placebo (n=12) infusion every 3 months for a total of four infusions. Mean age of the enrolled male participants was 14 in both groups. Primary outcome was the upper limb function on the PUL scale. Patients who received CAP-1002 had a greater change in PUL score from baseline after 12 months compared to placebo (percentile difference 36.2, 95% CI 12.7-59.7). On the PUL scale, the placebo group had a mean change of -3.4 points from baseline, while the CAP-1002 had a -0.8 point change (difference of 2.6 points). This can also be interpreted as a 71% slowing of loss of function in the CAP-1002 group. Three patients in the CAP-1002 group had infusion-related hypersensitivity reactions, one leading to discontinuation. No other adverse events were seen in the two groups.
2022 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.
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#VisualAbstract: Cardiosphere-derived cell therapy slows disease progression in Duchenne muscular dystrophy - Physician's Weekly
Mavacamten Demonstrated Significant Reduction in Need for Septal Reduction Therapy in Symptomatic Obstructive HCM Patients in Phase 3 VALOR Trial -…
By daniellenierenberg
-- Yescarta is First CAR T-cell Therapy to Receive NCCN Treatment Guideline Category 1 Recommendation --
Kite, a Gilead Company (Nasdaq: GILD), today announced the U.S. Food and Drug Administration (FDA) has approved Yescarta (axicabtagene ciloleucel) CAR T-cell therapy for adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Yescarta demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS; hazard ratio 0.398; P
This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220401005519/en/
Earlier this month, the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology for B-cell Lymphomas to include Yescarta for "Relapsed disease
Christi Shaw, Chief Executive Officer of Kite : "Kite started with a very bold goal: creating the hope of survival through cell therapy. Today's FDA approval brings that hope to more patients by enabling the power of CAR T-cell therapy to be used earlier in the treatment journey. This milestone has been years in the making. On behalf of the entire Kite community, we would like to thank the patients and physicians who have been on this journey with us. You are what drives us every day to explore the full potential of cell therapy."
CAR T-cell therapies are individually made starting from a patient's own white blood cells, called T-cells. The cells are removed through a process similar to donating blood and sent to Kite's specialized manufacturing facilities where they are engineered to target the patient's cancer, expanded, and then returned to the hospital for infusion back into the patient. Referring physicians and patients can immediately begin accessing Yescarta CAR T-cell therapy for this new FDA-approved indication through Kite's 112 authorized treatment centers across the U.S.
Frederick L. Locke, MD, ZUMA-7 Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida : "Today's approval marks an exciting new standard of care. The ZUMA-7 trial enabled us to look at the broader picture of what happens to patients after a decision is made to follow a particular treatment path. What we found was that axi-cel resulted in three times as many patients receiving treatment with curative intent (CAR T-cell therapy), and an overall better outcome for patients than the previous standard of care. Additionally, we have now amassed significant experience with CAR T-cell therapy to better manage or prevent side-effects, making this treatment more accessible for older patients and those with medical conditions for whom the standard of care might be difficult."
SOC therapy for this patient population has historically been a multi-step process expected to end with a stem cell transplant. The process starts with chemoimmunotherapy, and if a patient responds to and can tolerate further treatment, they move on to high-dose chemotherapy (HDT) followed by a stem cell transplant (ASCT).
Jason Westin, MD, MS, FACP, ZUMA-7 Principal Investigator, Director, Lymphoma Clinical Research, and Associate Professor, Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center : "Definitive clinical trial results such as these do not come along often and should drive a paradigm shift in how patients with relapsed or refractory LBCL are treated moving forward. Patients who do not respond to or relapse after initial treatment should quickly be referred to a CAR T-cell therapy authorized treatment center for evaluation."
Kite CAR T-cell therapy products are widely covered by commercial and government insurance programs in the U.S. Kite has also invested in expansion of manufacturing capacity ahead of today's FDA decision to support patient access.
Lee Greenberger, PhD, Chief Scientific Officer of The Leukemia & Lymphoma Society (LLS): "LLS was an early supporter of CAR T-cell therapy research, and to be able to see this innovative advance become available as an earlier line of treatment is truly remarkable. Current standard of care is a difficult process for patients, and no one knows at the start who will make it to stem cell transplant. With today's FDA decision, patients will have earlier access to this potentially curative treatment."
Yescarta was initially approved by the FDA in 2017 based on the ZUMA-1 trial for a smaller population of LBCL patients who failed two or more lines of therapy. The ZUMA-1 trial has recently reported durable 5-year survival results, with Yescarta showing 42.6% of study patients alive at 5 years and that 92% of those patients alive at 5 years have needed no additional cancer treatment at this important milestone.
As the only company dedicated exclusively to the research, development, commercialization, and manufacturing of cell therapy on a global scale, Kite has all functions critical to cell therapy vertically integrated. This structure enables the continual refinement and support of the highly specialized and complex end-to-end processes needed to support and improve upon patient outcomes with CAR T-cell therapy.
About ZUMA-7 Study
The FDA approval of Yescarta CAR T-cell therapy for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy is based on results from the ZUMA-7 study. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous stem cell transplant (ASCT). Results were presented in a Plenary session at the American Society of Hematology's (ASH) Annual Meeting & Exposition in December 2021 and simultaneously published in the New England Journal of Medicine (NEJM).
ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus current standard of care (SOC) for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and ASCT in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or current SOC second-line therapy. The primary endpoint is event-free survival (EFS) as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes (PROs) and safety.
Yescarta demonstrated a 2.5-fold increase in patients who were alive at two years and did not experience cancer progression or require the need for additional cancer treatment (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC (hazard ratio 0.398; 95% CI: 0.308-0.514, P
Nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (35%) who received on-protocol HDT+ASCT. More patients responded to Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P
Fifty-five percent of patients in the SOC arm subsequently received CD19-directed CAR T-cell therapy off study.
In the study, Yescarta had a safety profile that was consistent with previous studies. Among the 168 Yescarta-treated patients evaluable for safety, Grade 3 cytokine release syndrome (CRS) and neurologic events were observed in 7% and 25% of patients, respectively. In the SOC arm, 83% of patients had high grade events, mostly cytopenias (low blood counts).
The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.
About LBCL
Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.
About Yescarta
Please see full Prescribing Information , including BOXED WARNING and Medication Guide.
YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
Limitations of Use : YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
U.S. IMPORTANT SAFETY INFORMATION
BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES
CYTOKINE RELEASE SYNDROME (CRS)
CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL.
Key manifestations of CRS ( 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.
Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.
NEUROLOGIC TOXICITIES
Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range:1- 133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.
The most common neurologic toxicities ( 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.
Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.
REMS
Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at http://www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS
Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.
SERIOUS INFECTIONS
Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL. Grade 3 infections occurred in 17% of patients, including Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.
Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.
In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
PROLONGED CYTOPENIAS
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.
HYPOGAMMAGLOBULINEMIA B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.
SECONDARY MALIGNANCIES
Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
ADVERSE REACTIONS
The most common non-laboratory adverse reactions (incidence 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.
The most common adverse reactions (incidence 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.
The most common non-laboratory adverse reactions (incidence 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.
About Kite
Kite, a Gilead Company, is a global biopharmaceutical company based in Santa Monica, California, with manufacturing operations in North America and Europe. Kite's singular focus is cell therapy to treat and potentially cure cancer. As the cell therapy leader, Kite has more approved CAR T indications to help more patients than any other company. For more information on Kite, please visit http://www.kitepharma.com .
About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.
Forward Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable results from ongoing or additional clinical trials involving Yescarta; Kite's ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Yescarta; Kite's ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Yescarta, and the risk that any such approvals may be subject to significant limitations on use; the risk that physicians may not see the benefits of prescribing Yescarta; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2021, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Kite and Gilead, and Kite and Gilead assume no obligation and disclaim any intent to update any such forward-looking statements.
U.S. Prescribing Information for Yescarta including BOXED WARNING , is available at http://www.kitepharma.com and http://www.gilead.com .
Kite, the Kite logo, Yescarta, Tecartus, XLP and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies.
For more information on Kite, please visit the company's website at http://www.kitepharma.com . Follow Kite on social media on Twitter ( @KitePharma ) and LinkedIn .
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Mary Lynn Carver, Media mcarver@kitepharma.com
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Mavacamten Demonstrated Significant Reduction in Need for Septal Reduction Therapy in Symptomatic Obstructive HCM Patients in Phase 3 VALOR Trial -...
U.S. STEM CELL, INC. Management’s Discussion and Analysis of Financial Condition and Results of Operations (form 10-K) – Marketscreener.com
By daniellenierenberg
The following is management's discussion and analysis ("MD&A") of certainsignificant factors that have affected our financial position and operatingresults during the periods included in the accompanying financial statements, aswell as information relating to the plans of our current management. This reportincludes forward-looking statements. Generally, the words "believes,""anticipates," "may," "will," "should," "expect," "intend," "estimate,""continue," and similar expressions or the negative thereof or comparableterminology are intended to identify forward-looking statements. Such statementsare subject to certain risks and uncertainties, including the matters set forthin this report or other reports or documents we file with the Securities andExchange Commission from time to time, which could cause actual results oroutcomes to differ materially from those projected. Undue reliance should not beplaced on these forward-looking statements which speak only as of the datehereof. We undertake no obligation to update these forward-looking statements.
The following discussion and analysis should be read in conjunction with ourfinancial statements and the related notes thereto and other financialinformation contained elsewhere in this Form 10-K
Our Ability To Continue as a Going Concern
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Results of Operations Overview
Comparison of Years Ended December 31, 2021 and December 31, 2020
Cost of sales consists of the costs associated with the production of MyoCathand test kits, product costs, labor for production and training and lab andbanking costs consistent with products and services provided.
Cost of sales was $52,030 in the year ended December 31, 2021 compared to$64,117 in the year ended December 31, 2020. The decrease is due to the decreasein revenues.
Research and development expenses were $0 in 2021 remaining the same as $0 in2020.
Selling, General and Administrative
Gain (loss) on settlement of debt
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In valuing our common stock, our Board of Directors considered a number offactors, including, but not limited to:
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Options outstanding at December 31, 2021 110,643,884 $ 0.0247
Options exercisable at December 31, 2021 93,491,384 $ 0.0256
Available for grant at December 31, 2021 34,168,070
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Our primary sources of revenue are from the sale of test kits and equipment,training services, patient treatments, laboratory services and cell banking.
Patient treatments and laboratory services revenue are recognized when thoseservices have been completed or satisfied.
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Depreciation is computed using the straight-line method over the assets'expected useful lives or the term of the lease, for assets under capital leases.
Cash and cash equivalents include cash on hand, deposits in banks withmaturities of three months or less, and all highly liquid investments which areunrestricted as to withdrawal or use, and which have original maturities ofthree months or less.
We allocate the proceeds received from equity financing and the attached optionsand warrants issued, based on their relative fair values, at the time ofissuance. The amount allocated to the options and warrants is recorded asadditional paid in capital.
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Our opinion is that inflation has not had, and is not expected to have, amaterial effect on our operations.
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In 2021, we continued to finance our operational cash needs with cash generatedfrom financing activities.
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As of December 31, 2021, we had $8,016,314 in outstanding debt, net of debtdiscount of $273,216.
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Epithelial Cell Culture Media Market to exceed USD 303040.33 thousand by 2028 says, The Insight Partners – Digital Journal
By daniellenierenberg
According to The Insight Partners new research study on Epithelial Cell Culture Media Market Forecast to 2027 COVID-19 Impact and Global Analysis by Product Type and End User, the market is expected to reach US$ 303,040.33 thousand by 2028 from US$ 128,155.95 thousand in 2020; it is estimated to grow at a CAGR of 11.4% from 2021 to 2028.
Certain age-related diseases, abnormalities, and trauma damage the tissues and organs. Regenerative medicines have the potential to replace or heal tissues and organs, along with normalizing congenital defects. In the last decade of the century, tissue engineering techniques have emerged impressively, and they are now being employed in broader areas of regenerative medicine. Thus, it has now become possible to use these techniques in the development of clinical therapies for the maintenance, repair, replacement, and enhancement of biological functions. Further, the regenerative medicines developed using cell-based models can potentially assist researchers in the early intervention of degenerative diseases and traumatic injuries.
Download sample PDF Copy of Epithelial Cell Culture Media Market study at: https://www.theinsightpartners.com/sample/TIPRE00022539/
PromoCell GmbH; Merck KGaA; ATCC; AXOL Bioscience Ltd.; Thermo Fisher Scientific, Inc.; Bio-Techne Corporation; Celprogen, Inc.; Lonza Group AG; HiMedia Laboratories; and Cell Biologics, Inc. are among the leading companies operating in the epithelial cell culture media market.
Geographically, the epithelial cell culture media market is segmented into North America, Europe, Asia Pacific (APAC), the Middle East and Africa (MEA), and South and Central America (SCAM). North America held the largest market share in 2020. In 2020, the US held the largest share of the market in North America. The market growth in North America is attributed to the key driving factors such as the presence of various market players and increasing demand for cell culture products from biopharmaceutical and biotechnology companies.
Human amniotic epithelial cells (hAECs) from placental tissues have gained substantial attention in the field of regenerative medicine owing to their proliferative capacity, easy access, multilineage differentiation potential, and safety. These are perinatal stem cells that have embryonic stem cell-like properties and the capability to be induced to differentiate. Thus, a growing focus on bringing advancements in regenerative medicine is likely to boost the adoption of epithelial cell cultures, thereby bolstering the demand for the respective culture.
Inquiry Before Buying on epithelial cell culture media market at: https://www.theinsightpartners.com/inquiry/TIPRE00022539/
Below is the list of the growth strategies done by the players operating in the epithelial cell culture media market:
In May-21 Bio-Techne has released MimEX GI, a new product line for generating 3-dimensional (3-D) gastrointestinal tissue on a 2-D surface.
In Sep-2020 Axol Bioscience and Censo Biotechnologies Announce Merger. The newentitywould become a global leader in the iPSC-based neuroscience, immune cell, and cardiac simulation industries for drug development and screening.
The report segments the epithelial cell culture media market as follows:
By Product Type
Human Mammary Epithelial CellsBronchia/Trachea Epithelial CellsRenal Epithelial CellsOthers
By End User
Biopharmaceutical CompaniesAcademic and Research Laboratories
Interested in Purchasing epithelial cell culture media market Report? Click here @ https://www.theinsightpartners.com/buy/TIPRE00022539/
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Epithelial Cell Culture Media Market to exceed USD 303040.33 thousand by 2028 says, The Insight Partners - Digital Journal
Is Stem Cell Therapy Right for You? – Health Essentials from Cleveland Clinic
By daniellenierenberg
Few of us know what they are or exactly how they work. But many of us have heard about the healing powers of stem cells, as well as the controversy surrounding them. Stem cells are well-debated and highly complex with promises ranging from fixing damaged knees to regenerating receding hairlines.
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services.Policy
But what are stem cells? And, whats all the fuss all about?
Director of the Center for Regenerative Medicine and Surgery, Amy Lightner, MD, shares the differences between stem cell types, how stem cells can be used and when to be cautious of claims that might be too good to be true.
When most of us think of stem cells, we probably recall images of Dolly the cloned sheep. While its true that Dolly was born of stem cells, her place in science history is just one of many advancements in the field.
In fact, there are many different types of stem cells, each of which has different responsibilities and abilities. What unifies them is their ability to regenerate into new cells.
Regenerative medicine is an emerging field that uses innovative treatments to help regenerate or heal cell function thats lost due to aging, disease or injury, Dr. Lightner explains. The way we achieve this is by using stem cells in large quantities, targeted to a certain area, that the body uses to promote healing.
Adult stem cells are the only type of stem cells that are currently approved for medical use in the United States by the U.S. Food and Drug Administration (FDA). The term adult stem cells is a little confusing because theyre actually found in infants, children and adults. These cells live in a variety of tissue in our bodies including bone marrow, muscles, your brain, your intestines and more.
Think of adult stem cells as a little army of cells that can regenerate themselves into new cells to maintain and repair the tissue or muscle where theyre found. The catch with adult stem cells is that they cant become different types of cells (for example, blood stem cells can only become new blood cells, not skin or brain cells).
Unlike adult stem cells, embryonic stem cells have many more possibilities. Harvested during an embryos blastocyst stage (about five or six days after an embryo has been fertilized in a lab), embryonic stem cells have the potential to become any type of cell (called pluripotent cells). For these reasons, embryonic stem cells are the type of stem cells that generate the controversy most people associate with the topic.
Stem cell therapy has been around since the 1970s, when the first adult bone marrow cells were used to treat blood disease. A bone marrow transplant allows a recipient whose bone marrow cells have been damaged by chemotherapy or disease to receive healthy bone marrow stem cells from a donor.
Those stem cells have the potential to mature within the blood system into different immune cells that recognize and fight off different types of blood cancer. And they also have the ability to heal, says Betty Hamilton, MD, Department of Hematology and Medical Oncology.
Bone marrow transplants are currently used to treat diseases including:
While you may have heard about the use of stem cell therapy for knees, back pain, arthritis, hair loss, diabetes and more, no other types of stem cell therapy beyond bone marrow transplants have yet been approved by the FDA. But thousands of clinical trials are available ranging from treatments for Crohns disease to multiple sclerosis and more. The common link between all these trials is the ability of the stem cells to reduce inflammation and repair damage to your body.
Dr. Hamilton and Dr. Lightner agree that were only just beginning to scratch the surface of stem cell therapy. In recent years, during the height of the COVID-19 pandemic, many clinical trials were underway to explore whether stem cells could be used to help treat the damaged lungs in people severely affected by the disease.
I think potential is the perfect word to describe stem cells, says Dr. Hamilton. We know they have these anti-inflammatory and regenerative properties where they can provide a significant improvement to someone suffering from a certain disease. There are so many diseases where inflammation happens, and something needs to be repaired, and so any help the immune system can get provides a lot of potential.
Scientists are also researching whether adult stem cells can turn into pluripotent stem cells, which would allow the cells to change into any cell type without involving the use of embryonic stem cells.
While the potential for stem cell therapy is great, doctors caution that were not quite there yet.
I always tell patients that ask about stem cell therapy clinics or traveling overseas for stem cell therapy treatment that if its not something that is a clinical trial with FDA oversight, then they have no real way of knowing whats being given to them, advises Dr. Lightner.
This means more harm can come than good if you dont know exactly whats being given to you. Or, in some cases, youre just spending thousands of dollars for what ends up being saline, Dr. Lightner says.
The best way to know that youre receiving sound medical treatment is to make sure the one youre considering is approved by the FDA on its Clinical Trials database.
Dr. Lightner cautions against treatments that sound too good to be true. While stem cell therapy has helped improve and save millions of lives, its best to know what exactly youre signing up for by seeking out a qualified medical provider offering an FDA-approved clinical trial.
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Is Stem Cell Therapy Right for You? - Health Essentials from Cleveland Clinic
7 Easy Ways to Transition Your Skin Care Routine for Spring – Vancouver Magazine
By daniellenierenberg
This spring, streamlineand save time and moneywith these seasonal tips and tricks
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The weather is getting warmer, the days a little longer, and flowers are starting to bloom. As the seasons change, so should our skin care routines. Vancouver-based Scentuals is celebrating the start of spring with seven easy ways to make the change.
Good skin starts from the inside out. Drink enough water, exercise regularly, eat healthy balanced meals, take your vitamins, and prioritize quality sleep.
Your skin care products have expiry dates too. Using products past their shelf life makes them less effectiveor entirely ineffectiveand can cause skin irritation.
ScentualsRefresh and gently balance your skin with an alcohol-free mist. Better yet, try one that smells like roses. Made with floral waters, witch hazel and hyaluronic acid, Scentuals Rose Facial Mist helps soothe and refine your skin.
Say goodbye to dull winter skin and hello to renewed healthy radiance. The Scentuals Radiance Facial Scrub gently exfoliates with ground apricot seeds, while cucumber extract calms skin irritation and reduces redness.
ScentualsSwap out thick cleansers and creams for lighter, fast-absorbing options. The Radiance Facial Cleanser and Cream by Scentuals have you covered.
ScentualsBrightening vitamin C leaves your skin with a healthy glow and promotes collagen production. Try the award-winning Scentuals Vitamin C Serum, effectively formulated with vitamin C, hyaluronic acid and plant stem cells.
Defend your skin against harmful UV rays by wearing sunscreen daily. Additional benefits to daily SPF include preventing sunburns, skin cancer and premature aging.
CREATED BY VANCOUVER MAGAZINE, IN PARTNERSHIP WITH SCENTUALS
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7 Easy Ways to Transition Your Skin Care Routine for Spring - Vancouver Magazine
Sailing the Genome in Search of Safe Harbors – Technology Networks
By daniellenierenberg
Cell and gene therapies are poised to have a major impact on the landscape of modern medicine, carrying the potential to treat an array of different diseases with unmet clinical need.
However, the number of approved, clinically adopted cell and gene therapies is mere compared to the amount that are currently in development. A major barrier for the translation of such therapies is the safe integration of therapeutic genes into the human genome. The insertion of therapeutic genes bears the risk of off target effects, or integration of the gene into an unintended location.
A number of different strategies have been proposed to mitigate this effect. The most recent body of work comes from a collaboration between Harvards Wyss Institute for Biologically Inspired Engineering, Harvard Medical School (HMS) and the ETH Zurich in Switzerland.
Published in Cell Report Methods, the research focused on identifying safe spots in the genome. These locations, known as genomic safe harbors (GSHs), are areas in the genome that meet the following criteria: they can be accessed easily by genome-editing strategies, are within a safe distance from genes that possess functional properties and permit expression of a therapeutic gene, only once it has landed in the harbor. A simple analogy is deciding which harbor to dock a boat there are many considerations, and these depend on the type of boat you are sailing, the weather conditions and ease of access.
The research team adopted computational strategies that enabled the identification of 2,000 predicted GSHs. From this initial identification, they successfully validated two of the sites both in vitro and in vivo using reporter proteins.
Technology Networks interviewed the studys first author, Dr. Erik Aznauryan, research fellow in the laboratory of Professor George Church at Harvard Medical School. Aznauryan dives into further detail on the history of GSH research, the methods adopted to validate the GSH sites and the potential applications of this research.
Molly Campbell (MC): Can you talk about the history of genomic safe harbor research, and how they were discovered?
Erik Aznauryan (EA): Three genomic sites were empirically identified in previous studies to support stable expression of genes of interest in human cells: AAVS1, CCR5 and hRosa26. All these examples were established without any a-priori safety assessment of the genomic loci they reside in.
Attempts have been made to identify human GSH sites that would satisfy various safety criteria, thus avoiding the disadvantages of existing sites. One approach developed by Sadelain and colleagues used lentiviral transduction of beta-globin and green fluorescence protein genes into induced pluripotent stem cells (iPSCs), followed by the assessment of the integration sites in terms of their linear distance from various coding and regulatory elements in the genome, such as cancer genes, miRNAs and ultraconserved regions.
They discovered one lentiviral integration site that satisfied all of the proposed criteria, demonstrating sustainable expression upon erythroid differentiation of iPSCs. However, global transcriptome profile alterations of cells with transgenes integrated into this site were not assessed. A similar approach by Weiss and colleagues used lentiviral integrations in Chinese hamster ovary (CHO) cells to identify sites supporting long-term protein expression for biotechnological applications (e.g., recombinant monoclonal antibody production). Although this study led to the evaluation of multiple sites for durable, high-level transgene expression in CHO cells, no extrapolation to human genomic sites was carried out.
Another study aimed at identifying GSHs through bioinformatic search of mCreI sites regions targeted by monomerized version of I-CreI homing endonuclease found and characterized in green algae as capable to make targeted staggered double-strand DNA breaks residing in loci that satisfy GSH criteria. Like previous work, several stably expressing sites were identified and proposed for synthetic biology applications in humans. However, local and global gene expression profiling following integration events in these sites have not been conducted.
All these potential GSH sites possess a shared limitation of being narrowed by lentiviral- or mCreI-based integration mechanisms. Additionally, safety assessments of some of these identified sites, as well as previously established AAVS1, CCR5 and Rosa26, were carried out by evaluating the differential gene expression of genes located solely in the vicinity of these integration sites, without observing global transcriptomic changes following integration.
A more comprehensive bioinformatic-guided and genome-wide search of GSH sites based on established criteria, followed by experimental assessment of transgene expression durability in various cell types and safety assessment using global transcriptome profiling would, thus, lead to the identification of a more reliable and clinically useful genomic region.
MC: If GSHs do not encode proteins, or RNAs with functions in gene expression, or other cellular processes what is their function in the genome?
EA: In addition to protein coding, functional RNA coding, regulatory and structural regions of the human genome, other less well understood and inactive DNA regions exist.
A large proportion of the human genome seems to have evolved in the presence of a variety of integrating viruses which, as they inserted their DNA into the eukaryotic genome over the course of million years, lead to an establishment of vast non-coding elements that we continue to carry to this day. Furthermore, partial duplications of functional human genes have resulted in the formation of inactive pseudogenes, which occupy space in the genome yet are not known to bear cellular functions.
Finally, functional roles of some non-coding portions of the human genome are not well understood yet. Our search of safe harbors was conducted using existing annotation of the human genome, and as more components of it are deciphered the identification of genomic regions safe for gene insertion will become more informed.
MC: Are you able to discuss why some regions of the genome were previously regarded as GSHs but are now recognized as non-GSHs?
EA: In the absence of other alternatives, AAVS1, CCR5 and hRosa26 sites were historically called GSHs, as they supported the expression of genes of interest in a variety of cell types and were suitable for use in a research setting.
Their caveats (mainly, location within introns of functional genes, closely surrounded by other known protein coding genes as well as oncogenes) however prevent them from being used for clinical applications. Therefore, in our paper we dont call them GSHs, and refer to our newly discovered sites as GSHs.
MC: You thoroughly scanned the genome to identify candidate loci for further study as potential GSHs. Can you discuss some of the technological methods you adopted here, and why?
EA: We used several publicly available databases to identify genomic coordinates of structural, regulatory and coding components of the human genome according to the GSH criteria we outlined in the beginning of our study (outside genes, oncogenes, lncRNAs etc.,). We used these coordinates and bioinformatic tools such as command lines bedtools to exclude these genomic elements as well as areas adjacent to them. This left us with genomic regions putative GSHs from which we could then experimentally validate by inserting reporter and therapeutic genes into them followed by transcriptomic analysis of GSH-integrated vs non-integrated cells.
MC: You narrowed down your search to test five, and then two GSHs. Can you expand on your choice of reporter gene when assessing two GSHs in cell lines?
EA: Oftentimes in research you go with what is available or what is of the most interest to the lab you are currently working in.
Our case was not an exception, and we initially (up until the T cell work) used the mRuby reporter gene as it was widely available and extensively utilized and validated in our lab at ETH Zurich back then.
When I moved to the Wyss Institute at Harvard, I began collaborating with Dr. Denitsa Milanova, who was interested in testing these sites in the context of skin gene therapy particularly the treatment of junctional epidermolysis bullosa caused by mutations in various anchor proteins connecting different layers of skin, among which is the LAMB3 gene. For this reason, we decided to express this gene in human dermal fibroblasts, together with green fluorescent protein to have a visualizable confirmation of expression. We hope we would be able to translate this study into clinics.
MC: Can you describe examples of how GSHs can be utilized in potential therapeutics?
EA: Current cell therapy approaches rely on random insertion of genes of interest into the human genome. This can be associated with potential side effects including cancerous transformation of therapeutic cells as well as eventual silencing of the inserted gene.
We hope that current cell therapies will eventually transition to therapeutic gene insertions precisely into our GSHs, which will alleviate both described concerns. Specific areas of implementation may involve safer engineering of T cells for cancer treatment: insertion of genes encoding receptors targeting tumor cells or cytokines capable of enhancing anti-tumor response.
Additionally, these sites can be used for the engineering of skin cells for therapeutic (as discussed earlier with the LAMB3 example) as well as anti-aging applications, such as expression of genes that result in youthful skin phenotype.
Finally, given the robustness of gene expression from our identified sites, they can be used for industry-scale bio-manufacturing: high-yield production of proteins of interest in human cell lines for subsequent extraction and therapeutic applications (e.g., production of clotting factors for patients with hemophilias).
MC: Are there any limitations to the research at this stage?
EA: A primary limitation to this study is the low frequency of genomic integration events using CRISPR-based knock-in tools. This means that cells in which the gene of interest successfully integrated into the GSH must be pulled out of the vastly larger population of cells without this integration.
These isolated cells would then be expanded to generate homogenous population of gene-bearing cells. Such pipeline is not ideal for a clinical setting and improvements in gene integration efficiencies are needed to help this technology easier translate into clinics.
Our lab is currently working on developing genome engineering tools which would eventually allow to integrate large genes into GSHs with high precision and efficiency.
MC: What impact might this study have on the cell and gene therapy development space?
EA: This study will hopefully lead to many researchers in the field testing our sites, validating them in other therapeutically relevant cell types and eventually using them in research as well as in clinics as more reliable, durable and safe alternatives to current viral based random gene insertion methods.
Additionally, since in our work we shared all putative GSHs identified by our computational pipeline, we hope researchers will attempt to test sites we havent validated yet by implementing the GSH evaluation pipeline that we outlined in the paper. This will lead to identification of more GSHs with perhaps even better properties for clinical translation or bio-manufacturing.
MC: What are your next steps in advancing this work?
We hope to one day translate our successful in vitro skin results and start using these GSHs in an in vivo context.
Additionally, we are looking forward to improving integration efficiencies into our GSHs, which would further support clinical transition of our sites.
Finally, we will evaluate the usability of our GSHs for large-scale production of therapeutically relevant proteins, thus ameliorating the pipeline of manufacturing of biologics.
Dr. Erik Aznauryan was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
Link:
Sailing the Genome in Search of Safe Harbors - Technology Networks
Learning from the single cell: A new technique to unravel gene regulation – EurekAlert
By daniellenierenberg
image:zebrafish notochord nuclei at 15-somite stage. Grey: nuclear DNA (DAPI). Color: histone H3K9me3 view more
Credit: Phong Nguyen, Franka Rang & Kim de Luca. Copryight Hubrecht Institute.
How is the activity of genes regulated by the packaging of DNA? To answer this question, a technique to measure both gene expression and DNA packaging at the same time was developed by Franka Rang and Kim de Luca, researchers from the group of Jop Kind (group leader at the Hubrecht Institute and Oncode Investigator). This method, EpiDamID, determines the location of modified proteins around which the DNA is wrapped. It is important to gather information about these modifications, because they influence the accessibility of DNA, thereby affecting the gene activity. EpiDamID is therefore valuable for research into the early development of organisms. The results of the study are published in Molecular Cell on April 1st 2022.
In order to fit DNA into the nucleus of a cell, it is tightly packed around nuclear proteins: histones. Depending on the tightness of this winding, the DNA can be (in)accessible to other proteins. This therefore determines whether the process of gene expression, translation of DNA into RNA and eventually into proteins, can take place.
DNA packaging determine gene activity
The tightness of DNA winding around histones is regulated by the addition of molecular groups, so-called post-translational modifications (PTMs), to the histones. For example, if certain molecules are added to the histones, the DNA winding is loosened. This makes the DNA more accessible for certain proteins and causes the genes in this part of the DNA to become active, or expressed. Furthermore, proteins that are crucial for gene expression can directly recognize and bind the PTMs. This enables transcription: the process of DNA copying.
The regulation of gene expression, for instance through PTMs, is also known as epigenetic regulation. Since all cells in a body have the same DNA, regulation of gene expression is needed to (de)activate specific functions in individual cells. For instance, heart muscle cells have different functions than skin cells, thus require different genes to be expressed.
Analysis of single cells using EpiDamID
To understand how PTMs affect gene expression, first authors Franka Rang and Kim de Luca designed a new method to determine the location of the modifications. Using this approach, called EpiDamID, researchers can analyze single cells, whereas previous methods were only able to measure a large group of cells. Analysis on such a small scale results in knowledge on how DNA winding differs per cell, rather than information on the average DNA winding of many cells.
EpiDamID is based on DamID, a technique which is used to determine the binding location of certain DNA-binding proteins. Using EpiDamID, the binding location of specific PTMs on histone proteins can be detected in single cells. Compared to others, a great advantage of this technique is that researchers need very limited material. Furthermore, EpiDamID can be used in combination with other methods, such as microscopy, to study regulation of gene expression on different levels.
Future prospects
Following the development of this technique, the Kind group will focus on the role of PTMs from the point of view of developmental biology. Because single cells are analyzed using EpiDamID, only a limited amount of material is needed to generate enough data. This allows researchers to study the early development of organisms from its first cell divisions, when the embryo consists of only a few cells.
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Publication
Rang, F. J.*, de Luca, K. L.*, de Vries, S. S., Valdes-Quezada, C., Boele, E., Nguyen, P. D., Guerreiro, I., Sato, Y., Kimura, H., Bakkers, J. & Kind, J. Single-cell profiling of transcriptome and histone modifications with EpiDamID. Molecular Cell, 2022.
*Authors contributed equally
Jop Kind is group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and Oncode Investigator.
About the Hubrecht Institute
The Hubrecht Institute is a research institute focused on developmental and stem cell biology. It encompasses 21 research groups that perform fundamental and multidisciplinary research, both in healthy systems and disease models. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit http://www.hubrecht.eu.
Experimental study
Cells
Single-cell profiling of transcriptome and histone modifications with EpiDamID
1-Apr-2022
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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Learning from the single cell: A new technique to unravel gene regulation - EurekAlert
Humectant: Examples and benefits for skin, hair, and lips – Medical News Today
By daniellenierenberg
Humectants are substances that attract water. In personal care products, they help hydrate the skin, hair, or nails. Hyaluronic acid and glycerin are examples of humectants.
The benefits of humectants depend on the ingredient. In general, however, the effects include relief of dry skin, reduction of thickened skin, and strengthening of the skin barrier.
Humectants are different from emollients and occlusives. These ingredients are also in many personal care products for dry skin. However, they work by forming a barrier over the skin, trapping moisture inside rather than attracting it. Oils, butters, and waxes, such as lanolin, are examples.
This article discusses humectants and the products that contain them, as well as examples and benefits. It also outlines the difference between a humectant and an emollient and an occlusive.
Humectants are ingredients that attract and bind water. In skin care, they draw water from the deeper layers of the skin to the outermost layer. If air humidity is higher than 70%, they also draw water from the surrounding environment to the skin.
In hair care, humectants perform a similar function. They attract water to the hair shaft, helping keep it hydrated.
Examples of products that can contain humectants include:
Many ingredients act as humectants, including:
All humectants have slightly different properties. Below is some of the research on common humectants.
The outermost layer of the skin, the stratum corneum, has an important function of serving as a barrier. It slows the evaporation of water from the skin and helps protect against microbes.
A 2021 review notes that urea helps enhance the stratum corneum by increasing hydration and improving the skin barriers integrity. Because of this, it has a long history as a skin care ingredient.
Urea can help with many skin conditions, such as:
An older 2013 study evaluated the effects of once and twice daily applications of a humectant-rich moisturizer containing 15% AHAs and 15% urea. The study involved 62 participants. Of them, 12 had no skin conditions, and 50 had hyperkeratosis, or thickened skin, on the feet.
Among the participants with hyperkeratosis, the results indicated that the moisturizer:
The participants with no skin conditions experienced an improvement in skin barrier function.
As people age, they have a higher risk of developing dry skin. A 2019 review analyzed databases from 19902018 that dealt with skin conditions of people over the age of 50 years. It found that leave-on products containing lipophilic humectants decreased skin dryness and itching. A lipophilic humectant is one that manufacturers have dissolved in fats or lipids.
Additionally, a 2021 research article notes that the humectant lactic acid can relieve rough, dry skin at concentrations up to 12%.
Older research from 2012 states that hyaluronic acid helps speed up wound repair and reduces scar appearance. These benefits stem from the humectants actions of promoting new blood vessel formation and increasing fibroblasts, which are cells in connective tissue that produce collagen and other fibers.
Another popular group of ingredients for moisturizing the skin and hair are emollients and occlusives. These work by creating a barrier, often consisting of a plant oil or butter, over the skin or hair. Instead of attracting moisture, they trap it beneath this barrier, preventing it from evaporating.
In comparison to humectants, emollients and occlusives tend to be thicker, heavier ingredients.
A 2017 study notes that emollients consist mostly of lipids, such as natural oils and waxes. They increase skin:
Examples of emollients include:
Occlusives are mostly oil-based. They provide a layer on the skin surface that helps protect against water evaporation. This preservation of skin hydration helps prevent dry skin and eczema, reports research from 2018.
Examples of occlusives include:
Whether a person should use humectants, emollients, or both depends on their skin type.
Emollients and occlusives tend to be heavier ingredients. Some add more oil to the skin and hair, which can be helpful for those with dry skin. However, individuals with oily skin or hair may find this unhelpful.
Some emollients and occlusives are also comedogenic, which means they have the potential to block pores and cause acne.
Humectants, on the other hand, tend to be noncomedogenic and non-oily. They can add hydration without the use of heavier ingredients. Some also have other benefits. For example, AHAs are also exfoliants.
According to the American Academy of Dermatology Association, a person with oily skin should choose skin care products that have oil-free and noncomedogenic on the label. People with hair that gets greasy quickly may prefer to look for hair products that do not contain much oil, if any.
In contrast, someone with dry skin or hair could benefit from products that contain humectants, emollients, and occlusives.
Learn about skin types and how to identify them here.
A humectant is a substance that draws water into the skin, hair, or nails. In the skin, this may come from the deeper layers, or from the air if it is humid enough. Humectants are useful for adding hydration without feeling heavy or oily.
Humectants include ingredients such as glycerin, urea, AHAs, and hyaluronic acid. People can find them in a wide range of personal care products.
Aside from humectants, personal care products often contain emollients and occlusives. While humectants provide hydration, emollients soften the skin, and occlusives help prevent water in the skin from evaporating.
People can consult a dermatologist to identify their skin type and find the best regimen for them.
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Humectant: Examples and benefits for skin, hair, and lips - Medical News Today
An Overview on Graft-Versus-Host Disease and Prophylaxis – Targeted Oncology
By daniellenierenberg
Transcript:
Nelson Chao, MD: Thank you for joining us at the Targeted Oncology Virtual Tumor Board, which is focused on practice updates in graft-versus-host disease [GVHD]. In todays presentation, my colleagues and I will review 3 clinical cases. We will discuss approaches to treating patients who are at risk or who develop graft-versus-host disease. We will share our perspectives on key clinical trial data that may impact our decisions. I am Dr Nelson Chao from Duke University [Durham, North Carolina]. Today, I am joined by Dr Corey Cutler from Dana-Farber Cancer Institute [Boston, Massachusetts] and Kerry [King] Minor from Duke University. Thank you for joining us.
I would like to start by giving a brief overview of the process for allogeneic transplant. We need to collect donor cells, which could be related or unrelated. The stem cells can be separated from the blood or given as a whole. There is a conditioning, or treatment of the recipient. Chemotherapy and/or radiation will kill the cancer and weaken the donor immune system. The cells are infused to the patient and then we wait for engraftment. Graft-versus-host disease is a leading cause of non-relapse mortality following allogeneic transplantation. In acute GVHD, the reaction of the donor immune cells against host tissues is the ideology of the disease. Three main tissues are affected: the skin, the liver, the gut. In chronic graft-versus-host disease, the syndrome is quite variable with features resembling autoimmune or other immunologic disorders. In chronic GVHD, you could have a single organ, or it might be widespread and have a significant impact on quality of life. The risk factors for acute and chronic are similar, although the greatest impact of chronic is having acute prior. With standard prophylaxis, 25% to 50% of patients receiving HLA [human leukocyte antigen]-matched transplant will develop acute GVHD. That may require high-dose systemic steroids, and up to 50% of patients will have inadequate response to steroid therapy, which is associated with poor prognosis.
So this is a sort of a classical slide down demonstrating the pathology where in number 1, the recipient, who received the conditioning regimen, ends up with tissue damage. Those tissues release inflammatory cytokines such as IL [interleukin]-1 and IL-6, and then there is damage to the small bowel, usually releasing LPS [lipopolysaccharides]. These go down through different pathways, one goes to host antigen-presenting cells, which will activate the donor cells that release IL-12, IFN [interferon-gamma]-, and IL-2. Both are within the small bowel because of the LPS, as well as the microbiota entry, and release of those pattern associated damage receptors. There is target cell apoptosis of the gut, which then amplifies the response from the cytotoxic lymphocytes and NK [natural killer] cells together with TNF [tumor necrosis factor]- and IL-1. So most commonly the GVHD prophylaxis includes calcineurin inhibitors; methotrexate; MMF [mycophenolate mofetil]; sirolimus [Rapamune]; T-cell antibody; Ex vivo T-cell depletion, such as CD34 selection; posttransplant cyclophosphamide; and then obviously the standard combination of tacrolimus and methotrexate. So Im going to stop here for a second and ask Dr Cutler to give us a sense of where these regimens fall within the Dana-Farber Cancer Institute.
Corey Cutler, MD, MPH, FRCPC: Sure. Thanks for the introduction, Nelson. At our center, the predominant regimen that we use in the mild of greater setting is still the classic combination of tacrolimus and methotrexate. In the reduced intensity setting, we often add in the M200 meter cells. We are using the posttransplant cyclophosphamide regimen whenever we do haploidentical transplants. At the moment, there isnt compelling data that suggests a superior regimen to tackling the methotrexate. So most of us dont use it as a matter of routine outside of either the clinical trials or the haploidentical setting.
Nelson Chao, MD: And Ms. Minor, what do you think are the major toxicities that you see with these standard regimens?
Kerry King Minor, MSN, ANP-BC: Well, we always educate the patients that are going to be receiving the methotrexate about the risk of mucositis. Thats probably 1 of the biggest things that we see in patient education with that prophylaxis agent and tacrolimus. We prepare them and monitor very closely for side effects, such as headaches, effects on their blood pressure, effects on their kidneys and their knees. Thats basically it. With cyclophosphamide, typically patients tolerate that fairly well.
Transcript edited for clarity.
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An Overview on Graft-Versus-Host Disease and Prophylaxis - Targeted Oncology
Healios K K : Joint Research with the Division of Regenerative Medicine, the Institute of Medical Science for Developing a Mass Production Method of…
By daniellenierenberg
April 1st, 2022
Company Name: Representative:
HEALIOS K.K.
Hardy TS Kagimoto, Chairman & CEO
(TSE Mothers Code: 4593)
Joint Research with the Division of Regenerative Medicine, the Institute of Medical Science for Developing a Mass Production Method of UDC Liver Buds
HEALIOS K.K. ("Healios") is currently developing a regenerative medicine treatment whereby liver organ buds created from iPS cells are injected into the liver and grown into functioning liver tissue, with the aim of improving or restoring the function of a damaged liver (development code: HLCL041). This treatment could potentially replace the need for an organ transplant for certain patients. Liver buds are created by co-culturing liver progenitor cells, which can differentiate into hepatocytes; MSCs, which have the ability to develop into various types of connective-tissues; and vascular endothelial cells, which form blood vessels. Healios has pursued research and generated data on functional assessments and quality standards for these component cells and the liver buds created from them, and it is also proceeding with the development of mass culturing and manufacturing methods.
In addition, as announced on October 20th, 2020, Healios established Universal Donor Cells ("UDCs")*, which are next-generation iPS cells created with gene-editing technology that have a reduced risk of immune rejection regardless of a patient's HLA type, and its proprietary clinical-grade UDC line. We are currently conducting research both internally and through joint collaborations with several institutions on new treatments for diseases for which there is no existing cure.
As part of these efforts, Healios is pleased to announce that it has entered into a joint research agreement with the Division of Regenerative Medicine (Prof. Hideki Taniguchi) of the Institute of Medical Science at the University of Tokyo, to advance HLCL041 utilizing UDCs. In this joint research, we plan to establish a new method for inducing differentiation of liver buds using UDCs and to develop a highly efficient and scalable cell culturing and mass manufacturing system.
For many diseases where the only effective treatment is an organ transplant, Healios believes that organ buds created from iPSCs, which have the potential to restore organ function, hold significant promise as an alternative to organ transplants and as a means to address the perennial shortage of organ donors.
This agreement does not have a material impact on our consolidated financial results for the current fiscal year. We will promptly make an announcement on any matter that requires disclosure in the future.
Outline of the Collaboration Partner
Name of the Collaborator: Division of Regenerative Medicine, The Institute of Medical Science Adress:4-6-1 Shirokanedai Minato-ku, Tokyo, 108-8639, Japan
Representative: Professor Taniguchi Hideki
* UDCs
UDCs are iPS cells created using gene-editing technology that allows them to avoid and / or reduce the body's immune rejection response. The production of Healios' UDCs involve the removal of certain HLA genes that elicit a rejection response, the introduction of an immunosuppression gene to improve immune evasion, and the addition of a suicide gene serving as a safety mechanism, each in an allogeneic iPS cell. This next-generation technology platform allows for the creation of regenerative medicine products with enhanced safety and a lower risk of immune rejection, while preserving the inherent ability of iPS cells to replicate themselves continuously and their pluripotency in differentiating into various other kinds of cells.
About the Division of Regenerative Medicine, The Institute of Medical Science:
Regenerative medicine is a challenging scientific field that is going to convert the pioneering knowledge of developmental biology and stem cell biology to clinical application. For patients with end-stage organ failure, organ transplantation is the only effective treatment; however, the paucity of transplantable organs hinders the application of this treatment for most patients. Recently, regenerative medicine with transplantable organs has attracted attention. Our laboratory is developing a novel therapeutic strategy to substitute organ transplantation. We have established novel organoid culture technologies to reconstruct human organs from stem cells, including human induced pluripotent stem cells (iPSCs), and we are going to realize transplantation of human liver primordia (liver buds [LBs]) generated from iPSCs for the treatment of liver diseases. https://stemcell-imsut.org/laboratory/?id=en#labo1
About Healios:
Healios is Japan's leading clinical stage biotechnology company harnessing the potential of stem cells for regenerative medicine. It aims to offer new therapies for patients suffering from diseases without effective treatment options. Healios is a pioneer in the development of regenerative medicines in Japan, where it has established a proprietary, gene-edited "universal donor" induced pluripotent stem cell (iPSC) line to develop next generation regenerative treatments in immuno-oncology, ophthalmology, liver diseases, and other areas of severe unmet medical need. Healios' lead iPSC-derived cell therapy candidate, HLCN061, is a next generation NK cell treatment for solid tumors that has been functionally enhanced through gene-editing. Its near-term pipeline includes the somatic stem cell product HLCM051, which is currently being evaluated in Japan in Phase 2/3 and Phase 2 trials in ischemic stroke and acute respiratory distress syndrome (ARDS), respectively. Healios was established in 2011 and has been listed on the Tokyo Stock Exchange since 2015 (TSE Mothers: 4593). https://www.healios.co.jp/en .
Contact:
Department of Corporate Communications, HEALIOS K.K.
E-mail:ir@healios.jp
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Healios K K : Joint Research with the Division of Regenerative Medicine, the Institute of Medical Science for Developing a Mass Production Method of...
Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team
By Dr. Matthew Watson
REDWOOD CITY, Calif., March 21, 2022 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. (NASDAQ: JSPR), a biotechnology company focused on hematopoietic cell transplant therapies, today announced changes to its management team, including the promotions of Jeet Mahal to the newly created position of Chief Operating Officer, and of Wendy Pang, M.D., Ph.D., to Senior Vice President of Research and Translational Medicine. Both promotions are effective as of March 21, 2022. Jasper also announced that a new position of Chief Medical Officer has been created, for which an active search is underway. Judith Shizuru, M.D. PhD, co-founder, and Scientific Advisory Board Chairwoman will lead clinical development activities on an interim basis and Kevin Heller, M.D., EVP of Research and Development, will be transitioning to a consultant role.
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Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team
Praxis Precision Medicines to Present at Stifel’s 4th Annual CNS Day
By Dr. Matthew Watson
BOSTON, March 21, 2022 (GLOBE NEWSWIRE) -- Praxis Precision Medicines, Inc. (NASDAQ: PRAX), a clinical-stage biopharmaceutical company translating genetic insights into the development of therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance, today announced that management will participate in a fireside chat at Stifel’s 4th Annual CNS Day on Tuesday, March 29, 2022 at 11:30 a.m. ET.
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Praxis Precision Medicines to Present at Stifel’s 4th Annual CNS Day
Taconic Biosciences Improves rasH2 Carcinogenicity Test System Access in Asia-Pacific Region
By Dr. Matthew Watson
Four-way distribution partnership provides quality, consistent rasH2 supply to India and China, better serving global customers Four-way distribution partnership provides quality, consistent rasH2 supply to India and China, better serving global customers
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Taconic Biosciences Improves rasH2 Carcinogenicity Test System Access in Asia-Pacific Region