Stem Cell Clinic

Genetic Mechanism Identified in Neonatal Diabetes Could Offer Insights into Other Forms of the Disease – Genetic Engineering & Biotechnology News

New insights into the genetic basis of a rare type of diabetes in babies have uncovered a biological pathway that is fundamental to insulin production by pancreatic cells, and which could boost research into new treatments for more common forms of diabetes. An international research team led by scientists at the University of Exeter, the Universit Libre de Bruxelles, and the University of Helsinki, used genome sequencing to reveal that a group of babies with shared clinical features, including the development of diabetes soon after birth, all had genetic changes in the YIPF5 gene, which is involved in cell trafficking from the endoplasmic reticulum (ER) to the Golgi. The team then combined stem cell research and CRISPR gene editing to show that this gene is essential for the function of the cells that produce insulin.

The research demonstrated how the genetic changes result in high levels of stress within the cells, causing cell death, and also showed, for the first time, that YIPF5 gene function is essential for neurons and insulin-producing cells, but appears to be dispensable for the function of other cells.

Co-study lead, Elisa De Franco, PhD, from the University of Exeter, said, This study highlights the importance of gene discovery to further our understanding of fundamental mechanisms in biology. In this case, our research has resulted in the identification of a gene essential for both insulin-producing cells and neurons, highlighting a biological pathway we previously did not know was so fundamental for insulin-producing cells. This has the potential to open new avenues of research and ultimately result in a better understanding of how other types of diabetes develop.

De Franco and colleagues reported on their findings in the Journal of Clinical Investigation (JCI), in a paper titled, YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

Neonatal diabetes develops before the age of six months, and is caused by reduced numbers of insulin-producing pancreatic cells, or impaired cell function, the authors explained. Previous research has found that neonatal diabetes is most likely caused by a mutation in a single gene, rather than presenting as an autoimmune type 1 form of the disease. To date, 30 genetic causes have been described, which account for 82% of cases, the team noted. Many patients with neonatal diabetes also have neurological symptoms, which is not surprising, the researchers continued, as cells and neurons have many genes and cellular functions in common. Pathogenic variants in 11 genes are already known to cause neonatal diabetes with neurological features, and one of the pathways known to be crucial for the function of both cells and brain cells is the endoplasmic reticulum stress response. In fact, Pathogenic variants in eight genes known to be involved in regulating the ER stress response have been found to caused diabetes (ranging from neonatal to adolescent/adult-onset diabetes), often associated with neurological features, the scientists pointed out.

To further study which genes are key to the function of insulin-producing cells, in the context of neonatal diabetes, the research team studied the genetics of almost 190 patients from all over the world who developed diabetes soon after birth. Identifying the genes causing syndromic forms of neonatal diabetes that include neurological features can highlight pathways important for development and function of -cells and neurons, giving insights into the pathogenesis of more common diseases, they noted. The results identified six babies who had neonatal diabetes and other very similar clinical featuresincluding epilepsy and microcephalyand who all exhibited mutations in the YIPF5 gene.

Researchers at the Universit Libre de Bruxelles and the University of Helsinki then carried out a series of studies in insulin-producing cells and in stem cells to try to understand the function of YIPF5 in the insulin-producing cells. We used three human cell models (YIPF5 silencing in EndoC-H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects cells, the investigators explained. Their results showed that when the gene was lacking, or had the same mutations as those found in the neonatal diabetes patients, the insulin-producing cells couldnt function normally to produce enough insulin. And an attempt to cope with this malfunction the cells activated stress mechanisms, which ultimately resulted in cell death. YIPF5 deficiency reduces -cell survival by enhancing the ER stress response and sensitizing human -cells to ER stress-induced apoptosis, they commented.

Co-senior study author Timo Otonkoski, from the University of Helsinki, explained, Using the CRISPR gene scissor DNA-editing technology we could correct the patient mutation in stem cells in order to fully understand its effects. The combination of gene editing with stem cells provides powerful new tools for the study of disease mechanisms. Colleague and co-senior author, Miriam Cnop, PhD, from the Universit Libre de Bruxelles, continued, The possibility to generate insulin-producing cells from stem cells has given us the possibility to study what goes wrong in cells from patients with this rare form and also other types of diabetes. It is an extraordinary disease-in-a-dish model to study mechanisms of disease and test treatments.

The teams study results offer new insights into which cellular steps are important for making insulin, and for maintaining the function of insulin-producing cells in the pancreas. This insight could help researchers develop better therapies to treat patients with common types of diabetes that affect 460 million people worldwide.

To the best of our knowledge, this is the first report of mutations in a gene affecting ER-to-Golgi trafficking resulting in diabetes by increasing -cell ER stress, uncovering a critical role of YIPF5 in the human -cell, the authors reported. Our findings highlight a biological pathway essential for -cells.

We are very grateful to the patients, their families, and their doctors for their participation in the study, noted Andrew Hattersley, PhD, one of the senior authors of the study, from the University of Exeter. Without them, we could not have accomplished this. It is our wish that further research will benefit the patients, to facilitate diagnosis and treatment of their diabetes.

Anna Morris, assistant director of research strategy and partnerships at Diabetes UK, which provided funding for the studies, said, These findings provide important new information on how beta cells in the body manufacture insulin and what happens when this process goes wrong. Understanding more about how rarer forms of diabetes develop brings us closer to discovering new ways to cure and prevent all forms of the condition. This is a key part of Diabetes UKs new strategy, and we are proud to have funded De Francos vital research.

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Genetic Mechanism Identified in Neonatal Diabetes Could Offer Insights into Other Forms of the Disease - Genetic Engineering & Biotechnology News

Doctors Debate: Is Intensive or Low-Intensity Chemotherapy Plus BCR-ABL TKI Therapy Best for Treatment of Ph+ ALL? – Targeted Oncology

Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) can be treated using either intensive chemotherapy with a BCR-ABL tyrosine kinase inhibitor (TKI) or nonintensive chemotherapy. Which strategy to employ is an ongoing clinical question that affects patients from the front-line to third-line settings.

During the Society of Hematologic Oncology Virtual Annual Meeting, Nicholas J. Short, MD, an assistant professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, argued that intensive chemotherapy combined with a BCR-ABL TKI still holds the place of standard-of-care treatment for Ph+ ALL. Sabina Chiaretti, MD, PhD, a researcher in the Department of Translational and Precision Medicine at Sapienza University in Rome, Italy, made the case that less is more, arguing for a targeted approach to managing Ph+ ALL.1,2

Perhaps the best reason to use the standard-of-care strategy for treating patients with Ph+ ALL is that it is known to improve survival in the front-line setting and has demonstrated increased molecular responses and survival in the second- and third-line settings, Short explained in his presentation. When complete molecular responses (CMRs) are observed with a therapy, Short says, it increases the chance of cure in patients.1

The best opportunity to cure someone with newly diagnosed acute leukemia of any type, and in particular, Philadelphia chromosomepositive ALL, is in the frontline setting. It is therefore very important that you choose the frontline regimen appropriately. This an important debate because of the emerging data with lower-intensity regimens that have brought on some desire to treat patients with less chemotherapy, Short told Targeted Therapies in Oncology (TTO) in an interview.

Understanding How Patients Benefit

Prior to 2016, the impact of CMRs on patients with Ph+ ALL had not yet been defined. Findings from a study conducted by Short and colleagues showed that achieving a CMR at 3 months can potentially identify which patients will have long-term overall survival (OS) and relapse-free survival (RFS) on intensive chemotherapy without stem cell transplant (SCT) compared with those who have lower CMRs at 3 months.3

The study enrolled 202 patients with Ph+ ALL to receive the frontline intensive chemotherapy combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). At 3 months, the OS was 127 months for patients who had higher CMRs compared with 38 months among those with lower CMRs (HR, 0.42; 95% CI, 0.21-0.82;P =.0). Also, at 3 months, the RFS among the higher-CMR population was 26 months versus 18 months for the lower-CMR population (HR, 0.43; 95% CI, 0.21-0.78;P =.01).

Overall, the findings showed that higher CMRs resulted in superior survival, whereas lower CMRs left patients with poor outcomes.

This research laid the groundwork for an understanding of how patients benefit from and which patients have the best responses to intensive chemotherapy.

Patient Outcomes With Intensive Chemotherapy Plus a BCR-ABL TKI

Short previously presented long-term safety and efficacy results from the combination of hyper-CVAD and the third-generation BCR-ABL inhibitor ponatinib (Iclusig) at the 2019 American Society of Hematology (ASH) Annual Meeting. Patients with newly diagnosed Ph+ ALL had sustained responses on this treatment without hematopoietic SCT (HSCT), demonstrating its potential for cure, Short noted.

The best outcomes that have been reported so far in the literature have been with the combination of intensive chemotherapy with hyper-CVAD plus ponatinib. For the study, we have long-term outcomes data available. Theres a 5-year overall survival rate of 74%, which is better than we see with other tyrosine kinase inhibitors and also better than what we weve seen to date with lower-intensity regimens, Short said.

This is likely driven by the higher rate of complete molecular response that we see with the combination of intensive chemotherapy plus ponatinib, he added.

Of the 68 patients evaluated, at a median follow-up of 43 months (range, 2-92), 71% were alive and still in remission at the time of data cutoff. After 3 years, the complete remission (CR) rate observed with the combination was 84%. Patients also achieved an event-free survival (EFS) rate of 70% and OS of 78% with hyper-CVAD plus ponatinib. It was estimated that the 5-year rates for CR, EFS, and OS would be 84%, 68%, and 73%, respectively.4

Notably, during this analysis, 11 patients relapsed after a median of 20 months in remission (range, 5-64 months). Three of the patients who relapsed were still receiving ponatinib, but 6 were being treated with another TKI, and 2 were not receiving any TKI. Among those who relapsed while receiving ponatinib, an ABL1 E255K kinase domain mutation was detected in 2 patients, which may have affected outcomes. The remaining patients who were treated with ponatinib but relapsed within 20 months did not have a tumor mutation.

It was also notable that a trend toward improved OS was observed in patients who did not undergo HSCT compared with those who did, according to a landmark analysis. Specifically, the OS rate for patients who did not undergo HSCT was 90% versus 66% for those who did (P=.07).

The safety profile of hyper-CVAD combined with ponatinib was tolerable in the newly diagnosed Ph+ ALL study population. The majority of adverse events (AEs) observed with the combination were grade 1 and 2 in severity. Still, dose reductions were necessary in 37% of patients as a results of AEs. The most common events that occurred were rash (n=7), liver function test abnormalities (n=5), pancreatitis (n=3), deep vein thrombosis (n = 2), and thrombocytopenia (n=2). There were 9 deaths in the study of patients who were in CR. Also, 2 ponatinib-related deaths occurred, leading to a protocol amendment regarding the dose level of the drug. After the amendment, no additional patients died.

Similar efficacy and safety were observed in earlier studies of hyper-CVAD plus a BCR-ABL TKI. First, results of the 2015 study of hyper-CVAD in combination with imatinib (Gleevac; NCT00038610) showed a 93% CR rate in the 45 patients with active disease at the time of enrollment. Additionally, at 5 years, the OS rate with hyper-CVAD plus imatinib was 43%.5

Satisfactory outcomes were reported with the intensive chemotherapy and BCR-ABL TKI combination of frontline hyper-CVAD and dasatinib (Sprycel) in patients with Ph+ ALL. Long-term follow-up results from the phase 2 study were published in the journal Cancer. The investigators concluded that the combination is able to achieve long-term remission in patients. In the 72 patients evaluated, the CR rate was 96% and the 5-year OS rate was 46%.6

Based on these 2015 data from 2 combinations, the 2019 data presented at ASH confirm the benefit of intensive chemotherapy combined with BCR-ABL TKI therapy, noted Short; however, the study conclusion mentioned that other BCR-ABL TKIs, such as blinatumomab (Blincyto), still must be evaluated in the frontline setting of Ph+ ALL.1,4

Is There a Role for Low-Intensity Chemotherapy?

To further support his argument around intensive chemotherapy plus TKI therapy, Short reviewed the emerging data of lower-intensity chemotherapy regimens. His overarching point was that the trials are too preliminary to change the current standard of care.

While I agree that lower-intensity therapies need to be evaluated, my argument is that those are not yet standard of care. There are not enough long-term data for those studies that show promise for treating patients with low-intensity chemotherapy outside of clinical trials, Short stated during the interview.

Short examined data from the 2007 study of imatinib plus chemotherapy in elderly patients with Ph+ ALL, which showed a superior CR rate compared with induction chemotherapy but did not show a survival benefit. The 1-year OS rate was 74%.7 In addition, the 2016 study of dasatinib with low-intensity chemotherapy in elderly patients, as well as the 2019 study of nilotinib (Tasigna) in patients with newly diagnosed Ph+ALL, demonstrated improved cure rates compared with induction therapy, but the OS was not satisfactory.8,9 Specifically, dasatinib plus low-intensity chemotherapy resulted in a 36% OS at 5 years, and nilotinib plus low-intensity chemotherapy led to a 2-year OS rate of 47%.

The most impressive survival results were observed with low-intensity chemotherapy plus ponatinib in elderly or unfit patients with Ph+ ALL treated in the phase 2 Gimema LAL1811 trial (NCT01641107). The combination led to a 2-year OS rate of 64%, which Short attributed to the higher CMR rate of 46%.10

After reviewing these data, Short maintained his argument that intensive chemotherapy combined with a BCR-ABL inhibitor is a proven frontline standard of care for Ph+ ALL. The only question that remains, Short told TTO, is whether the ability to skip transplant is an important accomplishment with the regimens.

Low-Intensity Chemotherapy as Ph+ ALL Treatment

Ph+ ALL is of the highest concern in patients 60 years and above. Perhaps due to the age of these patients, the satisfactory outcomes observed with intensive chemotherapy are often cancelled out by the overwhelming toxicity, Chiaretti explained during her presentation. Because of the toxicity of intensive chemotherapy, Chiaretti argues that long-term outcomes for this strategy are unsatisfactory, with ponatinib being the only exception.2

Today, we are lucky enough to be able to manage our patients with targeted therapies instead of chemotherapy. We should aim to use the best drugs that we have, which are TKIs and targeted therapies. The outstanding question is which are those patients who are at higher risk of relapse, so that we can use the best treatment for those patients, Chiaretti told TTO in an interview.

Success With Low-Intensity Chemotherapy and TKIs

In terms of low-intensity chemotherapy with a BCR-ABL TKI, the research around the GIMEMA strategy has shown high complete hematological response (CHR) rates, Chiaretti said, beginning with the study of imatinib in combination with steroids and without additional chemotherapy in elderly patients with Ph+ ALL (LAL0201-B; NCT00376467). Of the 30 participants aged 60 to 89 years, 29 were evaluable for response. The CHR rate achieved was 100%.11 Later, in the GIMEMA LAL1205 protocol study (NTC02744768), patients aged 18 to 84 with Ph+ ALL were treated with frontline dasatinib in combination with intrathecal chemotherapy and also achieved a 100% CHR rate.12

Chiaretti made note that all the GIMEMA protocols resulted in satisfactory CHR without additional chemotherapy, demonstrating that intensive chemotherapy may no longer be necessary for this patient population.

In the LAL0904 study (NCT00458848), a 96% CHR rate was observed in 49 evaluable patients. The regimen consisted of imatinib plus induction and consolidation chemotherapy in patients aged 16 to 60 years with Ph+ ALL. The treatment was deemed feasible for adult patients with Ph+ ALL based on this protocol.13 Similarly, 39 patients with Ph+ ALL 60 years and older in the LAL1408 study (NCT01025505) achieved a CHR rate of 94% on treatment with nilotinib in combination with imatinib. Investigators led by Giovanni Martinelli, MD, concluded that the results of this combination were not different from those observed with single-agent imatinib.14

For patients 60 years and older in the LAL1811 study, the CHR was 95% with ponatinib. This study confirmed the activity of ponatinib in this patient population.15

Finally, Chiaretti noted unpublished results from the LAL1509 trial (NCT01361438), which evaluated dasatinib total therapy in patients aged 18 to 60 . The CHR rate was reported as 97%.2 Notably, the safety profile of the drugs evaluated in all these GIMEMA studies were well tolerated.

Homing in on the difference in survival in patients treated with intensive chemotherapy versus de-intensified chemotherapy, intensive chemotherapy appeared to have better rates. Results of a 2012 study showed a 2-year event-free survival of 63% (95% CI, 39%-87%) with de-intensified chemotherapy in 29 patients with Ph+ ALL.16 In another study of 30 patients, low-intensity chemotherapy with imatinib led to a 5-year EFS rate of 32.1% compared with 42.2% with intensive chemotherapy. The 5-year OS rate in this study was 43% with low-intensity chemotherapy compared with 48.3% with intensive chemotherapy.17 Chiaretti noted, however, that the CT rate was not significantly different between these studies. Moreover, both responses and survival would be improved upon with a more target treatment approach, Chiaretti said.

Targeted Treatment of Ph+ ALL

Highlighting the results of the Gimema LAL2116 D-ALBA trial of front-line dasatinib in combination with blinatumomab as treatment of adults patients with Ph-ALL (NCT02744768), Chiaretti made the case of targeted therapy without addition of chemotherapy in this patient population.

The study of 63 evaluable patients at a median age of 54.50 years (range, 24.1-81.7 years) achieved a CMR rate of 60.4% (95% CI, 46%-73.5%), meeting the studys primary end point. Median follow-up was 14.3 months (range, 0.9-25), and the OS rate observed with the amount of follow-up was 95.2% (95% CI; 90.1%-100%). The disease-free survival rate was 89.7% (95% CI, 82.2%-97.9%).18

In terms of safety, 148 AEs were observed, and 41 serious AEs were observed. The most common AEs included infections and infestations, general disorders, and gastrointestinal disorders.

The key takeaway from Chiarettis presentation was that although low-intensity chemotherapy with a TKI is less toxic than intensive chemotherapy, ultimately, patients would have better overall outcomes with chemotherapy removed from the course of treatment: We dont want patients to succumb to their disease. If we use chemotherapy, the risk of treatment-related morality is very high.

Chiaretti concluded that a chemotherapy therapy-free induction and consolidation approach may be best for patients with Ph+ ALL.

References:

1. Short N. Is less more? intensive vs non-intensive approach to adults with Ph+ALL: intensive approach. Presented at: 2020 Society of Hematologic Oncology Annual Meeting; September 9-12, 2020; virtual.

2. Chiaretti S. Is less more: intensive vs nonintensive approach to adults with Ph+ ALL: non-intensive approach. Presented at: 2020 Society of Hematologic Oncology Annual Meeting; September 9-12, 2020; virtual.

3. Short N, Jabbour E, Sasaki K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosomepositive acute lymphoblastic leukemia. Blood. 2016;128(4):504-507. doi:10.1182/blood-2016-03-707562

4. Short NJ, Kantarjian HM, Ravandi F, et al. Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134 (suppl 1):283. doi:10.1182/blood-2019-125146

5. Daver N, Thomas D, Ravandi F, et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015;100(5):653-661. doi:10.3324/haematol.2014.118588

6. Ravandi F, OBrien SM, Cortes J, et al. Long-term follow-up of phase II study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121(23):4158-4164. doi:10.1002/cncr.29646

7. Ottmann OG, Wassmann B, Pfeifer H, et al; GMALL Study Group. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer. 2007;109(10):2068-2076. doi:10.1002/cncr.22631

8. Ottmann OG, Pfeifer H, Cayuela JM, et al. Nilotinib (Tasigna) and low intensity chemotherapy for first-line treatment of elderly patients withBCR-ABL1-positive acute lymphoblastic leukemia: final results of a prospective multicenter trial (EWALL-PH02). Blood. 2018;132(suppl 1):31. doi:10.1182/blood-2018-99-114552

9. Liu B, Wang Y, Zhou C, et al. Nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a single-center prospective study with long-term follow-up. Ann Hematol. 2019;98(3):633-645.doi:10.1007/s00277-019-03594-1

10. Martnelli G, Piciocchi A, Papayanndis C, et al. First report of the GIMEMA LAL1811 phase II prospective study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood.2017;130 (suppl 1):99.

11. Vignetti M, Fazi P, Camino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosomepositive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dellAdulto (GIMEMA) LAL0201-B protocol. Blood. 2007;109(9):3676-3678. doi:10.1182/blood-2006-10-052746

12. Fo R, Vitale A, Vignetti M, et al; MIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosomepositive acute lymphoblastic leukemia. Blood.2011;118 (25):6521-6528. doi:10.1182/blood-2011-05-351403

13. Chiaretti S, Vitale A, Vignetti M, et al. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016;101(12):1544-1552. doi: 10.3324/haematol.2016.14453

14. Martinelli G, Papyannidis C, Piciocchi A, et al. Extremely high rate of complete hematological response of elderly Ph+ acute lymphoblastic leukemia (ALL) patients by innovative sequential use of nilotinib and imatinib. a GIMEMA protocol LAL 1408. Presented at: American Association for Cancer Research Annual Meeting 2014; April 5-9, 2014; San Diego, CA. Abstract 5552.

15. Papayannidis C, De Benedittis C, Soverini S, et al. Ponatinib is well tolerated and active in patients with relapsed/refractory Philadelphia positive acute lymphoblastic leukemia (PH+ ALL) and advanced phase of chronic myelogenous leukemia (DML) harbouring T315i mutation: the Bologna experience. Blood. 2013;122(21):3911. doi:10.1182/blood.V122.21.3911.3911

16. Ribera JM, Garca J, Fernndez-Abelln P, et al; PEHEMA Group. Lack of negative impact of Philadelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols. Br J Haematol. 2012;159(4):485-488. doi:10.1111/bjh.12043

17. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24);3711-3719. doi:10.1182/blood-2015-02-627935

18. Chiaretti S, Bassan R, Vitale A, et al. A Dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ all patients. preliminary results of the GIMEMA LAL2116 D-ALBA trial; on behalf of GIMEMA Acute Leukemia Working Party. Presented at: European Hematology Association 2019 Annual Meeting; June 13-16, 2019; Amsterdam, the Netherlands. Abstract S1617.

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Doctors Debate: Is Intensive or Low-Intensity Chemotherapy Plus BCR-ABL TKI Therapy Best for Treatment of Ph+ ALL? - Targeted Oncology

Record number of stem cell donors apply after Ex On The Beach star plea – expressandstar.com

Ashley Cain with his girlfriend Safiyya and daughter Azaylia Diamond

A blood cancer charity has seen record numbers of people applying to become stem cell donors following a plea from former footballer and Ex On The Beach star Ashley Cain.

Mr Cains 12-week-old daughter Azaylia Diamond Cain was diagnosed with an aggressive form of leukaemia when she was two months old.

Doctors recently told the reality star and his girlfriend Safiyya that, while their daughter had responded well to her chemotherapy and treatment, she would require a stem cell transplant from a stranger to be cured.

Anthony Nolan, a charity which recruits people aged between 16 and 30 to join the stem cell register, is now searching for a donor for Azaylia.

Mr Cain appealed for potential donors to sign up on Friday and the charity has since seen 41,000 people apply within 48 hours, compared to the usual 100 per day.

Mr Cain said: You know your own child and we knew she wasnt well.

She has a rare and aggressive form leukaemia thats made even rarer by her being only eight-weeks-old when she was diagnosed.

She has tumours on her lungs, stomach and kidneys.

Finding out that your baby has a serious and life-threatening illness is something no parent in the world should have to go through.

It was the single most upsetting, terrifying and heartbreaking experience we have ever been through.

Something that is not only incomprehensible, but it also has a devastating impact on our physical and mental health.

Azaylia has Caribbean, Indian and northern European ethnicity, which means she has a 20% chance of finding an unrelated stem cell donor match, compared to a 69% chance for people with white European heritage.

Mr Cain added: Its out of Azaylias hands now, shes almost climbed this mountain, but she now needs someone elses hand to help her get to the top.

She cant do this on her own, she needs a donor.

As well as appealing for more donors to apply, Anthony Nolan is appealing for financial support as it costs 40 for each donor to be registered.

Henny Braund, chief executive at the charity, said: We are extremely grateful to Ashley for using his platform to raise awareness of the need for more stem cell donors.

Its incredible that so many people have been inspired by Azaylias story to join the register.

Every single one of the new potential donors has the potential to give hope to little girls, like Azaylia, who are in desperate need of an urgent stem cell transplant.

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Record number of stem cell donors apply after Ex On The Beach star plea - expressandstar.com

Bisbee: A commitment to health care initiatives The Journal Record – Journal Record

Julie Bisbee

This month marks the 20th anniversary of voters creation of the Oklahoma Tobacco Settlement Endowment Trust, a grant-making state agency devoted to preventing cancer and cardiovascular disease, Oklahomas leading causes of death. Past accomplishments and new initiatives give Oklahomans reason to be proud of TSET.

In 1998, 46 states including Oklahoma reached the Master Settlement Agreement with Big Tobacco, resolving a lawsuit over the tobacco industrys practice of lying to the public about smoking dangers. In 2000, voters approved a constitutional amendment that safeguarded the bulk of the MSA payments in an endowment. Endowment investment earnings fund grants and programs to improve health.

On Nov. 3, voters affirmed the wisdom of TSETs structure, with each of Oklahomas 77 counties rejecting a state question that sought to reduce the contribution to the TSET endowment. This vote upholds the voter-created structure that funds tobacco use cessation and prevention, cancer research, community-based programs and other initiatives that improve quality of life.

Since 2000, TSETs funding of cancer research has given Oklahomans access to cutting-edge cancer treatment. TSETs funding of Phase 1 clinical trials helped the Stephenson Cancer Center achieve the prestigious National Cancer Institute designation.

To date, TSET has funded not only the Stephenson Cancer Center but also the TSET Health Promotion Research Center and the Oklahoma Center for Adult Stem Cell Research. For every dollar TSET has invested, research institutions have attracted an additional $3 in outside funding.

TSET also addresses physician shortages. This year, TSETs partnership with the Physician Manpower Training Commission filled all 42 slots in its loan repayment program, which helps pay off medical school loans when doctors agree to practice in rural and underserved areas.

TSETs Healthy Living Program is another success. Now in its second five-year grant cycle, the program works at the local level to improve health and make it easy for people to make healthy choices.

Policies help shape the environment. Tobacco-free policies protect the public from toxic secondhand smoke and encourage tobacco users to quit. Thanks to work of TSET grantees at the local level, more than 80% of school districts had adopted a tobacco-free policy before state law was enacted to protect all Oklahoma children from tobacco and e-cigarette use.

TSET remains committed to preventing cancer and cardiovascular disease. Visit tset.ok.gov.

Julie Bisbee is executive director of the Tobacco Settlement Endowment Trust, a voter-created grant-making trust devoted to preventing cancer and cardiovascular disease, Oklahomas leading causes of death.

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Bisbee: A commitment to health care initiatives The Journal Record - Journal Record

California election results: Where state propositions stand as of Thursday at 5 p.m. – Desert Sun

Associated Press Published 2:01 p.m. PT Nov. 4, 2020 | Updated 11:53 p.m. PT Nov. 5, 2020

Uber and Lyft decals are shown on a vehicle at Palm Springs International Airport on Wednesday, Jan. 22, 2020 in Palm Springs, Calif.(Photo: Vickie Connor/The Desert Sun)

Access to Uber and Lyft rides proved to be important to California voters Tuesday, but raising property taxes on commercial properties in the statewas narrowly defeated in one of the most hotly contested of 12 state propositions.

Voters also gave a huge defeat to an attempt to require certified doctors at kidney dialysis clinics and also rejected anattempt to re-establish affirmative action in hiring in California.

Following are results as of Thursday at 5 p.m. as reported by the California Secretary of State.

Uber, Lyft and other app-based ride-hailing and delivery services spent $200 million in a winning bet on Proposition 22 to circumvent California lawmakers and the courts to preserve their business model by keeping drivers from becoming employees eligible for benefits and job protections.

The titans of the so-called gig economy bankrolled the most expensive ballot measure in state history, which was decided Tuesday with 58.5% of voters choosing to keep drivers classified as independent contractors able to set their own hours.

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More: Photos: Election Day voting across Coachella Valley, Riverside County

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The outcome was a defeat for labor unions that had pushed for a state law aimed directly at Uber and Lyft, mandating they provide drivers with protections like minimum wage, overtime, health insurance and reimbursement for expenses.

Supporters of Proposition 22 said the outcome showed voters wanted to preserve the flexibility of the current system. Opponents said the companies had bought their own law and vowed to continue fighting for drivers' rights.

A ballot measure to partially dismantle Californias longtime system of tying property taxes to the last sales price appears to have lost byjust over 400,000 among the 11.5 million ballots cast. No votes on Proposition 15 garnered 51.8%of the votes.

The measure would have reassessed commercial and industrial properties every three years. Residential property would have remained under current rules. Since a 1978 ballot measure Proposition 13 sparked a national outcry for tax cuts and helped pave Gov. Ronald Reagans path to the White House, California has limited tax increases to 2% a year for inflation until a property is sold.

Supporters saidasplit-roll system would go a long way toward fixing inequities that shield wealthy corporations, depriving property tax proceeds for schools and local governments.

Opponents called it a massive tax increase that will cripple businesses in a pandemic-wracked economy. Their advertising portrayedit as a step toward completely dismantling the system established under 1978's Proposition 13, even though supporters disavowed plans to change how residential property is assessed.

A ballot measure to reinstate affirmative action in California government saw a 56.1% No vote Tuesday. Public polling had indicated that Proposition 16 was struggling, suggesting that voters were not inclinedto repeal a quarter-century-old ban on affirmative action in the state.

A national awakening on race drove a well-funded campaign to reinstate preferential treatment based on race and gender in public hiring, contracting and college admissions. Supporters said such programs are critical to undoing generations of systemic racism and sexism. Opponents said merit alone should determine whether someone gets a job or gets accepted into college.

Democratic vice presidential nominee Kamala Harris backedthe effort. Opponents saidthe government should treat every person equally, and never use race, ethnicity or gender to promote or discriminate against an individual.

The biggest margin of victory on the night belonged to No votes on Proposition 23, the second ballot measure on kidney dialysis in the state in as many elections. Voters rejected the ballot measure to require a doctor or highly trained nurse at each of Californias 600 dialysis clinics, with "no" votes taking64%.

The measure drew more than $110 million in spending. Supporters said a doctor is needed at clinics whenever the states 80,000 dialysis patients are being treated to make sure they get quality care. Opponents, financed by dialysis clinic companies, said the measure would have created a financial burden that could lead some clinics to close.

Proposition 23 was the second attempt by the unions to increase regulation of dialysis clinics in California, where DaVita Inc. and Fresenius Medical Care two of the countrys largest for-profit dialysis providers operate about three-quarters of the states dialysis market.

California voters also voted to maintain the status quo on criminal justice. They rejected an attempt to eliminate cash bail, with Proposition 25 losing with 55.5% of thevotes cast as No.

On Proposition 20, which would have scaled back two earlier ballot measures approved by voters in 2014 and 2016, about 62% of voters were opposed. The proposition would again bar those convicted of certain serious offenses from earlier release and increase penalties for repeated retail thefts.

By rejecting Proposition 25, voters in the most populous state overturned a 2018 law that stalled when the bail industry challenged it at the ballot box through the proposition.Supporters of the change had said the traditional bail system punishes the poor often racial minorities because they lack the money to buy their freedom or can least afford to pay a bail bondsman.Opponents included some prominent civil rights groups who said the alternatives risk assessment tools also are racially and socioeconomically biased.

A proposition that would keep alive Californias first-of-its-kind stem cell research program appears to have won in a tight race. Proposition 14 saw voters give it 51% Yes votes Tuesday. The measure would authorize a $5.5 billion bond sale to bail out the California Institute for Regenerative Medicine, which was created by a similar $3 billion bond measure in 2014 but is now nearly broke. With dozens of stem cell research trials underway, supporters say the money is desperately needed. Opponents saidthat in a pandemic-induced economic crisis, California simply cant afford it.

Voters rejected a measure that would have allowed cities to expand rent control. Proposition 21 would have let cities limit rent hikes on properties that are more than 15 years old. No votes led with 59.8% of the vote. Opponents argued that the measure would have discouraged new home construction at a time when its sorely needed. Proponents said the measure was an urgent attempt to slow spiraling rent increases. A recent report said more than half of Californias renters spend over 30% of their incomes on rent.

A measure to expand California's digital privacy law easily won with 56.1% of the voters approving Proposition 24. The measure would update a law approved two years ago that gave Californians the right to know what personal information companies collect about them online. The proposition also would triple the fines for companies that violate kids privacy.

Proponents saidthe measure will strengthen Californias privacy law and help hold big business accountable. Opponents argued that the 52-page initiative was too complicated for voters and its too soon to rewrite a law that just took effect.

California voters appeared to give narrow approval to Proposition 19, which would give Californians 55 or older a big property tax break when buying a new home. To fund that new tax break, the measure would curtail a separate tax break Californians may receive on homes inherited from parents and grandparents.

Yes on Prop. 19 was leading with 51.4% of the vote.

In one of two measures involving voting rights, voters decisively passed a ballot measure restoring the right to vote for felons on parole. Proposition 17 will change the state Constitution to allow an estimated 50,000 felons to vote, with 59% ofvoters approving the measure.

Another voting rights measure, Proposition 18, which would have allowed 17-year-olds to vote in primaries if they turn 18 before the general election, was rejected by55.% of voters.

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California election results: Where state propositions stand as of Thursday at 5 p.m. - Desert Sun