CAR-T- therapy safe and effective for leukemia

Results of the global, multicenter, pivotal phase 2 study that led to the first FDA approval of a gene therapy/cell therapy approach known as CAR T-cell therapy. The therapy, tisagenlecleucel, uses a patient's own white blood cells that have been genetically re-engineered to specifically target and kill cancer cells. It was approved to treat pediatric acute lymphoblastic leukemia (ALL), the most common childhood cancer. Senior authors on the study include Stephan A. Grupp, MD, PhD, of Children's Hospital of Philadelphia and Michael A. Pulsipher, MD, of Children's Hospital Los Angeles (CHLA).

 Researchers evaluate 75 patients between 3 to 21 years of age with relapsed or treatment refractory B-cell ALL. 61% of these patients had relapsed after allogeneic hematopoietic stem cell transplantation, an intensive therapy intended to be curative and whose failure leaves few remaining options. For comparison, the paper cites another FDA-approved therapy for the treatment of children with relapsed or refractory ALL; it produced a response rate of 20% with a median overall survival time of 13 weeks.

Patients who relapsed after transplant or did not respond to treatment - there wasn't much else we had to offer them and often, they went to hospice. Now, instead of sending them to hospice - we treat them with CAR-T-cells, make them better, then send them home. The updated analysis showed an overall remission rate of 81% within 3 months of treatment. All patients who responded to therapy showed no minimal residual disease by flow cytometry - the most sensitive means of analysis.

Overall survival was 90% at 6 months and 76% at 12 months. The median length of remission was not reached, with tisagenlecleucel remaining in the blood for up to 20 months. CAR-T therapy is truly a game changer for pediatric leukemia. Substantial side effects are associated with this therapy; grade 3 or 4 adverse events that may have been related to the therapy occurred in 73% of patients. The most significant side effects included cytokine release syndrome, often requiring admission to an intensive care unit, and neurological events in 40% of
patients.
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Effects of obesity on bone marrow cells

According to new research, obesity causes durable and harmful changes to the hematopoietic stem cell compartment-the blood-making factory in human body. Blood stem cell compartment is made up of numerous cell subsets, age and environmental stresses can lessen the healthy diversity of cells in human blood-making machinery. This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates.

Obesity related stresses alter the cellular architecture of the hematopoietic stem cell compartment and reduce its long-term functional fitness. Tests in obese mice show these effects are progressive and that some of the harmful manifestations persist even after researchers normalize the animals' weight through dietary controls. Alterations of the body's blood-making system appear to be linked to over- expression of a transcription factor called Gfi1- a regulatory gene that controls other genes. The researchers show that oxidative stresses in the body caused by obesity drive overexpression of Gfi1.

 This produces a lasting alteration of hematopoietic stem cell compartment and molecular mayhem. The study also provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancer. Hematopoietic stem cells are an important tool for treating leukemia and other blood diseases.
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Levels of genetic code can cause neuropsychiatric disorders

Studying the genetic code allows researchers to know whether some patients with neuropsychiatric disorders either have extra copies of the CHRNA7 gene or are missing copies. Pluripotent stem cell technology helps better understand neuropsychiatric disorders. Taking skin biopsies from patients with these conditions, grow the cells in culture in the lab and reprogram them to become brain cells. Using this approach, researchers gained insights into the mechanisms of disease at the neuronal level.

The CHRNA7 gene is translated into CHRNA7 proteins that form a channel on the cell membrane that allows calcium to enter the cells. By regulating calcium levels, the CHRNA7 gene plays an important role on how neurons communicate and function with each other. The researchers found that neurons with fewer copies of the gene show a reduction in calcium flux, almost half of what they see in control samples, which they expect will have functional consequences on neuronal functioning in those patients.

These results provide insights into why the patients with fewer copies of the gene share clinical characteristics with the patients with extra copies of the gene, despite having opposite underlying genetic makeup. In both cases, the result of the genetic imbalance is a decrease in calcium flux in the neurons. Clinically, while the patients with fewer copies present with moderate to severe cognitive impairment, high prevalence of autism and other neuropsychiatric problems, those with extra copies present with similar but less severe characteristics.

Opposite genetic imbalance results in similar biological effect mediated by different mechanisms. In the case of neurons with fewer copies of the gene, and therefore fewer CHRNA7 proteins to form calcium channels, the researchers proposed that the reduction in calcium flux in the cells results from having fewer calcium channels.For the neurons with extra copies of the gene, we found that having extra copies of the gene results in more CHRNA7 proteins, which overwhelms the process that assembles them together, causes cellular stress and disturbs the formation of calcium channels.
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Pomegranate extract alters breast cancer stem cell

Research team has found evidence suggesting that the same antioxidant that gives pomegranate fruit their vibrant red color can alter the characteristics of breast cancer stem cells, showing the superfood's potential for aiding in much more than diabetes or heart disease as previously thought.
Pomegranate extract, derived mainly from the skin of the fruit, is known for having high levels of powerful antioxidants called polyphenols.

Stem cells are unlike other types of cells in that they have a remarkable ability to self-divide and reproduce themselves, even giving rise to other types of cells. This self-dividing nature alone is not dangerous; in fact, normal tissue stem cells can replace dying cells and even repair damaged tissue.
The danger arises if stem cells become cancer stem cells, because their division and renewing ability carries over to cancer progression by aiding in tumor initiation, growth, and even re-initiating cancerous tumors long after a person has been declared cancer-free.

Compounding these issues are the fact that cancer stem cells are thought to be more resistant to therapy than other types of cancer cells. Cancer stem cells have become an important target in cancer therapy and prevention more so than other cancer cells, because of the idea that if the stem cells can be slowed or made "less stem-like," the cancer itself could be slowed too.

Researchers conducted experiments using cancer cells lines that are the prototypes of breast cancer stem cells. These cells, which display the exact properties of cancer stem cells, were treated with diluted pomegranate extract and incubated for periods ranging from one to six days.
During this time, the team measured several markers of breast cancer stem cells in both the pomegranate extract treated cells and untreated cells . They then compared the results between the groups and observed significant differences between the cancer stem cell prototypes that were treated with pomegranate extract.

Additionally, the cells that were treated with pomegranate extract were treated with relatively small amounts – thought to be manageable for a person to consume by simply purchasing the product at a grocery store and incorporating it into their diet. Low concentrations of the extract are able to modify the ability of cancer stem cells to reproduce themselves.

Pomegranate extract inhibits breast cancer cells ability to self-renew. Pomegranate extract converts cancer stem cells to cells that look like more traditional cancer cells and which may successfully be eliminated by cancer drugs.Pomegranate extract shows promising potential for having a positive effect in both the primary cancer prevention and inhibition of the disease progression.
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Transplanted hematopoietic stem cells reverse damage caused by neuro-muscular disorder

Single infusion of wildtype hematopoietic stem and progenitor cells (HSPCs) into a mouse model of Friedreich's ataxia (FA) measurably halted cellular damage caused by the degenerative disease. Friedreich's ataxia is an inherited, degenerative neuromuscular disorder that initially impairs motor function, such as gait and coordination, but can lead to scoliosis, heart disease, vision loss and diabetes. Cognitive function is not affected.

The disease is progressively debilitating, and ultimately requires full-time use of a wheelchair. FA is caused by reduced expression of a mitochondrial protein called frataxin (FXN) due to a two mutated or abnormal copies of the FXN gene. Researchers used a transgenic mouse model that expresses two mutant human FXN transgenes, and exhibits the resulting progressive neurological degeneration and muscle weakness.

Human hematopoietic stem and progenitor cells (HSPCs), derived from bone marrow, have become a primary vehicle for efforts to replace or regenerate cells destroyed by a variety of diseases. Transplanting wildtype or normal mouse HSPCs resulted in long-term kidney, eye and thyroid preservation in a mouse model of cystinosis, another genetic disorder.

Researchers transplanted wildtype HSPCs into an FA mouse model, reporting that the HSPCs engrafted and soon differentiated into macrophages in key regions of the mice's brain and spinal cord where they appeared to transfer wildtype FXN into deficient neurons and muscle cells. Transplantation of wildtype mouse HSPCs essentially rescued FA-impacted cells expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.
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Food preservatives interfere with hormone and cause obesity

Food preservatives are added to foods to preserve them for long-term use.
Scientists tested the effects of endocrine disruptors on humans. The three chemicals tested are: Butylhydroxytoluene BHT, Perfluorooctanoic acid PFOA and tributyltin TBT.

Butylhydroxytoluene BHT, is an antioxidant commonly added to breakfast cereals and other foods to protect nutrients and keep fats from turning rancid.

Perfluorooctanoic acid PFOAis a polymer found in some cookware, carpeting and other products.

Tributyltin TBT is a compound in paints that can make its way into water and accumulate in seafood.

Scientists used hormone-producing tissues grown from human stem cells to demonstrate how exposure to these chemicals can interfere with the digestive system and the brain.

 These chemicals enable people to continue eating, causing them to gain weight. Each of these chemicals damaged hormones that communicate between the gut and the brain.

 BHT produced some of the strongest detrimental effects, these compounds can disrupt hormones that are critical to gut-to-brain signaling and preventing obesity.

Scientists obtained blood samples from adults, and then, by introducing reprogramming genes, converted the cells into induced pluripotent stem cells.

 Then, using these stem cells, they grew human epithelium tissue, which lines the gut, and neuronal tissues of the brain's hypothalamus region, which regulates appetite and metabolism.

Scientists exposed the tissues to BHT, PFOA and TBT, one by one and also in combination, and discovered that the chemicals disrupted networks that prepare signaling hormones to maintain their structure and be transported out of the cells, thus making them ineffective.

The chemicals also damaged the cellular structures that convert food and oxygen into energy and drive the body's metabolism. Because the chemical damage occurred in young cells, a defective hormone system could impact a pregnant mother and her fetus.
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