A study by the University of Tampere in Finland used protein profiling to find new prostate cancer mechanisms that are not shown by aberrations at the genomic level. Several new potential biomarkers of prostate cancer were also found.
Genes that affect prostate cancer evolution have been studied for a long time. However, changes in the protein levels are not well known.
The Center for Prostate Cancer Research and the Center for Proteomics and Personalized Medicine at the University of Tampere cooperated to profile the protein expression of prostate cancer by using mass spectrometry for the first time. The researchers compared protein expression to genomic and messenger RNAs in the same samples.
The result was that the changes in gene copy numbers and DNA methylation largely explain messenger RNA expression but not the changes on the protein level. The association between messenger RNA expression and protein levels was also weak. The study thus uncovered such mechanisms of prostate cancer that are not indicated by the alterations at the genomic level.
“In particular, changes in the citric acid cycle emerged in our analyses,” Adjunct Professor Leena Latonen says.
“The results enable exploring the significance of these changes," Latonen continues.
In addition to the disease mechanisms, protein profiling revealed several potential new biomarkers.
According to Professor Tapio Visakorpi, biomarkers able to recognize the aggressive forms of prostate cancer would be especially useful. That is one of the aspects on which the researchers will focus next.
“Discovering these protein biomarkers was enabled by the long-term interdisciplinary work of the research groups on the Kauppi campus of the University of Tampere,” says Professor Hannu Uusitalo, Director of the Center for Proteomics and Personalized Medicine.
University of Tamperewww.uta.fi/en/news/story/proteins-reveal-new-mechanisms-prostate-cancer

Two patients with mycosis fungoides (MF) can appear to have identical diseases upon first diagnosis but can have radically different outcomes. MF in an unusual cancer of the T lymphocyte that begins in the skin rather than in the lymph nodes, with the first sign often being a rash. Most patients with MF, the most common type of cutaneous T cell lymphoma (CTCL), have a very slow-growing disease and often have normal life expectancies. But a subset of patients will develop an aggressive, deadly form of the disease that can spread throughout the skin and beyond, becoming untreatable. If identified early, patients with this aggressive form of MF may be eligible for a stem cell transplant to cure the disease, but once MF progresses and becomes treatment resistant, it is nearly impossible to achieve the complete remission required for a successful stem cell transplant.
A tool to accurately determine which early-stage patients are at risk of dying from MF and which patients are likely to only require conventional therapy is desperately needed. Investigators from Brigham and Women’s Hospital have found that next-generation, high-throughput sequencing of a specific gene (T-cell receptor beta or TCRB) is a stronger predictor of which early-stage patients will develop aggressive, progressive MF than any other established factor.
“We are excited to bring precision medicine to the management of MF patients,” said senior author Thomas Kupper, MD, chair of the BWH Department of Dermatology. “While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease, and treat them in a more aggressive fashion with the intent to better manage, and ideally cure, their cancer.”

Brigham and Women’s Hospitalwww.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=3009

A large-scale international study led by the University of Exeter Medical School has discovered new genes linked to parents’ lifespan – which could one day be targeted to help prolong human life.
How long we live is determined by a range of factors including our lifestyle and how well we treat factors including blood pressure and cholesterol from midlife. However, genetics, and how long our parental relatives lived, also plays a role.
Now, the number of genes we know influence lifespan has expanded, potentially paving the way to new therapeutic targets to prolong life.
The study, funded by the Medical Research Council and conducted in collaboration with a number of US universities, undertook a genome-wide search for variants influencing how long participants’ parents lived. The team studied 389,166 volunteers who took part in the UK Biobank, with confirmation in the US Health and Retirement Study and the Wisconsin Longitudinal Study. The DNA samples from the volunteers carry the genetics of their biological parents, so provide a practical way of studying exceptionally long lifespans.
Eight genetic variants had already been linked for lifespan, mainly involved in heart disease and dementia. The latest study has expanded this to 25 genes in all, with some specific to mothers’ or fathers’ lifespan separately.
Dr Luke Pilling, who undertook most of analyses said: “We have identified new pathways that contribute to survival, as well as confirming others. These targets, including inflammatory and cardiovascular pathways, offer potentially modifiable targets to reduce risk of an earlier death and improve health.”
Genes involved in senescence, the ‘frozen’ state that cells enter into after being damaged, played an important role in longevity. Drugs targeting senescence have already been shown to extend life in laboratory animals.
Genes related to inflammation and auto-immunity-related genes were also prominent, opening up the possibility that precision anti-inflammatory treatments may one day be helpful in extending life.
The results confirm that many genetic variants combine to influence human lifespan: no single gene variant was found to be responsible.
The study found evidence to suggest that the genetic variants for average lifespan also influence exceptionally long life expectancy. A genetic risk score combining the top ten variants was statistically associated with parents being centenarians.
Exeter Universityhttps://tinyurl.com/yakjsfoj

Researchers have identified a type of human leukocyte antigen (HLA) that is associated with the skin disease bullous pemphigoid (BP) in diabetic patients administered with DPP-4 inhibitory drugs.
DPP-4 inhibitor (DPP-4i) is widely used to treat type 2 diabetes, but increased cases of bullous pemphigoid (BP) have been reported among patients taking the medicine. BP is the most common autoimmune blistering disorder, characterized by itchy reddening of the skin as well as tense blisters over the whole body. Afflicted patients, mostly elderly, suffer from autoimmune attacks on a type of collagen in skin, making it hard to cure and compromising their quality of life. Previously, no risk factor triggering BP in diabetic patients administered with DPP-4i had been identified.
BP is classified into two types: inflammatory and non-inflammatory, the latter of which is found more in diabetic patients administered with the drug. The research team, including Dr. Hideyuki Ujiie of Hokkaido University Hospital, examined 30 BP patients administered with DPP-4i, and investigated their symptoms and autoantibodies to group them as inflammatory or noninflammatory.
The researchers then analysed human leukocyte antigen (HLA) genes of the 30 patients to identify their white blood cell type since HLA genes are known to be involved in various immune diseases. To compare, the team also analysed the HLA of 72 BP patients who had not been administered with DPP-4i and 61 diabetic patients who were using the drug but not affected by BP. Their findings were compared with the HLA genes of 873 Japanese from the general population.
According to the results, 70 percent of the 30 BP patients administered with DPP-4i fell into the non-inflammatory type with less reddening of the skin (erythema). HLA analyses found 86 percent of the non-inflammatory BP patients administered with DPP-4i had an HLA gene called “HLA-DQB1*03:01.” The rate of having the HLA gene was much higher than was detected among the general population (18 percent) and non-BP type-2 diabetic patients administered with DPP-4i (31 percent). Meanwhile, 26 percent of BP patients who were not administered with the drug had the same HLA gene.
The findings show HLA-DQB1*03:01 is not linked to ordinary BP nor type-2 diabetes, but is closely associated with the development of BP among DPP-4i takers. “However, as the probability of patients exposed to DPP-4i to develop BP remains unclear, further research investigating a much larger number of cases is needed,” says Hideyuki Ujiie.
“Our results suggest people with HLA-DQB1*03:01 have a higher risk of developing BP when exposed to DPP-4i than those without the HLA gene. The gene could serve as a biomarker to help estimate the risk of developing BP when patients are administered with DPP-4i. The mechanism that connects the HLA gene and BP needs to be addressed to help prevent the development of the disease,” Ujiie added.
ScienceDailyhttps://tinyurl.com/y9u48zv3 

 New findings from the groundbreaking Trial Assigning Individualized Options for Treatment (Rx), or TAILORx trial, show no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. The study found that for women with hormone receptor (HR)-positive, HER2-negative, axillary lymph node-negative breast cancer, treatment with chemotherapy and hormone therapy after surgery is not more beneficial than treatment with hormone therapy alone. The new data will help inform treatment decisions for many women with early-stage breast cancer.
The trial was supported by the National Cancer Institute (NCI), part of the National Institutes of Health, and designed and led by the ECOG-ACRIN Cancer Research Group.
“The new results from TAILORx give clinicians high-quality data to inform personalized treatment recommendations for women,” said lead author Joseph A. Sparano, M.D., associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York City and vice chair of the ECOG-ACRIN Cancer Research Group. “These data confirm that using a 21-gene expression test to assess the risk of cancer recurrence can spare women unnecessary treatment if the test indicates that chemotherapy is not likely to provide benefit.”
TAILORx, a phase 3 clinical trial, opened in 2006 and was designed to provide an evidence-based answer to the question of whether hormone therapy alone is not inferior to hormone therapy plus chemotherapy. The trial used a molecular test (Oncotype DX Breast Recurrence Score) that assesses the expression of 21 genes associated with breast cancer recurrence to assign women with early-stage, HR- positive, HER2-negative, axillary lymph node–negative breast cancer to the most appropriate and effective post-operative treatment. The trial enrolled 10,273 women with this type of breast cancer at 1,182 sites in the United States, Australia, Canada, Ireland, New Zealand, and Peru.
When patients enrolled in the trial, their tumours were analysed using the 21-gene expression test and assigned a risk score (on a scale of 0–100) for cancer recurrence. Based on evidence from earlier trials, women in the trial who had a score in the low-risk range (0–10) received hormone therapy only, and those who had a score in the high-risk range (26 and above) were treated with hormone therapy and chemotherapy.
Women in the trial who had a score in the intermediate range (11–25) were randomly assigned to receive hormone therapy alone or hormone therapy with adjuvant chemotherapy. The goal was to assess whether women who received hormone therapy alone had outcomes that were as good as those among women who received chemotherapy in addition to hormone therapy.
“Until now, we’ve been able to recommend treatment for women with these cancers at high and low risk of recurrence, but women at intermediate risk have been uncertain about the appropriate strategy to take,” said Jeffrey Abrams, M.D., associate director of NCI’s Cancer Therapy Evaluation Program. “These findings, showing no benefit from receiving chemotherapy plus hormone therapy for most patients in this intermediate-risk group, will go a long way to support oncologists and patients in decisions about the best course of treatment.”
The researchers found that the primary endpoint of the trial, invasive disease-free survival—the proportion of women who had not died or developed a recurrence or a second primary cancer—was very similar in both groups. Five years after treatment, the rate of invasive disease-free survival was 92.8 percent for those who had hormone therapy alone and 93.1 percent for those who also had chemotherapy. At nine years, the rate was 83.3 percent for those with hormone therapy alone and 84.3 percent for the group that had both therapies. None of these differences were considered statistically significant.
The rates of overall survival were also very similar in the two groups. At five years, the overall survival rate was 98.0 percent for those who received hormone therapy alone and 98.1 percent for those who received both therapies, and at nine years the respective overall survival rates were 93.9 percent and 93.8 percent.
The researchers also found that women with a score of 0–10 had very low recurrence rates with hormone therapy alone at nine years (3 percent). This confirms similar findings from earlier studies. In addition, they found that women with a score of 26–100 had a distant recurrence rate of 13 percent despite receiving both chemotherapy and hormone therapy. This finding indicates the need to develop more effective therapies for women at high risk of recurrence.

ECOG-ACRIN Cancer Research Group
ecog-acrin.org/news-and-info/press-releases/tailorx-trial-finds-most-women-with-early-breast-cancer-do-not-benefit-from-chemotherapy