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

Scientists have known for decades that the Hox family of transcription factors are key regulators in the formation of blood cells and the development of leukemia. Exactly how this large family of genes, which are distributed in four separate chromosomal clusters named A through D, is regulated has been less clear. Now, new research from the Stowers Institute for Medical Research reveals that a DNA regulatory element within the Hoxb cluster globally mediates signals to the majority of Hoxb genes to control their expression in blood-forming stem cells.
“It’s like we found a general control that simultaneously turns the lights on and off in many rooms, rather than having a single switch that controls each individual room,” says Stowers Investigator Linheng Li, PhD, who co-led the study along with Stowers Scientific Director and Investigator Robb Krumlauf, PhD. These findings also help explain why a particular form of leukemia resists treatment and points to potential new therapeutic avenues.
In mammals, the blood system contains a number of mature cell types — white blood cells, red blood cells, platelets — that arise from blood-forming, or hematopoietic, stem cells (HSCs). HSCs renew themselves and differentiate into other cells to replenish the body’s blood supply in a process called hematopoiesis. Hox genes, which are well known for their roles in establishing the body plan of developing organisms, are also important for HSCs to maintain their critical balancing act in the adult blood system, and have been implicated in the development of leukemia.
In an article Li, Krumlauf, and co-authors including first author Pengxu Qian, PhD, second author Bony De Kumar, PhD, and other collaborators provide new details as to how Hox genes are regulated in HSCs. They report that a single cis-regulatory element, DERARE, works over a long range to control the majority of Hoxb genes in HSCs in a coordinated manner. The researchers found that the loss of the DERARE decreased Hoxb expression and altered the types of blood cells arising from HSCs, whereas “turning on” DERARE allowed Hoxb cluster gene expression in progenitor cells and increased the progression of leukemia.
Genes can be regulated by non-coding DNA sequences termed cis-regulatory sequences. These sequences get input from multiple types of molecules, such as transcription factors, histone modifiers, or various morphogens. The DERARE, or distal element RARE (retinoic acid response element), is a cis-regulatory element that responds to signals from the vitamin A derivative retinoic acid and determines the fate of HSCs.
Using human leukemia cell lines and mouse models, the Stowers researchers and collaborators have identified a mechanism for how the retinoid-sensitive DERARE maintains normal hematopoiesis and prevents acute myeloid leukemia (AML) by regulating Hoxb cluster genes in a methylation-dependent manner.
Methylation is the process of adding methyl groups to the DNA molecule, which can change the activity of the DNA segment. The researchers demonstrated that DNA methyltransferases mediate DNA methylation on DERARE, leading to reduced Hoxb cluster expression. AML patients with mutations in the DNA methyltransferase DNMT3A exhibit reduced DERARE methylation, elevated Hoxb expression, and adverse outcomes.
“In two human AML cell lines carrying a DNMT3A mutation, we used an adaptation of genome editing technology called dCas9-DNMT3A to specifically increase the DNA methylation on DERARE. This targeted methylation technique was able to reduce Hoxb cluster expression and alleviate the progression of leukemia,” says Qian. “It is known that Hoxb cluster genes show a dramatic increase in expression in patients with DNMT3A-mutated AML. Our work provides mechanistic insights into the use of DNA methylation on the DERARE as a potential screening tool for therapeutic drugs that target DNMT3A-mutated AML, thus leading to the development of new drugs for treating AML, in which DNA methylation is abnormal.”

Stowers Institutehttps://tinyurl.com/yarf3xfd

Siemens Healthineers is developing “The Enterprise Project” with the Hermes Pardini Group of Minas Gerais, Brazil. The Enterprise Project is the largest and most complex clinical analysis laboratory known to date and is expected to be capable of handling 110 million sample tubes per year upon completion. Siemens Healthineers, in collaboration with Inpeco, has designed and will deliver this fully automated multidisciplinary solution on an unprecedented scale, which will include at least 100 analysers—including more than 50 Atellica Solution clinical chemistry and immunoassay analysers from Siemens Healthineers, the largest IVD supplier in this project. The highly sophisticated solution will provide automation of clinical and operational workflow, from sample reception through testing to disposal. Sited in Vespasiano, Grande Belo Horizonte in Minas Gerais, the lab will occupy 3,500 square meters of floor space, will conduct operations 24 hours a day, and is expected to be fully operational during 2019.
“The automation track will be more than 330 meters long upon completion and will be used to automatically transport and distribute sample tubes to specific analysers that can run the specific type of test requested by clinicians,” said Guilherme Collares, Chef Operations Officer of the Hermes Pardini Group. “Unlike conventional laboratory set-ups, where sample tubes have to be moved manually between different analysers, our enterprise lab is designed to employ a ‘one-touch, one workflow’ concept to eliminate the need for manual interventions, ensure sample traceability, and reduce the turnaround time to results. The Enterprise Project also will rely on Atellica Process Manager, an IT solution that delivers a 3D view of the laboratory configuration, to enable operators to manage alerts, control instruments and reagent monitoring remotely, and see test progression in real time. Siemens Healthineers will implement the first Laboratory Control Room, which will centralize management and provide holistic visibility of operations in the central Vespasiano laboratory, and other Hermes Pardini satellite lab units in São Paulo, Rio de Janeiro, Goiania, and Belo Horizonte.
https://tinyurl.com/y9h4mtgm

Hip replacements relieve pain and restore mobility for hundreds of thousands of patients in the United States each year, but of the more than 400,000 hip replacements performed in the U.S. annually, about 10 percent will fail within 10 to 15 years. One main cause of this failure — which results in a need for a second hip replacement surgery (known as a revision surgery) — is the destruction of bone tissue around the replacement joint, a condition called osteolysis, which may cause the joint to loosen.
Now a research team at Rush University Medical Center has identified a pair of biomarkers that indicate which patients are likely to develop osteolysis.
The discovery could lead to tests that would enable surgeons to identify those patients in advance and adjust post-operative monitoring routines for them. It even might lead to treatments to prevent osteolysis in these patients.
“We are hopeful that early biomarkers for implant loosening will alert surgeons to be especially vigilant in their follow-up of at-risk patients and may eventually lead to treatments delaying or avoiding the need for revision surgery,” said the paper’s senior author D. Rick Sumner, PhD, chairperson of the Department of Cell & Molecular Medicine in Rush Medical College and the Mary Lou Bell McGrew Presidential Professor for Medical Research.
With the U.S. population aging, many individuals remaining very active late in life and others becoming heavier, hip replacements are projected to increase by 174 percent by 2030, with a projected 137 percent increase in the number of hip revision surgeries to fix or replace the failed implant over the same time period.
“We need to find effective strategies to handle this demand. These joints need to last, if possible, for the rest of a patient’s life,” said Joshua Jacobs, MD, a co-investigator on the study. Jacobs is Rush University’s vice provost for research and the William A. Hark, MD/Susanne G. Swift Professor and chairperson of the Rush Department of Orthopedic Surgery.
For their study, Sumner and his colleagues took what he calls “a candidate protein approach.” They drew on a previous review of medical literature they had conducted, which identified 40 possible biomarkers of future osteolysis development.
They divided the markers into four groups based on their likelihood to predict osteolysis and focused on the two groups that were most likely. The researchers winnowed the field of candidate proteins by eliminating markers found in blood rather than urine and those for which tests weren’t readily available.

Two combined biomarkers provided strongest indication of risk
Ultimately they tested for the presence of seven biomarkers and compared findings to the medical history of the patients – 16 of whom eventually had developed osteolysis. A biostatisican on the team then conducted an analysis to determine which combinations of the biomarkers correlated most with the osteolysis development.
“We looked at each marker independently, but none of them worked that well by themselves. Then he looked at panels of markers,” Sumner explained. “When we did that, we found we got a much better discrimination between patients that developed osteolysis and those that did not.”
The analysis found that a higher than normal levels of the connective tissue protein alpha CTX (a marker for bone resorption) and the immune response protein interleukin 6 (a marker of inflammation) were highly accurate in identifying patients at risk for osteolysis. The combination was detectable in patients up to six years before they were diagnosed with osteolysis.

Rush University
www.rush.edu/news/press-releases/early-indicators-bone-loss-after-hip-replacement-discovered

A USC research team identified 150 proteins affecting cell activity and brain development that contribute to mental disorders, including schizophrenia, bipolar condition and depression.
It’s the first time these molecules, which are associated with the disrupted-in-schizophrenia 1 (DISC1) protein linked to mental disorders, have been identified. The scientists developed new tools involving stem cells to determine chemical reactions the proteins use to influence cell functions and nerve growth in people.
“This moves science closer to opportunities for treatment for serious mental illness,” said Marcelo P. Coba, the study author and professor of psychiatry at the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC.
Schizophrenia affects less than 1 percent of the U.S. population, but has an outsized impact on disability, suicide and premature deaths.
The DISC1 gene was linked to schizophrenia nearly 20 years ago. It controls how nerve cells called neurons develop, as well as how the brain matures. DISC1 also directs a network of signals across cells that can contribute to the disease. Scientists say errors in these chemical reactions contribute to schizophrenia.
But the identity of proteins that DISC1 can regulate is poorly understood, prompting the USC researchers and colleagues from the State University of New York Downstate Medical Center to undertake the research. The challenge was to simulate conditions inside the human brain, Coba explained.
Using stem cells, they conducted assays resembling habitat where DISC1 does its work. They then used gene editing to insert a molecular tag on DISC1, allowing them to extract it from brain cells and identify the proteins with which it associates.
Identifying the proteins that interact with DISC1 in brain cells could lead to understanding how the risk factors for psychiatric diseases are connected to specific molecular functions, Coba explained. The discovery enables researchers to determine specific processes that differ in patients suffering from specific mental illnesses.
This gives researchers specific trails to follow within cells from both healthy patients and those diagnosed with disorders.
Schizophrenia is one of the top 15 leading causes of disability worldwide. People with schizophrenia live an average of nearly 29 years less than those without the disorder, according to the National Institutes of Mental Health (NIMH).
The illness is often accompanied by conditions such as heart disease and diabetes, which contribute to the high premature mortality rate among people with schizophrenia. About 5 percent of people with schizophrenia die by suicide, a rate far greater than the general population, with the highest risk in the early stages of illness, according to the NIMH.

University of Southern California
news.usc.edu/144238/usc-scientists-discover-schizophrenia-gene-roles-in-brain-development/