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/
 

As the result of a six-year long research process, Fredrick R. Schumacher, PhD, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.
The changes, known as genetic markers or SNPs ("snips"), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G), and cytosine (C). The order of these bases determines DNA’s instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are three billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.
One in seven men will be diagnosed with prostate cancer during their lifetimes.
“Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions,” said Schumacher. PSA is a blood test used to screen for prostate cancer. It measures the amount of prostate-specific antigen (PSA) in the blood. PSA is a protein produced by both cancerous and noncancerous tissue in the prostate.
Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.
In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn’t have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.
The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. “We probably only need to know ten percent to twenty percent of these to provide relevant screening guidelines,” continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine.
Currently, researchers don’t know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for “watchful waiting” and monitoring.
The research lays a foundation for determining who and how often men should undergo PSA tests. “In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening,” said Schumacher. “We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every 2-5 years.” A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. “Someday it may be feasible to target treatments based on a patient’s prostate cancer genetic risk score,” said Schumacher.

Cape Western Reserve University School of Medicine
casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=1297&news_category=8

Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signalling in the brain. These two pathways have been separately implicated in bipolar disorder, but the link between levels of the neurotransmitter serotonin and mitochondrial dysfunction had not been established. Researchers at the RIKEN Center for Brain Science (CBS) in Japan now report that mitochondrial dysfunction affects the activity of serotonergic neurons in mice with mutations of ANT1.
Mitochondria are the vital organelles that deliver energy to all cells and mitochondrial damage has been found, for example, in brain imaging of bipolar patients and in post-mortem brains. Roughly 20% of patients with mitochondrial disease also have bipolar disorder, a major psychiatric disease characterized by manic and depressive episodes. Altered serotonin functioning, on the other hand, seems to be involved in bipolar disorder because drugs that target serotonin levels can effectively treat the condition. "Our study suggests that mitochondrial dysfunction can alter activity of serotonergic neurons in bipolar disorder, and this is the first time these two lines of evidence have been linked," says Tadafumi Kato, research group leader at CBS.
The study started by identifying ANT1 mutations in patients with bipolar disorder. Kato and colleagues then looked at mice lacking the ANT1 gene in the brain only. Compared with non-mutant mice, the mitochondria in these knockout mice could not retain calcium and had leakier pores. The ANT1-mutant mice also showed lower impulsivity in behaviour tests, and consistent with this, their brains showed elevated serotonin turnover. This hyper-serotonergic state is likely a result of a cascade of changes that starts with the loss of the ANT1 gene and the resulting dysfunctional mitochondria. Enhanced serotonergic activity may then further impair mitochondria in a vicious cycle.
Serotonergic neurons were found to deteriorate in a brain area called the dorsal raphe, which is a region also affected in Parkinson’s disease–another condition that may have its roots in mitochondrial dysfunction. The ANT1 mutation does not cause bipolar disorder, says Kato, but is associated with elevated risk. The implication of this research is that emerging therapies for the underlying mitochondrial dysfunction could one day treat bipolar disorder more successfully than today’s variable serotonin-targeting drugs.

EurekAlert
www.eurekalert.org/pub_releases/2018-06/r-mlb060818.php

A new study from BUSM and BUSPH identifies a pattern of inflammation associated with cardio-metabolic risks among participants in the Black Women’s Health Study, as well as two independent groups of vulnerable women. These findings could help underserved patients benefit from precision medicine and personalized profiles of disease risk.
According to the researchers, body mass index alone is an imperfect measure of obesity-associated disease risks, such as for Type 2 diabetes, because there are some individuals with chronic obesity who are apparently protected from cardio-metabolic complications and lean individuals with high cardiovascular and diabetes risks. Abnormal, unresolved inflammation in blood and adipose (fat) tissue, rather than obesity per se, is thought to be important for development of disease. Certain biomarkers show promise in predicting obesity-associated diabetes risk; however, the clinical utility of single biomarkers is limited for complex disease phenotypes such as these.
The research team took a data-driven, systems biology approach to discover six cytokine signatures associated with Type 2 diabetes risk in a vulnerable population: African American women with obesity and varying degrees of metabolic health. These six distinct signatures are patterns of sixteen cytokines/chemokines that promote or reduce inflammation.
Analyses of plasma samples from participants in the Black Women’s Health Study, formed the basis for the discovery dataset, which was then validated in two separate groups, African American women volunteers with obesity who had donated plasma to the Komen Tissue Bank, and African American women with obesity who were breast reduction surgical patients at a safety net hospital in Greater Boston. The patterns or signatures in the validation cohorts closely resembled the distributions in the discovery cohort.
“These findings are highly relevant to an understudied and underserved population that experiences elevated risks for co-morbidities of obesity. The overall impact of this report is high because of the potential utility of the new signatures just discovered and validated, which could assist clinical decision making with more personalized information,” explained corresponding author Gerald V. Denis, PhD, Associate Professor of Pharmacology and Medicine at BUSM.

Boston University School of Medicine
www.bumc.bu.edu/busm/2018/05/08/new-study-provides-insight-into-blood-signatures-of-inflammation/