Tag: Medication

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PD-L1 Inhibitors for Cancer Treatment Could Be Repurposed to Treat Bone Loss in Obesity

Bone loss related to obesity is partly caused by changes inside the bone marrow fat compartment that reshape immune signaling and increase osteoclast formation, according to researchers at the MaineHealth Institute for Research. In a study published in Bone Research, the team found that expansion of bone marrow adipose tissue in obese people changes the marrow environment toward immunosuppression through PD-L1 signaling, which in turn promotes bone-resorbing osteoclast activity that reduces bone volume.

“We discovered that bone marrow fat is not simply a passive tissue but actively reshapes immune signaling in ways that accelerate bone loss in obesity,” said senior author Clifford J. Rosen, MD, senior scientist at the MaineHealth Institute for Research.

The team noted that obesity influences bone health not just due to a higher body weight but also by altering the bone marrow environment. The increase in bone marrow fat promotes immunosuppressive PD-L1 signaling, which enhances osteoclast formation and accelerates bone loss.

The study identified a pathway in which bone marrow adipocytes increase expression of MCP-1, a signaling molecule that recruits myeloid immune cells. These recruited cells shift toward a PD-L1–expressing phenotype, with PD-L1 interacting with PD-1 receptors, which are found not only on T cells but also on osteoclast precursors. In immune biology, PD-1/PD-L1 signaling is typically known for suppressing T-cell activation and promoting immune braking. This new study shows that this same form of suppressive signaling also directly enhances osteoclast differentiation.

According to the study results, as PD-L1+ myeloid cells accumulate, they suppress T-cell activity in bone marrow, creating an immunosuppressive environment. At the same time, PD-L1 engagement with PD-1 on osteoclast precursors promotes their maturation into active osteoclasts, which break down bone tissue, increase resorption and reduce bone density.

To learn more about this mechanism, the investigators used diet-induced obese mouse models, co-culture systems, and genetic depletion approaches. An important model in this work were mice lacking bone marrow adipocytes, which allowed the researchers to isolate the role of marrow fat. The team also blocked PD-1/PD-L1 signaling during early osteoclast formation in vitro. In both cases, osteoclast differentiation decreased and bone structure improved. The mice lacking bone marrow adipocytes showed fewer PD-L1+ myeloid cells, fewer PD-1+ osteoclast precursors, and higher trabecular bone volume even under high-fat diet conditions.

Earlier research has shown a link between obesity and bone loss, but studies reported trabecular bone loss without cortical effects, while others found no significant bone changes under diet-induced obesity. The MaineHealth team noted that these earlier studies often focused on shifts in osteoblast activity as opposed to their approach which identified a pro-osteoclastic mechanism driven by immune signaling.

In addition, the Maine Health finding also added to evidence that has established that obesity is associated with impaired immune responses, including reduced vaccine effectiveness and altered macrophage activity. In this study, the marrow environment in obese mice resembled features seen in tumor-associated immune suppression, where PD-L1 expression is elevated and immune activity is dampened. The researchers wrote that “the increase in PD-L1 expression seen in OB-HFD mice is related to the increase in Mcp-1 in part because previous cancer research has suggested the recruitment of myeloid cells via Mcp-1 creates an immunosuppressive tumor microenvironment.”

The findings suggest potential strategies for preserving bone bones in obese people by targeting bone marrow adiposity or the PD-1/PD-L1 pathway. Because PD-1/PD-L1 inhibitors are already used in oncology, there is a compelling case for repurposing or adapting immune checkpoint modulation therapies already approved for cancer treatment for bone disorders linked to metabolic disease. The authors also noted another strategy could be to reduce the amount of bone marrow fat itself to restore immune balance and limit osteoclast-driven bone loss.

The post PD-L1 Inhibitors for Cancer Treatment Could Be Repurposed to Treat Bone Loss in Obesity appeared first on Inside Precision Medicine.

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Removing Harmful Protein from Blood Helps Women with Preeclampsia

An early stage clinical study shows removing a protein known as soluble Fms-like tyrosine kinase 1 (sFlt-1) from the blood of pregnant women with early stage, severe preeclampsia seems to help both mothers and babies with no significant side effects.

The treatment, which involved filtering the patient’s blood through a machine to remove the harmful protein, reduced blood pressure and allowing pregnancies to continue for around 10 extra days.

Up to 5% of pregnancies in the U.S. are affected by preeclampsia, a condition where a woman develops high blood pressure during pregnancy, and organs like the kidneys, liver, or brain can also be affected. It can be life threatening in some cases and there are currently no available treatments, so the only real option is to deliver the baby, which can cause problems for the baby if delivered preterm.

The single exact cause of preeclampsia is unknown, but most evidence points to problems with how the placenta and its blood vessels develop early in pregnancy, which then triggers widespread damage in the mother’s blood vessels. Women with preeclampsia seem to have high levels of sFlt-1 in their blood and research suggests it binds and neutralizes VEGF and PlGF, key proteins that normally help keep blood vessels healthy and relaxed.

In this study, published in Nature Medicine, the researchers tested whether filtering the blood of women with early onset preeclampsia (at 24-32 weeks gestation) to remove the excess sFlt-1 protein could help improve their symptoms and prolong pregnancy.

This was an early stage study to check safety and tolerability and included 16 women in total. Seven women were in an initial group to test the safety of the filtering process and to assess how much protein could be removed. This showed the treatment was safe and well tolerated with no major side effects observed.

The second group of nine women had several treatments and the researchers looked at how effective the treatment was in this group. In the second group, the women’s symptoms improved; blood pressure went down by 4.1 mmHg on average and pregnancy was extended by 3-19 days (median 10 days).

“Even a few extra days in the womb can make a meaningful difference in outcomes for premature infants,” said co-lead study author Ananth Karumanchi, MD, professor of medicine and director of the Renovascular Research Center at Cedars-Sinai, in a press statement. “We found a way to potentially buy that time safely. Our approach could shift how we manage very early preeclampsia.”

The researchers acknowledge the treatment needs to be tested further but are hopeful it could be a good treatment option for women with this condition in the future, particularly as it does not involve introducing a drug or therapy into the body and therefore reduces the risk of side effects for both mother and baby.

The post Removing Harmful Protein from Blood Helps Women with Preeclampsia appeared first on Inside Precision Medicine.

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Mailed FIT-DNA Test Improves Colorectal Cancer Screening Rates in U.S.

A screening test mailed to participants that looks for blood and DNA markers of cancer in human stool, Fecal immunochemical test (FIT)-DNA, was more popular than a test looking for blood alone, show results from a study carried out in Boston and Los Angeles.

The community-based study, published in JAMA Internal Medicine, showed that uptake of the FIT-DNA test at 90 days was 28% versus 23% in the FIT test group that looks at blood alone.

“Stool-based screening tests are common in community health centers where access to colonoscopy is limited…. Although FIT is typically provided during a visit, there is increasing evidence for mailed outreach to increase uptake,” explain lead author Jennifer Haas, MD, of the Division of Internal Medicine in the Mass General Brigham Department of Medicine.

“FIT-DNA is a newer stool-based screening test, with increasing popularity in community health centers, commonly performed every three years and mailed directly to patients by the manufacturer.”

This study aimed to assess the uptake of mailed FIT and FIT-DNA tests in 5127 participants from the greater Boston area in Massachusetts and Los Angeles County in California. English or Spanish speaking participants aged 45–75 years were eligible.

Some participants were sent FIT‑DNA kits along with the manufacturer’s standard outreach program, while others received FIT kits by mail plus automated text reminders from the study team. Those with abnormal results on either test were directed to have a colonoscopy.

The uptake of the FIT-DNA and FIT tests at 90 and 180 days was 28% and 32%, respectively in the FIT-DNA group and a respective 23% and 27% in the FIT group. Overall, screening was higher in the Boston-based participants than the Los Angeles participants.

The researchers believe the FIT-DNA test may have been more popular due to good outreach support of that test and the fact that it is only needed once every three years.

Notably, only 36% of people referred for colonoscopy from both the FIT and FIT-DNA groups actually attended an appointment, which the researchers say is “suboptimal.”

“Effective screening is essential because it allows us to catch and treat cancer early,” Haas said in a press statement. “There are evidence-backed, preventive interventions for colorectal cancer, but they need to be implemented systematically in a way that addresses barriers for both the community health centers and the patients they are serving. The best screening test will always be the one that people are able to complete.”

The post Mailed FIT-DNA Test Improves Colorectal Cancer Screening Rates in U.S. appeared first on Inside Precision Medicine.

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Genetic Medicine Delivery Enhanced by Producer Cell Modifications

Gene editing has emerged as a powerful approach for targeting the genetic causes of disease, yet delivering the editing machinery into the correct cells efficiently, safely, and at the scale needed for therapies remains one of the biggest bottlenecks.  

Among the leading delivery vehicles are engineered virus-like particles (eVLPs), which can enter human cells similar to viruses but carry no viral genes. Instead, these delivery vehicles carry gene editing tools for therapeutic applications.  

In a new study published in Nature Communications titled, “Genome-wide screening reveals producer-cell modifications that improve virus-like particle production and delivery potency,” researchers from Whitehead Institute have developed a platform that systemically identifies which genes drive or block particle assembly to engineer cells that yield more potent delivery vehicles. 

“We can engineer the particles as much as we want, but if we don’t understand how the producer cells are actually making the particles, we’re limited in how much we can improve production,” said Aditya Raguram, PhD,  Valhalla Fellow at Whitehead Institute and corresponding author of the study.

As virus-like particles are assembled inside cultured human cells, the authors ran a genome-wide search to identify which genes are crucial in the production process by generating a large pool of producer cells in which nearly every gene in the human genome was switched off in the population. This approach generates eVLPs loaded with guide RNAs that identify the genetic perturbation in the cell that produced a particular particle. The team could then identify which gene shutdowns enabled and disabled particle production. 

“One thing that surprised me was how clearly the search was able to highlight specific pathways that play a major role in the production of these particles,” said Diana Ly, research technician at Whitehead Institute and first author of the study. 

The single gene whose removal most boosted production normally reduces the cell’s output of guide RNAs. Disabling this gene enabled cells to generate more guide RNA and particles to carry more functional cargo. 

The improvement also extended across different gene editing tools and particle designs. The team tested the modified producer cells with diverse gene editors and four other delivery-vehicle systems from external labs, and produced improved particles. 

“Because guide RNA loading is basically universal across different cargo types and particle types, this improvement could be quite broadly useful beyond the particles we’ve developed,” Raguram says. 

Looking ahead, the authors are extending the screening platform to expand beyond switching off one gene at a time to examine how other cellular changes influence particle production. The team is sharing its engineered cell lines with the research community to improve the delivery of gene editing tools into immune cells, neurons, and other cell types important for treating disease. 

For Raguram, the work speaks to a broader task facing the gene editing field. 

“This delivery challenge is one of the last remaining bottlenecks that really limits the widespread application of gene editing technologies,” he says. “Solving the challenges associated with production could move virus-like particles closer to being ready for use in patients.” 

The post Genetic Medicine Delivery Enhanced by Producer Cell Modifications appeared first on GEN – Genetic Engineering and Biotechnology News.

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Case Report: Early onset pulmonary embolism following antipsychotic polypharmacy in an acute psychiatric setting

Pulmonary embolism (PE) is a potentially life-threatening condition that may occur in patients receiving antipsychotic medication. Several studies have shown an increased risk of venous thromboembolism (VTE) associated with the use of antipsychotics, particularly during the first weeks or months of treatment. However, very early onset of VTE within hours of treatment initiation has been rarely reported. We present the case of a 69-year-old woman who developed acute pulmonary embolism within a few hours after initiation of psychopharmacological treatment for a psychotic episode. Due to acute agitation, the patient received olanzapine, quetiapine, levomepromazine, and lorazepam. The patient had no known predisposing risk factors for VTE. Shortly after begin of psychopharmacological treatment she presented with deterioration of her general condition, soporous, hypotensive, tachycardic and with reduced oxygen saturation. PE was suspected clinically and confirmed by computed tomography pulmonary angiography. After diagnosis, PE was successfully treated with anticoagulation. This case is notable for the unusually rapid development of VTE, occurring within hours rather than the typically reported days to weeks. It underscores the need for heightened clinical vigilance even in the very early phase of antipsychotic therapy and in patients without risk factors for VTE.
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STAT+: Doctor, wife of acting U.S. attorney general, appointed to NIH advisory council

Kristine Blanche, an integrative medicine doctor and wife of acting Attorney General Todd Blanche, has been named as a member to one of the advisory councils that provides critical funding recommendations to the National Institutes of Health. Her appointment, to serve on the advisory council to the National Center for Complementary and Integrative Health, is the first of such appointments to be made in over a year.

It’s unclear if Blanche’s selection — which has not been publicized by the NIH — is a sign of a thawing in the pipeline of advisory council appointments. But it’s done little to quiet simmering concerns among the wider research community about whether the Trump administration would attempt to stack councils with ideological allies who will use their positions to advance its political goals.  

It’s “the worst kind of political patronage,” Joshua Gordon, a former director of the National Institute of Mental Health, told STAT. He and others worry the move will erode taxpayers’ trust in how the largest funder of biomedical research in the world spends its $48 billion budget. “It’s clearly meant to contribute to an intentional degradation of confidence in the NIH.”

Continue to STAT+ to read the full story…