Radically different
A patient came to my office recently and told me she had stopped her statin. She’d been on it for two years. Her coronary artery calcium score was 280 and LDL was 168, up almost 100 points since she had stopped taking her statin. Her father had died from a heart attack at 58.
When I asked about the decision, she crossed her arms and furrowed her brow.
The U.S. Supreme Court ruling this week against Colorado’s ban on licensed mental health providers engaging in gender and sexuality “conversion therapy” could narrow the authority of state medical boards to regulate aspects of health providers’ care that involves speech, according to legal experts. The implications could extend far beyond matters related to LGBTQ+ rights to other forms of talk therapy, telehealth, and physician advice on Covid-19, vaccines, or reproductive care.
Because the therapist who challenged the law, Kaley Chiles, engages in talk therapy — without prescribing medications or having any physical contact with patients — the majority decided that the Colorado law constitutes a restriction on her speech due to her particular viewpoint, or opinion. In an 8-1 decision, the judges sent the case back to a lower court for a higher level of judicial scrutiny, which will likely result in the ban being overturned.
Nature Medicine, Published online: 02 April 2026; doi:10.1038/s41591-026-04379-6
Author Correction: Real-world clinical utility of tumor whole-genome sequencing in solid cancers
Pharmacoepidemiological studies have expanded the capacity to detect therapeutic benefits and adverse drug effects of medications. In the case of glucagon-like peptide-1 receptor agonists (GLP-1RAs), their fast uptake for treating diabetes and obesity has generated substantial real-world experience, facilitating exploration of benefits for additional indications. In the context of psychiatric disorders, studies based on pharmacovigilance data and large electronic health record (EHR) databases have shown that initial concerns regarding suicidality with GLP-1RA were not supported by the evidence.
A computer program that can predict which genes help bacteria to defend themselves against viruses could lead to the next generation of precision genetic engineering tools.
The artificial intelligence model recognizes genetic sequences involved in defenses that act against bacteriophages—viral invaders that infect bacteria.
These anti-viral immune systems have already been repurposed into powerful gene-editing technology, such as CRISPR-Cas, that enable DNA sequences to be precisely cut, modified, or deleted within an organism.
The DefensePredictor tool, outlined in Science, is available as an open-source tool to enable the discovery of more prokaryotic immune systems.
“Identifying new antiphage defense systems may yield the next generation of precision molecular tools while also shedding important light on the ongoing arms race between bacteria and phages,” said MIT-based molecular biologist Michael Laub, PhD, and co-workers.
Intense selective pressure to evade or survive infection has driven the evolution of numerous antiphage defense mechanisms, including restriction enzymes and the CRISPR-Cas systems.
While antiphage immunity genes often cluster into “defense islands” in prokaryotic genomes, this does not always occur and many systems are dispersed or carried on mobile elements such as plasmids, prophages, and transposons.
In an attempt to create a model to identify antiphage proteins, Laub and team first looked at around 17,000 genomes of prokaryotic organisms.
They labelled homologs of known defense and nondefense genes and built representations of the proteins coded by these genes as well as their four nearest neighbors on the genome.
DefensePredictor was trained through this to distinguish whether a gene was involved in defense systems.
After performing well in silico, it was tested on 69 diverse Escherichia coli genes and identified 624 different proteins that it confidently predicted were involved in defense, including 154 that shared no detectable homology to known defense proteins.
Nearly half of the defense proteins identified were not encoded in plasmids, prophages, or defense islands, showing that the model was able to identify systems in a wide range of genomic contexts.
Of 94 predicted genes tested in the lab, 42 provided protection against at least one of 24 phages tested, giving a validation rate of around 45%.
Fifteen protein domains across these 42 systems had not previously been validated as defensive, suggesting new immune systems remain undiscovered.
Expanding the predictive capacity of DefensePredictor beyond E. coli to 1000 diverse prokaryotic genomes revealed more than 5000 predicted defense proteins that were not clear homologs of those already known.
Another Science research article in the same issue of the journal also showed how AI could uncover unexplored diversity in bacterial immunity.
Ernest Mordret, PhD, from the Pasteur Institute, and co-workers demonstrated how deep-learning frameworks could lead to the large-scale discovery of antiphage and a vast atlas of bacterial antiviral immunity.
The team developed three complementary deep-learning models to predict antiphage proteins by leveraging genomic context (ALBERTDF), amino acid sequence (ESMDF), or both (GeneCLRDF).
Twelve newly predicted antiphage systems were then experimentally validated in Escherichia coli and Streptomyces albus.
When applied to more than 30,000 bacterial genomes, the models predict 2.39 million antiphage proteins, 85% of which had no previously known link to immunity, corresponding to approximately at least 23,000 predicted antiphage operon families.
All predictions have been made freely available through an interactive antiphage atlas.
“We developed deep learning models to predict antiphage systems,” the authors summarized.
“These methods extract cues about the “defensiveness” of a protein from two seemingly orthogonal sources: its genomic context across thousands of genomes, and its own amino acid sequence.
“By combining these complementary signals, we move from a fragmented, incomplete view of bacterial immunity toward a more resolved and quantitative understanding of its repertoire.”
The post Bacteria Defense Insights Could Revolutionize Genetic Editing appeared first on Inside Precision Medicine.
Researchers at Johns Hopkins University and the University of Maryland School of Pharmacy have developed a set of novel, first-in-class small molecule drugs that inhibit hypoxia-inducible factors 1 and 2 (HIF-1/2), a pair of transcription factors considered to be “master regulators” of cancer progression. Their study showed that these drugs can overcome resistance to immune checkpoint blockade therapy, and when combined with immunotherapy, can completely eliminate breast, colorectal, melanoma, and prostate tumors in mice, suggesting that they could eventually be used to treat a broad range of cancers in humans.
Research lead Gregg L. Semenza, MD, PhD, a professor at Johns Hopkins University School of Medicine, is co-senior author of the team’s published paper in Journal of Experimental Medicine, titled “Targeting conserved domains of hypoxia-inducible factors for cancer therapy.”
Hypoxia-inducible factors 1 and 2 are known as master regulators of cancer progression because they control the activity of hundreds of genes crucial for the survival, growth, and spread (metastasis) of cancer cells. HIF-1/2 levels rise in response to low oxygen levels (hypoxia), a condition commonly found in the center of rapidly growing tumors, the authors explained. “In response to hypoxia, cells in most metazoans activate a transcriptional pathway mediated by HIFs, which play a crucial role in adaptation to low O2 levels,” they wrote. “Many oncogene gain-of-function and tumor suppressor loss-of-function mutations increase HIF activity in an O2-independent manner.”
![Computer-aided drug design using the SILCS technology identified three sites on HIF-2 that are highly similar in HIF-1 and HIF-2 and are suitable for targeting with small molecule inhibitors. [© 2026 Salman et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20251009]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Salman_et_al_1-280x300.jpg)
Among other functions, HIF-1/2 promote the formation of new blood vessels to supply tumors with nutrients and enhance the ability of tumor cells to invade surrounding tissues. They also suppress the ability of immune cells to attack tumors, which limits the effectiveness of immunotherapies such as immune checkpoint inhibitors. “The limited therapeutic efficacy of ICB reflects multiple mechanisms by which cancer cells evade detection and killing by immune cells, and many of these are mediated by HIF-1/2 target gene products,” the scientists noted.
The presence of hypoxia, and elevated HIF-1/2 levels, is a key predictor of treatment failure and poor patient survival in a broad range of cancers. “The expression of HIF target genes and the expression of HIF-1α or HIF-2α protein in tumor biopsies are associated with patient mortality in many cancers, reflecting the role of HIFs in directing tumor vascularization, metabolic reprogramming, epithelial–mesenchymal transition, cell motility, extracellular matrix remodeling, cancer stem cell specification, immune evasion, invasion, metastasis, and treatment failure.”
Belzutifan, a specific inhibitor of HIF-2, has been approved for therapeutic use in several cancers, including advanced renal cell carcinoma. But, since HIF-1 and HIF-2 have distinct roles in promoting cancer progression, drugs that target both transcription factors simultaneously could be more effective. “Given the distinct roles of HIF-1 and HIF-2 in cancer progression, dual HIF-1/2 inhibition presents a promising therapeutic strategy, particularly for cancer types with a known propensity for intratumoral hypoxia and/or resistance to conventional therapy,” the team further noted.
“Dual HIF-1/2 inhibition presents a promising therapeutic strategy, particularly for cancer types with a known propensity for intratumoral hypoxia and/or resistance to conventional therapy,” Semenza added. For their newly reported study Semenza and colleagues worked with the group of Alexander D. MacKerell, PhD, at the Computer-Aided Drug Design Center at the University of Maryland School of Pharmacy, to identify drug molecules capable of binding to both HIF-1 and HIF-2. They used the computer-aided drug design technology site identification by ligand competitive saturation (SILCS) to predict small molecules that might bind based on the known crystal structure of HIF-2.
“The SILCS approach enabled the selection of compounds with a high probability of binding to HIF-2, allowing experimental efforts to focus on testing hundreds, rather than millions, of chemical compounds, thereby accelerating the drug discovery process,” MacKerell said.
Semenza’s team, including first author Shaima Salman, PhD, tested these candidate molecules and identified several compounds that bound to both HIF-1 and HIF-2, triggering their degradation and preventing them from activating their target genes. “Here, we describe small-molecule dual HIF-1/2 inhibitors (HIFi) that bind directly to the most highly conserved domains of HIF-1/2α, block dimerization with HIF-1β, and cause HIF-1/2α degradation,” they stated. “These compounds showed broad and potent HIF inhibitor activity in a variety of cancer cell lines,” Salman said.
![Treatment with a dual HIF-1/2 inhibitor (bottom) greatly reduces the size of blood vessels in a tumor compared to tumor tissue from a vehicle-treated mouse (top). [© 2026 Salman et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20251009]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Salman_et_al_2-215x300.jpg)
Individually, the drugs were able to inhibit the growth of breast, colorectal, head and neck, melanoma, and prostate tumors in mice, reducing tumor vascularization and limiting tumor invasiveness. The drugs were even more effective in combination with the immune checkpoint inhibitors anti-CTLA-4 or anti-PD1. Combination therapy caused complete remission in over 50% of mice with either breast, colorectal, melanoma, or prostate tumors, many of which were resistant to treatment with immune checkpoint inhibitors alone. These animals remained tumor free, even when rechallenged with an injection of fresh tumor cells. “… dual HIF-1/2 inhibition has major effects on multiple critical aspects of cancer progression,” the team wrote in their discussion. “The powerful effects of HIFi on angiogenesis, immune evasion, and tissue invasion reflect the inhibition of hundreds of HIF-1/2 target genes in both cancer and stromal cells within the tumor.”
Semenza and colleagues found that dual HIF-1/2 inhibitors alter the type of immune cells found within tumors, decreasing immunosuppressive cell types while increasing the frequency of T cells and NK cells that are capable of killing tumor cells (especially when treated with immune checkpoint inhibitors).
“We saw an increased response to immune checkpoint inhibitors with HIF inhibitor treatment across a broad sampling of cancer types, suggesting that this combination will have widespread clinical utility,” Semenza commented.
Adding to the drugs’ therapeutic potential, the researchers note that their dual HIF-1/2 inhibitors can be administered orally and showed no safety concerns in mice, even when given for extended periods in amounts well above the effective dose. “The drugs are orally bioavailable, and no safety concerns were identified even after extended or supratherapeutic dosing,” they noted.
The post Combining Novel Dual HIF Inhibitors with Immunotherapy Erases Multiple Tumor Types in Mice appeared first on GEN – Genetic Engineering and Biotechnology News.
How has the Food and Drug Administration’s recent decisions on rare disease drugs affected investment trends? Why is Eli Lilly getting into sleep medicine? And where did Allison go on her vacation?
We discuss all that and more on this week’s episode of “The Readout LOUD,” STAT’s weekly biotech podcast. Biotech investor Rod Wong joins us to talk about why an industry-patient coalition he’s part of sent a letter to President Trump asking for more regulatory flexibility at the FDA.