Estrogen receptor α (ER) is one of the most successfully prosecuted therapeutic targets in oncology. Selective ER degraders (SERDs) are being pursued as next-generation therapies. Giredestrant is a potent orally bioavailable SERD and full ER antagonist, which has demonstrated clinical superiority over standard-of-care therapy. Here, we describe its key pharmacological attributes, and account for its benefit across the ER+ breast cancer spectrum. The antiproliferative potential of giredestrant is dictated by ER activity; it outperforms approved agents in ER activity-high contexts. ER immobilization likely underlies giredestrant’s profound inhibitory potential. ER immobilization is not observed for heterobifunctional chimera degraders, which fail to match the antiproliferative potential of giredestrant despite superior ER degradation. Giredestrant redistributes enhancers, decreasing the expression of estrogen-induced genes and inducing the expression of putative tumor suppressors. These molecular data, together with results from recent trials, rationalize giredestrant’s potential to serve as an optimized endocrine backbone for ER+ breast cancer.

Shows that palbociclib sensitive cell lines have low CDK2 activity post-mitosis, while palbociclib resistant cell lines have predominately high CDK2 activity

Equine alphaherpesvirus-1 (EHV-1) is a highly contagious virus that can cause the neurological form, equine herpesvirus myeloencephalopathy (EHM). Understanding transmission-related risk factors is crucial for improving prevention strategies and guiding effective control measures. In this study, we collected data from 63 horses that had previously participated in the February 2022 winter horse show season at the Desert International Horse Park (DIHP) (26 cases and 37 controls) to identify host and management factors associated with EHV-1 infection and/or EHM development during the February 2022 outbreak at the DIHP in Thermal, California. Risk factors were evaluated using multivariable logistic regression and a random forest model with conditional permutation importance. Greater age was associated with higher odds of becoming a case (OR = 1.33; 95%CI: 1.04-1.69, p-value: 0.01). Compared with hunters, jumpers had greater odds of developing EHV-1 and/or EHM (OR = 7.37; 95%CI: 1.57-34.61, p-value: 0.01). Sharing a barn was also strongly associated with EHV-1 and/or EHM case status (OR = 7.37; 95%CI: 1.79-30.29, p-value: <0.01). The machine-learning-based rankings were concordant with the regression estimates. Age, main activity, and sharing a barn were the most influential risk factors associated with elevated odds of developing EHV-1 and/or EHM. These results highlight specific demographic and management-related risk factors that could inform targeted prevention strategies.

PI3 kinase / mTOR (vistusertib; AZD2014) combinations with palbociclib in TNBC

Abstract Addison’s disease (AD) results in glucocorticoid and mineralocorticoid deficiencies and is often immune-mediated. While AD is uncommon in dogs, Nova Scotia Duck Tolling Retrievers (NSDTRs) exhibit increased incidence, suggesting genetic predisposition. Detailed clinical evaluation of 24 juvenile-onset cases revealed that while all dogs presented with adrenal insufficiency, at least 10 dogs (41.7%) had concurrent autoimmune conditions. This suggests juvenile-onset AD in NSDTRs represents part of a broader multiple autoimmune syndrome (MAS) with variable expressivity. Strikingly, NSDTRs affected by juvenile-onset AD had severely decreased lifespans, with a median survival of 2 years despite appropriate treatment. Genome-wide association identified a significant association on chromosome 27 (chr27:29,724,286, p = 6.96 × 10− 13). Whole-genome, short-read sequencing identified a recessive missense variant in RESF1 (Chr27:29,736,795). The variant exhibited 76% penetrance for early-onset disease, and the decreased penetrance was not attributable to differences in Dog Leukocyte Antigen (DLA) haplotypes. Immunohistochemistry confirmed T cell infiltration in the adrenal cortex of two unrelated affected dogs, with necropsy findings including severe bilateral lymphocytic adrenalitis, multisystemic granulomatous inflammation, and lymphoplasmacytic conjunctivitis supporting autoimmune pathogenesis. This study identifies RESF1 as a novel gene associated with autoimmune disease in NSDTRs, ranging from isolated juvenile-onset AD to multi-organ autoimmune manifestations. The findings represent a rare example of monogenic autoimmune disease and establish RESF1 as a candidate gene for further investigation of immune tolerance mechanisms.

CDK2high and CDK2low cell subpopulation arise from single cell

Cell cycle lengths (hours) according to CDK2 status (CDK2high vs. CDK2low)

For each cell lines used in this study, we show a list of mutations that have been found specifically in known cancer genes.

Description of supplementary figures

Horses obtain vitamin E, an essential nutrient for neuromuscular health, through green pasture. Vitamin E dietary deficiencies can lead to neuromuscular diseases such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy, equine motor neuron disease and vitamin E deficient myopathy. Some horses are genetically susceptible to developing these neuromuscular diseases, but not all horses that are vitamin E deficient exhibit clinical signs. Vitamin E supplementation is effective at slowing or halting clinical signs of some of these diseases, but the neuromuscular damage is usually irreversible, except in the case of vitamin E deficient myopathy. Adequate access to vitamin E early in life is essential to preventing these conditions.

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disease associated with vitamin E deficiency in the first year of life. It is the second most common cause of spinal ataxia in horses euthanized for neurologic disease. Equine NAD/EDM is characterized by sudden onset of neurologic signs including symmetric ataxia (> grade 2/5), wide-base stance at rest, and proprioceptive defects. There are currently no antemortem tests for eNAD/EDM in any breed. Conclusive diagnosis requires postmortem histologic evaluation of the brainstem and spinal cord at necropsy. Research studies on antemortem biomarker and genetic testing are ongoing. The development of a genetic test for eNAD/EDM would have widespread impact, even if it were breed specific. Currently, the best approach to eNAD/EDM is to focus on preventing cases by providing pregnant mares and foals with access to pasture. Alternatively, dams’ diets can be supplemented with high doses of water-soluble RRR-α-tocopherol during the last trimester of gestation, with continued supplementation of foals through the first two years of life. It is important to measure horses’ baseline serum vitamin E levels prior to supplementing. While considered generally safe, oversupplementation of vitamin E is possible and can lead to coagulopathies.

PDF file - 254K, siRNA-mediated depletion of wild-type and oncogenic Ras in additional cell lines

qPCR primer sequences for Apopanel of BCL2 family members

Correlation of mRNA expression of BCL2 family members and sensitivity to venetoclax or navitoclax in HMCLs

PDF file - 54K, Combining oncogenic Ras depletion with EGFR inhibition in the MIA PaCa-2 and RD cell lines

PDF file - 237K, Pharmacological MEK inhibition sensitizes RAS mutant cancer cells to acute EGFR activation

Immunoblots of BCL-2, BCL-XL and MCL-1 in HMCL tumor xenografts

BCL2, BCL2L1 and MCL1 mRNA in CD138 primary MM patient samples and sensitivity to veneteclax ex vivo

PDF file - 135K, Depletion of oncogenic Ras sensitizes cells to the acute activation of various receptor tyrosine kinases in a cell line-dependent manner