The rockefeller university

Tumor cell intravasation is essential for metastatic dissemination, but its exact mechanism is incompletely understood. We have previously shown that in breast cancer, the direct and stable association of a tumor cell expressing Mena, a Tie2hi/VEGFhi macrophage, and a vascular endothelial cell, creates an intravasation portal, called a "tumor microenvironment of metastasis" (TMEM) doorway, for tumor cell intravasation, leading to dissemination to distant sites. The density of TMEM doorways, also called TMEM doorway score, is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that tumor cells utilize TMEM doorway-associated transient vascular openings to intravasate, the precise signaling mechanisms involved in TMEM doorway function are only partially understood. Using two mouse models of breast cancer and an in vitro assay of intravasation, we report that CSF-1 secreted by the TMEM doorway tumor cell stimulates local secretion of VEGF-A from the Tie2hi TMEM doorway macrophage, leading to the dissociation of endothelial junctions between TMEM doorway-associated endothelial cells, supporting tumor cell intravasation. Acute blockade of CSF-1/CSF-1R signaling decreases macrophage VEGF-A secretion as well as TMEM doorway-associated vascular opening, tumor cell trans-endothelial migration, and dissemination. These new insights into signaling events regulating TMEM doorway function should be explored further as treatment strategies for metastatic disease.

ImportanceHealth care workers (HCW) faced chronic stress during the COVID-19 pandemic and were at high risk of illness, death and burnout.ObjectiveTo understand the experiences of and assess the acceptability and usability of the "Stress First Aid" (SFA) intervention for HCWs.DesignWe used a mixed methods approach to conduct: (1) a quantitative post-intervention survey of experiences with the SFA intervention within a cluster randomized controlled trial (cRCT); and (2) a qualitative descriptive analysis. The intervention was rolled out over three waves from March 2021 - October 2022 simultaneously with the sites' COVID-19 response.SettingOur team engaged and recruited eight pairs of hospitals and six pairs of Federally Qualified Health Centers (FQHCs), balanced across region, including nine states, and matched on size, type, and COVID-19 burden.ParticipantsA total of 862 HCWs received the SFA intervention and completed both the pre- and post-intervention surveys (FQHC n = 245 and hospital n = 617). For the qualitative analysis, among HCWs who agreed to be contacted for a post-intervention interview, we purposively sampled a subset of 35 HCWs balanced by site, gender, age, race/ethnicity and HCW type.InterventionSFA is an evidence-informed intervention adapted to mitigate the psychosocial impact of COVID-19 on HCWs through individual peer support actions.Main Outcome(s) and Measure(s)Quantitative measures are binary indicators of agreement with 6 questions about experiences with the SFA intervention. For the qualitative analysis, we utilized a semi-structured interview protocol to provide additional context on experience with SFA and how SFA affects HCW well-being.ResultsBetween 48.2 and 59.4% of HCWs agreed or strongly agreed that they: found SFA helpful (48.2%), felt comfortable supporting colleagues (59.4%), would recommend SFA (51.2%), and would continue to use SFA principles (57.2%). Non-White HCWs (particularly Black HCWs), those in assistant/technician positions and those who reported attending a greater number of booster sessions were more likely to agree with positive statements about SFA experiences.Conclusions and RelevanceGiven the continued resurgence of public health emergencies, its lasting effects on HCWs, and related emerging challenges, we expect there to be a continued need for support of patient-facing HCWs.Clinical trial registrationClinical Trials.gov Number: NCT04723576 Registered on 01/22/2021 Clinicaltrials.govNCT04723576.

The 2025 Lasker similar to DeBakey Clinical Medical Research Award has been given to Michael Welsh, Jesus (Tito) Gonzalez, and Paul Negulescu for their key roles in developing a novel treatment for cystic fibrosis (CF)-a three-drug combination that saves the lives of people with this lethal genetic disease [D. Keating etal., N. Engl. J. Med. 379, 1612-1620 (2018)]. The disease is caused by mutations that disrupt the function of a gene known as CF Transmembrane Conductance Regulator which encodes a chloride channel expressed in epithelial cells including the lung. Collectively the three recipients were responsible for the development of novel high-throughput drug screens that led to the development of the new drugs. Welsh is a pulmonologist who played a key role in understanding the physiology and pathophysiology of the disease. Gonzalez is a physical organic chemist who developed a novel technology that enabled robust high-throughput screens for drugs that correct the channel defects. Negulescu led a group of extremely talented biologists, chemists, and physicians who built on these advances to develop novel three-drug combinations that have miraculous benefits for the majority of afflicted patients. This advance represents a true milestone in medicine and fulfills a dream of research scientists and families-the conversion of a fatal disease into a fully treatable one. It is also a stunning example of the power of medical research to save people's lives.

We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.

In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC50) below 10 mu M. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.

Scientists can contribute to society in numerous ways. Some scientists discover new biological principles and found entirely new fields. Some scientists are inspiring mentors and create the next generation of inclusive lab leaders. Some scientists are entrepreneurs who develop clinically effective therapeutics. Some scientists are trusted advisors to government and pharmaceutical companies. Some scientists are visionary institutional leaders who build new departments. From this menu of activities, most scientists select two or at most three. It is exceedingly rare for a single scientist to excel in all of these areas, consistently, over the course of a career. Lucy Shapiro is this extraordinary scientist. She founded the field of bacterial cell biology and trained the next generation of microbiologists, launched biotech companies to develop new antifungal drugs, served as an unofficial advisor to two presidential administrations and numerous companies, institutions, and foundations, and built and led successful academic departments. The 2025 Lasker similar to Koshland Special AchievementAward in Medical Science is awarded to Lucy Shapiro "for a 55-y career in biomedical science-honored for discovering how bacteria coordinate their genetic logic in time and space to generate distinct daughter cells; for founding Stanford's distinguished Department of Developmental Biology; and for exemplary leadership at the national level."

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Delta ex3-4;Trp53-/- animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2-deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.

BackgroundWe sought to determine the comparative effectiveness of two strategies for assigning care coordinators to people living with dementia (PLWD) and their caregivers.MethodsWe conducted a pragmatic randomized clinical trial embedded in a Medicare accountable care organization (ACO) in New York, NY in 2022-2024. We included community-dwelling PLWD >= 65 years who were attributed to the ACO and had highly fragmented ambulatory care in the previous year (reversed Bice-Boxerman Index >= 0.86). The trial compared usual care (assigning care coordinators to PLWD after hospital discharge) to usual care plus proactive outreach, which assigned care coordinators to PLWD if they or their caregivers reported difficulty with care coordination on a telephone survey. Participants were followed for the combined outcome of emergency department (ED) visit or hospitalization.ResultsAmong the 385 PLWD in the trial, the mean age was 82.6 years (SD 6.9), and 56.4% were female. Overall, participants had had a mean of 14.9 ambulatory visits to 8.9 different providers the previous year. The acceptance rate of care management was higher in the control group (73.7%) than in the intervention group (38.0%). Care coordinators were ultimately assigned to 14 of 192 PLWD in the control group (7.3%) and 19 of 193 PLWD in the intervention group (9.8%). The intention-to-treat analysis (N = 385) found a trend toward fewer ED visits in the intervention group (0.14 ED visits per 100 person-days alive vs. 0.18 ED visits per 100 person-days alive, p = 0.07) but no difference in the combined outcome of ED visit or hospitalization (p = 0.71).ConclusionAlthough the particular intervention we tested was not more effective than usual care, this trial is novel in that it used highly fragmented care as an inclusion criterion and shows that more work is needed to address fragmented care among PLWD.

Background/Objectives: While single variants may have only small effects on common heritable traits like schizophrenia, methods for combining such effects over multiple variants have been proposed for more than 30 years. The currently favored approaches are polygenic risk scores. Their main aim is the genetic prediction of phenotypes. Methods: To accommodate the inherent genetic heterogeneity between males and females, we separated them into two independent datasets and in each developed allelic polygenic risk scores. We focused on variants with high predictability rather than high statistical significance and derived a statistical test to assess the significance of results obtained in one sex and replicated in the other sex. Results: As few as 5000 highly predictive variants achieved accuracy exceeding 95% in each of males and females, and only 2.8% and 3.3% of cases and controls were misclassified in females and males, respectively. Conclusions: Our allelic polygenic risk scores are based on individual genotypes rather than summary statistics and produce highly accurate, cross-validated phenotype predictions. Although variants were originally selected as being highly predictive rather than statistically significant, 544 disease-associated variants were shown to be significantly shared between males and females, which represents a replication in an independent dataset.