tbuckley/cabot-search huggingface dataset:
The Association of Where Patients with Prostate Cancer Live and Receive Care on Racial Treatment Inequities
Authors: Noah Hammarlund, Sarah K Holt, Ruth Etzioni, Danté Morehead, Jenney R Lee, Erika M Wolff, Yohali Burrola-Mendez, Liz Sage, John L Gore, Yaw A Nyame
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Black individuals are less likely to be treated for prostate cancer even though they are more than twice as likely to die compared to White individuals. The complex causes of these inequities are influenced by social and structural factors, including racism, which contribute to the differential delivery of care. This study investigates how factors related to the location of where individuals live and receive care affect treatment inequities for prostate cancer between Black and White individuals. We hypothesize that both location and race independently influence treatment inequities. We used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims to estimate the treatment inequity, as defined by differences in radiation or radical prostatectomy. Fixed effects at the physician, hospital, and patient ZIP code levels were incorporated to adjust for all time-invariant factors at these levels. The results indicate that residential location-related factors explain only half of the treatment inequity, while provider- and hospital-level factors do not significantly account for disparities. Even after accounting for all time-invariant factors, significant differences in treatment rates persist. The study highlights the importance of understanding race as a social construct and racism as a systemic and structural phenomenon in addressing treatment inequities. These findings provide a necessary step toward understanding equitable care and designing interventions to solve this inequity.
Proinflammatory Dietary Pattern and Risk of Total and Subtypes of Breast Cancer Among U.S. Women
Authors: Andrea Romanos-Nanclares, Walter C Willett, Bernard Rosner, Daniel G Stover, Sagar D Sardesai, Michelle D Holmes, Wendy Y Chen, Rulla M Tamimi, Fred K Tabung, A Heather Eliassen
Journal: JNCI Journal of the National Cancer Institute (2024)

Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been associated with certain cancers. Investigating whether this dietary pattern is associated with breast cancer-where the role of inflammation is less well-defined-could provide valuable insights and potentially improve strategies for preventing this cancer. We prospectively followed 76,386 women from Nurses' Health Study (NHS, 1984-2018) and 92,886 women from Nurses' Health Study II (NHSII, 1991-2019). Diet was assessed by food frequency questionnaires (FFQs) every 4 years, starting at baseline. The inflammatory potential of diet was evaluated using the validated EDIP based on plasma CRP, IL-6, and TNFα-R2. Higher scores indicate higher dietary inflammatory potential. Hazard ratios and 95%CIs of overall and subtypes of breast cancer were estimated using multivariable-adjusted Cox regression models. During 4,490,842 person-years of follow-up, we documented 11,026 breast cancer cases. Women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vs.Q1=1.12; 95% CI, 1.05, 1.19; P-trend<0.001). The association was stronger for ER-negative tumors (HRQ5vs.Q1=1.29; 95% CI, 1.09, 1.53; P-trend=0.003). Also, we observed that the association of EDIP with breast cancer risk differed by molecular subtype, with the strongest association observed with basal-like tumors (HRQ5vs.Q1=1.80; 95% CI, 1.20, 2.71; P-trend=0.004). Higher EDIP scores were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors. These results support the hypothesis that diet-related inflammation plays a role in breast cancer etiology, particularly tumors lacking hormone receptors.
Vagal stimulation ameliorates murine colitis by regulating SUMOylation
Authors: Ayman Youssef, Ata Ur Rehman, Mohamed Elebasy, Jatin Roper, Shehzad Z. Sheikh, Jorn Karhausen, Wei Yang, Luis Ulloa
Journal: Science Translational Medicine (2024)

Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of Sumo3 protected against development of colitis and delayed onset of disease, whereas deletion of Sumo1 halted the progression of colitis. Bone marrow transplants from Sumo1 -knockout (KO) but not Sumo3 -KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in Sumo1 -KO mice and resulted in milder symptoms in Sumo3 -KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.
Mechanism and Impact of Left Atrial Dyssynchrony on Long-Term Clinical Outcome During Cardiac Resynchronization Therapy
Authors: Lars-Egil R Hammersboen, Marie Stugaard, Alexis Puvrez, Camilla K Larsen, Espen W Remme, Erik Kongsgård, Jürgen Duchenne, Elena Galli, Faraz H Khan, Ole Jakob Sletten, Martin Penicka, Erwan Donal, Jens-Uwe Voigt, Otto A Smiseth, John M Aalen
Journal: JACC. Cardiovascular imaging (2024)

Left bundle branch block (LBBB) causes left atrial (LA) dyssynchrony. It is unknown if LA dyssynchrony impacts long-term prognosis.
Angiotensin Receptor Neprilysin Inhibition and Cardiovascular Outcomes Across the Kidney Function Spectrum
Authors: Finnian R Mc Causland, Muthiah Vaduganathan, Brian Claggett, Mauro Gori, Pardeep S Jhund, Martina M McGrath, Brendon L Neuen, Milton Packer, Marc A Pfeffer, Jean L Rouleau, Michele Senni, Karl Swedberg, Faiez Zannad, Michael Zile, Martin P Lefkowitz, John J V McMurray, Scott D Solomon
Journal: JACC Heart Failure (2024)
The Association of Echocardiographically Measured Donor Left Ventricular Mass and 1-Year Outcomes After Heart Transplantation
Authors: Christian O'Donnell, Natalie Tapaskar, Pablo A Sanchez, Brian Wayda, Everton J Santana, Rafael C Pulgrossi, Kirsten Steffner, Shiqi Zhang, Yingjie Weng, Louise Y Sun, Darren Malinoski, Jonathan Zaroff, Francois Haddad, Kiran K Khush
Journal: JACC Heart Failure (2024)
Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells
Authors: Luiz Henrique Geraldo, Yunling Xu, Gaspard Mouthon, Jessica Furtado, Felipe Saceanu Leser, Levi L. Blazer, Jarrett J. Adams, Sophia Zhang, Lana Zheng, Eric Song, Mark E. Robinson, Jean-Leon Thomas, Sachdev S. Sidhu, Anne Eichmann
Journal: Science Translational Medicine (2024)

Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECDs) and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling regulates pathological ocular neovascularization, which is a major cause of vision loss worldwide, but pharmacological tools to prevent SLIT-ROBO signaling are lacking. Here, we developed human monoclonal antibodies (mAbs) against the ROBO1 and ROBO2 ECDs. One antibody that inhibited in vitro SLIT2 signaling through ROBO1 and ROBO2 (anti-ROBO1/2) also reduced ocular neovascularization in oxygen-induced retinopathy (OIR) and laser-induced corneal neovascularization (CNV) mouse models in vivo. Single-cell RNA sequencing of OIR retinas revealed that antibody treatment affected several cell types relevant to physiological and pathological angiogenesis, including endothelial cells, pericytes, and a heterogeneous population of myeloid cells. mAb treatment improved blood-retina barrier integrity and prevented pathological pericyte activation in OIR. SLIT-ROBO signaling inhibition prevented pathological activation of myeloid cells and increased neuroprotective myeloid populations normally seen in the developing retina. Microglia/infiltrating macrophage–specific ablation of Robo1 and Robo2 or knockout of the downstream effector phosphatidylinositol 3-kinase ( Pik3cg ) encoding PI3Kγ in both OIR and CNV models phenocopied anti-ROBO1/2 treatment, further demonstrating the key role of myeloid cells as drivers of ocular neovascular diseases. ROBO1/2 blocking antibodies may thus provide a promising strategy to combat inflammation in blinding eye diseases.
Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration
Authors: Kenyi Saito-Diaz, Paula Dietrich, Tripti Saini, Md Mamunur Rashid, Hsueh-Fu Wu, Mohamed Ishan, Xin Sun, Sydney Bedillion, Archie Jayesh Patel, Anthony Robert Prudden, Camryn Gale Wzientek, Trinity Nora Knight, Ya-Wen Chen, Geert-Jan Boons, Shuibing Chen, Lorenz Studer, Michael Tiemeyer, Bingqian Xu, Ioannis Dragatsis, Hong-Xiang Liu, Nadja Zeltner
Journal: Science Translational Medicine (2024)

The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world’s population suffers from nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration; therefore, there are no available treatments. Familial dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1 . FD specifically affects the development and causes degeneration of the PNS. We previously used patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient-derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin cross-linked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of yes-associated protein–dependent genes. Last, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system) in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
NIT2 dampens BRD1 phase separation and restrains oxidative phosphorylation to enhance chemosensitivity in gastric cancer
Authors: Ziyang Wang, Yuqin Di, Xiangqiong Wen, Ye Liu, Lvlan Ye, Xiang Zhang, Jiale Qin, Youpeng Wang, Huiying Chu, Guohui Li, Weijing Zhang, Xiongjun Wang, Weiling He
Journal: Science Translational Medicine (2024)

5-Fluorouracil (5-FU) chemoresistance contributes to poor therapeutic response and prognosis of gastric cancer (GC), for which effective strategies to overcome chemoresistance are limited. Here, using a CRISPR-Cas9 system, we identified that nitrilase family member 2 (NIT2) reverses chemoresistance independent of its metabolic function. Depletion or low expression of NIT2 led to 5-FU resistance in GC cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, NIT2 interacted with bromodomain-containing protein 1 (BRD1) to inhibit HBO1-mediated acetylation of histone H3 at lysine-14 (H3K14ac) and RELA-targeted oxidative phosphorylation (OXPHOS) gene expression. Upon 5-FU stimulation, NIT2 phosphorylation by Src at Y49 promoted the dissociation of NIT2 from BRD1, followed by binding to E3 ligase CCNB1IP1, causing autophagic degradation of NIT2. Consequently, reduced NIT2 protein resulted in BRD1 forming phase separation and binding to histone H3, as well as increased RELA stability due to suppression of inhibitor of growth family member 4–mediated RELA ubiquitination. In addition, NIT2 expression negatively correlated with H3K14ac and OXPHOS and positively correlated with the chemotherapeutic responses and prognosis of patients with GC. Our findings reveal the moonlighting function of NIT2 in chemoresistance and underscore that OXPHOS blockade by metformin enhances 5-FU chemosensitivity upon NIT2 loss.
Symptoms Burden as a Clinical Outcomes Assessment in Heart Failure Patients With Atrial Fibrillation
Authors: Ian A Carroll, Jonathan P Piccini, Benjamin A Steinberg, Wendy S Tzou, Jennifer C Richards, David L DeMets, Michael R Bristow
Journal: JACC Heart Failure (2024)

Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period.
Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease
Authors: Stephen R. Welch, Jessica R. Spengler, Jonna B. Westover, Kevin W. Bailey, Katherine A. Davies, Virginia Aida-Ficken, Gregory R. Bluemling, Kirsten M. Boardman, Samantha R. Wasson, Shuli Mao, Damien L. Kuiper, Michael W. Hager, Manohar T. Saindane, Meghan K. Andrews, Rebecca E. Krueger, Zachary M. Sticher, Kie Hoon Jung, Payel Chatterjee, Punya Shrivastava-Ranjan, Michael K. Lo, JoAnn D. Coleman-McCray, Teresa E. Sorvillo, Sarah C. Genzer, Florine E. M. Scholte, Jamie A. Kelly, M. Harley Jenks, Laura K. McMullan, César G. Albariño, Joel M. Montgomery, George R. Painter, Michael G. Natchus, Alexander A. Kolykhalov, Brian B. Gowen, Christina F. Spiropoulou, Mike Flint
Journal: Science Translational Medicine (2024)

Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.
Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis
Authors: Xi Chen, Gayathri Shibu, Baila A. Sokolsky, Tamar Nicole Soussana, Logan Fisher, Dinesh K. Deochand, Marija Dacic, Ian Mantel, Daniel C. Ramirez, Richard D. Bell, Tinghu Zhang, Laura T. Donlin, Susan M. Goodman, Nathanael S. Gray, Yurii Chinenov, Robert P. Fisher, Inez Rogatsky
Journal: Science Translational Medicine (2024)

Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the Pol II transcription cycle, we used two covalent inhibitors of the transcription factor II H-associated cyclin-dependent kinase 7 (CDK7), THZ1 and YKL-5-124. Both reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed preestablished inflammatory macrophage polarization. In mice, CDK7 inhibition ameliorated both acute and chronic progressive inflammatory arthritis. Lastly, CDK7 inhibition down-regulated a pathogenic gene expression signature in synovial explants from patients with rheumatoid arthritis. We propose that interfering with Pol II early elongation by targeting CDK7 represents a therapeutic opportunity for rheumatoid arthritis and other inflammatory diseases.
Burden and Excess Risk of Adverse Outcomes in Patients With Type 1 Diabetes Using KDIGO Classification: A National Cohort Study
Authors: Kianoush Makvandi, Björn Eliasson, Hanne Krage Carlsen, Seema Baid-Agrawal
Journal: Diabetes Care (2024)

OBJECTIVE The widely adopted Kidney Disease: Improving Global Outcomes (KDIGO) classification system has been underused in assessing the burden and risk of adverse outcomes in type 1 diabetes. This observational study aimed to clarify how each KDIGO category correlates with outcomes, including mortality, in this patient group. RESEARCH DESIGN AND METHODS In 40,199 individuals with type 1 diabetes from the Swedish National Diabetes Register, we examined the 1) prevalence of different KDIGO categories at baseline; 2) incidence of adverse kidney and cardiovascular (CV) outcomes, including mortality, within each category; and 3) association of baseline category with excess risk of five outcomes: 40% decline in estimated glomerular filtration rate (eGFR), kidney failure, major adverse kidney/CV events, and all-cause mortality. Cox regression analyses were conducted using three different reference categories: 1) the conventional low-risk “combined G1A1 + G2A1”; 2) “G1A1” alone to assess whether G2A1 had excess risk; and 3) “G1bA1” alone to evaluate whether eGFR ≥105 mL/min/1.73 m2 had increased risk. RESULTS Among 39,067 included patients, with a mean follow-up of 9.1 years, 18.5% presented with chronic kidney disease (CKD), defined as eGFR &amp;lt;60 mL/min/1.73 m2 and/or albuminuria. A progressive increase in the incidence and adjusted hazard ratio for all studied outcomes was found with advancing eGFR and albuminuria categories, including in G2A1 (non-CKD). A eGFR ≥105 mL/min/1.73 m2 without albuminuria was not associated with increased risk. CONCLUSIONS A progressively increasing burden of all studied adverse outcomes was observed with advancing KDIGO categories. Even individuals with preserved eGFR and normoalbuminuria (G2A1) conventionally perceived as non-CKD, had an excess risk for all outcomes.
A multivariable disease specific model enhances prognostication beyond current Merkel cell carcinoma staging: an international cohort study of 10,958 patients.
Authors: Tom W Andrew, Sophie Erdmann, Mogdad Alrawi, Ruth Plummer, Sophia Z Shalhout, Vern Sondak, Isaac Brownell, Penny E Lovat, Aidan Rose
Journal: Journal of the American Academy of Dermatology (2024)
A cross-tissue, age-specific flow cytometry reference for immune cells in the airways and blood of children
Authors: Shivanthan Shanthikumar, Liam Gubbels, Karen Davies, Hannah Walker, Anson Tsz Chun Wong, Jovana Maksimovic, Alicia Oshlack, Richard Saffery, Eric Levi, Sarath C Ranganathan, Melanie R Neeland
Journal: Journal of Allergy and Clinical Immunology (2024)