tbuckley/cabot-search huggingface dataset:
Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure
Authors: Qianqian Yang, Qian Yang, Xueyan Wu, Ruizhi Zheng, Hong Lin, Shuangyuan Wang, Jacob Joseph, Yan V. Sun, Mian Li, Tiange Wang, Zhiyun Zhao, Min Xu, Jieli Lu, Yuhong Chen, Guang Ning, Weiqing Wang, Yufang Bi, Jie Zheng, Yu Xu
Journal: Cell Reports Medicine (2024)

The prevalence of heart failure (HF) subtypes, which are classified by left ventricular ejection fraction (LVEF), demonstrate significant sex differences. Here, we perform sex-stratified genome-wide association studies (GWASs) on LVEF and transcriptome-wide Mendelian randomization (MR) on LVEF, all-cause HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). The sex-stratified GWASs of LVEF identified three sex-specific loci that were exclusively detected in the sex-stratified GWASs. Three drug target genes show sex-differential effects on HF/HFrEF via influencing LVEF, with NPR2 as the target gene for the HF drug Cenderitide under phase 2 clinical trial. Our study highlights the importance of considering sex-differential genetic effects in sex-balanced diseases such as HF and emphasizes the value of sex-stratified GWASs and MR in identifying putative genetic variants, causal genes, and candidate drug targets for HF, which is not identifiable using a sex-combined strategy.
Karyotypic stasis and swarming influenced the evolution of viral tolerance in a species-rich bat radiation
Authors: Nicole M. Foley, Andrew J. Harris, Kevin R. Bredemeyer, Manuel Ruedi, Sebastien J. Puechmaille, Emma C. Teeling, Michael F. Criscitiello, William J. Murphy
Journal: Cell Genomics (2024)

The emergence of COVID-19 and severe acute respiratory syndrome (SARS) has prioritized understanding bats' viral tolerance. Myotis bats are exceptionally species rich and have evolved viral tolerance. They also exhibit swarming, a cryptic behavior where large, multi-species assemblages gather for mating, which has been hypothesized to promote interspecific hybridization. To resolve the coevolution of genome architecture and their unusual antiviral tolerance, we undertook a phylogenomic analysis of 60 Old World Myotis genomes. We demonstrate an extensive history of introgressive hybridization that has replaced the species phylogeny across 17%-93% of the genome except for pericentromeric regions of macrochromosomes. Introgression tracts were enriched on microchromosome regions containing key antiviral pathway genes overexpressed during viral challenge experiments. Together, these results suggest that the unusual Myotis karyotype may have evolved to selectively position immune-related genes in high recombining genomic regions prone to introgression of divergent alleles, including a diversity of interleukin loci responsible for the release of pro-inflammatory cytokines.
A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage
Authors: Ting Li, Ning Ding, Hanqing Guo, Rui Hua, Zehao Lin, Huohuan Tian, Yue Yu, Daiming Fan, Zuyi Yuan, Frank J. Gonzalez, Yue Wu
Journal: Cell Host & Microbe (2024)

Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how this impacts intestinal homeostasis remains unclear. Herein, using clinical cohorts and aspirin-treated mice, we identified an intestinal microbe, Parabacteroides goldsteinii, whose growth is suppressed by aspirin. Mice supplemented with P. goldsteinii or its BA metabolite, 7-keto-lithocholic acid (7-keto-LCA), showed reduced aspirin-mediated damage of the intestinal niche and gut barrier, effects that were lost with a P. goldsteinii hdhA mutant unable to generate 7-keto-LCA. Specifically, 7-keto-LCA promotes repair of the intestinal epithelium by suppressing signaling by the intestinal BA receptor, farnesoid X receptor (FXR). 7-Keto-LCA was confirmed to be an FXR antagonist that facilitates Wnt signaling and thus self-renewal of intestinal stem cells. These results reveal the impact of oral aspirin on the gut microbiota and intestinal BA metabolism that in turn modulates gastrointestinal homeostasis.
Selective vulnerability of layer 5a corticostriatal neurons in Huntington’s disease
Authors: Christina Pressl, Kert Mätlik, Laura Kus, Paul Darnell, Ji-Dung Luo, Matthew R. Paul, Alison R. Weiss, William Liguore, Thomas S. Carroll, David A. Davis, Jodi McBride, Nathaniel Heintz
Journal: Neuron (2024)

The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.
Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease
Authors: May-Yun Wang, Zhuzhen Zhang, Shangang Zhao, Toshiharu Onodera, Xue-Nan Sun, Qingzhang Zhu, Chao Li, Na Li, Shiuhwei Chen, Megan Paredes, Laurent Gautron, Maureen J. Charron, Denise K. Marciano, Ruth Gordillo, Daniel J. Drucker, Philipp E. Scherer
Journal: Cell Metabolism (2024)
Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of <i>KRAS</i>-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study
Authors: Daniel H. Ahn, Afsaneh Barzi, Maya Ridinger, Errin Samuëlsz, Ramanand A. Subramanian, Peter J.P. Croucher, Tod Smeal, Fairooz F. Kabbinavar, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2024)

Onvansertib is a highly specific inhibitor of polo-like kinase 1 (PLK1), with demonstrated safety in solid tumors. We evaluated, preclinically and clinically, the potential of onvansertib in combination with chemotherapy as a therapeutic option for KRAS-mutant colorectal cancer.
Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors
Authors: Xiang Li, Yangzhong Zhou, Bing Xu, Yunhe Qin, Jiuliang Zhao, Mengtao Li, Jiachen Xu, Guanqiao Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, indicating overestimation of results from phase II studies. Our research aims to systematically assess overestimation in early-phase trials involving programmed cell death-1 (PD-1)/programmed cell death-ligand 1(PD-L1) inhibitors compared with phase III trials and identify contributing factors. Methods We matched 51 pairs of early-phase and phase III clinical trials from a pool of over 9,600 PD-1/PD-L1 inhibitor trials. The matching criteria included identical treatment regimens, cancer types, treatment lines, and biomarker enrichment strategies. To assess overestimation, we compared the overall response rates (ORR) between early-phase and phase III trials. We established independent variables related to eligibility criteria, and trial design features of participants to analyze the factors influencing the observed discrepancy in efficacy between the two phases through univariable and multivariable logistic analyses. Result Early-phase trial outcomes systematically overestimated the subsequent phase III results, yielding an odds ratio (OR) comparing ORR in early-phase versus phase III: 1.66 (95% CI: 1.43 to 1.92, p&lt;0.05). This trend of inflated ORR was consistent across trials testing PD-1/PD-L1 monotherapies and combination therapies involving PD-1/PD-L1. Among the examined factors, the exclusion of patients with autoimmune diseases was significantly associated with the disparity in efficacy between early-phase trials and phase III trials (p=0.023). We calculated a Ward statistic of 2.27 to validate the effectiveness of the model. Conclusion These findings underscore the tendency of overestimation of efficacy in early-phase trials involving immunotherapies. The observed differences could be attributed to variations in the inclusion of patients with autoimmune disorders in early-phase trials. These insights have the potential to inform stakeholders in the future development of cancer immunotherapies.
Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms
Authors: Andrew J. Dunbar, Robert L. Bowman, Young C. Park, Kavi O'Connor, Franco Izzo, Robert M. Myers, Abdul Karzai, Zachary Zaroogian, Won Jun Kim, Inés Fernández-Maestre, Michael R. Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F. Cai, Benjamin Wang, Wenbin An, Julie L. Yang, Shoron Mowla, Shira E. Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L. Glass, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R. Martinez Benitez, Aaron D. Viny, Richard P. Koche, Sara C. Meyer, Dan A. Landau, Ross L. Levine
Journal: Cancer Discovery (2024)

Abstract Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo. Significance: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695
Novel Operation Mechanism and Multifunctional Applications of Bubble Microrobots
Authors: Yuting Zhou, Wen Cheng, Liguo Dai, Songyi Guo, Junfeng Wu, Xiaodong Wang, Anhua Wu, Lianqing Liu, Niandong Jiao
Journal: Advanced Healthcare Materials (2024)

Abstract Microrobots have emerged as powerful tools for manipulating particles, cells, and assembling biological tissue structures at the microscale. However, achieving precise and flexible operation of arbitrary‐shaped microstructures in 3D space remains a challenge. In this study, three novel operation methods based on bubble microrobots are proposed to enable delicate and multifunctional manipulation of various microstructures. These methods include 3D turnover, fixed‐point rotation, and 3D ejection. By harnessing the combined principles of the effect of the heat flow field and surface tension of an optothermally generated bubble, the bubble microrobot can perform tasks such as flipping an SIA humanoid structure, rotating a bird‐like structure, and launching a hollow rocket‐like structure. The proposed multi‐mode operation of bubble microrobots enables diverse attitude adjustments of microstructures with different sizes and shapes in both 2D and 3D spaces. As a demonstration, a biological microenvironment of brain glioblastoma is constructed by the bubble microrobot. The simplicity, versatility, and flexibility of this proposed method hold great promise for applications in micromanipulation, assembly, and tissue engineering.
Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations
Authors: Maud Maillard, Rina Nishii, Wenjian Yang, Keito Hoshitsuki, Divyabharathi Chepyala, Shawn H R Lee, Jenny Q Nguyen, Mary V Relling, Kristine R Crews, Mark Leggas, Meenu Singh, Joshua L Y Suang, Allen E J Yeoh, Sima Jeha, Hiroto Inaba, Ching-Hon Pui, Seth E Karol, Amita Trehan, Prateek Bhatia, Federico G Antillon Klussmann, Deepa Bhojwani, Cyrine E Haidar, Jun J Yang
Journal: JNCI Journal of the National Cancer Institute (2024)

Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.
Associations of tenascin C with Th2 response, edema degree, and disease severity in patients with chronic rhinosinusitis with nasal polyps
Authors: Min Wang, Haiyang Meng, Nan Zhang, Jian Jiao, Yifei Wang, Mengdi Liu, Ying Li, Xiangdong Wang, Luo Zhang, Claus Bachert
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Cancer statistics, 2024
Authors: Rebecca L. Siegel, Angela N. Giaquinto, Ahmedin Jemal
Journal: CA A Cancer Journal for Clinicians (2024)

Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data collected by the National Center for Health Statistics (through 2021). In 2024, 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States. Cancer mortality continued to decline through 2021, averting over 4 million deaths since 1991 because of reductions in smoking, earlier detection for some cancers, and improved treatment options in both the adjuvant and metastatic settings. However, these gains are threatened by increasing incidence for 6 of the top 10 cancers. Incidence rates increased during 2015–2019 by 0.6%–1% annually for breast, pancreas, and uterine corpus cancers and by 2%–3% annually for prostate, liver (female), kidney, and human papillomavirus‐associated oral cancers and for melanoma. Incidence rates also increased by 1%–2% annually for cervical (ages 30–44 years) and colorectal cancers (ages &lt;55 years) in young adults. Colorectal cancer was the fourth‐leading cause of cancer death in both men and women younger than 50 years in the late‐1990s but is now first in men and second in women. Progress is also hampered by wide persistent cancer disparities; compared to White people, mortality rates are two‐fold higher for prostate, stomach and uterine corpus cancers in Black people and for liver, stomach, and kidney cancers in Native American people. Continued national progress will require increased investment in cancer prevention and access to equitable treatment, especially among American Indian and Alaska Native and Black individuals.
Optimal hepatitis C treatment adherence patterns and sustained virologic response among people who inject drugs: The HERO study
Authors: Moonseong Heo, Brianna L. Norton, Irene Pericot-Valverde, Shruti H. Mehta, Judith I. Tsui, Lynn E. Taylor, Paula J. Lum, Judith Feinberg, Arthur Y. Kim, Julia H. Arnsten, Sophie Sprecht-Walsh, Kimberly Page, Cristina Murray-Krezan, Jessica Anderson, Alain H. Litwin, Alain H. Litwin, Moonseong Heo, Irene Pericot-Valverde, Hagan Walker, Ashley Coleman, Shruti H. Mehta, Courtney Borsuk, Brian Dickerson, Oluwaseun Falade-Nwulia, Michael Fingerhood, Taryn Haselhuhn, Angela Mason, Juhi Moon, Yngvild Olsen, Vickie Walters, Arthur Y. Kim, Jillian M. Roche, William Schmitt, Virginia Lijewski, Anita Pitts, Syeda Raji, Taniya Silva, Fiona Evans, Hope Koene, Joelle Brown, Brianna Norton, Linda Agyemang, Julia Arnsten, Alison Karasz, Paul Meissner, Kiara Lora, Jennifer Hidalgo, Irene Soloway, Karen Jefferson, Joyce Wong, Andrea Kermack, Melissa Stein, Gilian Joseph, Karyn London, Lincoln Allen, Venecia Marte, Tatiana Vera, Romy Alvarez, M. Diane Mckee, Paula J. Lum, Ellen S. Stein, Anne F. Luetkemeyer, Caycee Cullen, Gurjot Gill, Hannah Tierney, Scott Shapiro, Soraya Azari, Joanna Eveland, Daniel Berrner, Pauli Grey, Jordan Akerley, Kimberly Page, Katherine Wagner, Herbert Davis, Cristina Murray-Krezan, Vanessa Jacobsohn, Jessica Anderson, Lynn E. Taylor, Karen Tashima, Sophie Sprecht-Walsh, Aurielle Thomas, Melissa Hordes, Danielle McGregor, Patrick Duryea, Kathryn Weenig, Judith I. Tsui, Kendra L. Blalock, Hyang Nina Kim, Meena S. Ramchandani, Jocelyn R. James, K. Michelle Peavy, Paul Grekin, Michael Ninburg, Judith Feinberg, Samuel Wilkinson, Danielle Thomas, Lacey Kelley, Andrea Calkins, Gabrielle Henry, Alice Ashler, Eyasu Teshale, Sebastian Seiguer, Lauren Brown, Katrina Rios, James Spellman, Daniel Raymond, Susan Beane, Ronni Marks, Tracy Swan, Chuck Walworth, Yolanda Lie, Jackie Reeves, Walter P. Ginter, Jules Devin, Ryan Clary, Tina Broder, Bekeela Davila, Nirah Johnson, Umaima Khatun, Colleen Flanigan, Ray Ahmed, Bob Polluck, Serene Mastrianni, James Morton, Emily Baldwin, Rick Pesano, Charissa Fotinos, Douglas Fish, James Becker, John W. Ward, Mark Parrino, Carleen Maxwell
Journal: Journal of Hepatology (2024)
OST-01, a natural product from Baccharis coridifolia, targets c-Myc-dependent ribogenesis in acute myeloid leukemia
Authors: HyunJun Kang, Dinh Hoa Hoang, Melissa Valerio, Khyatiben Pathak, Lianjun Zhang, Ralf Buettner, Fang Chen, Katrina Estrella, William Graff, Zhuo Li, Jun Xie, David Horne, Ya-Huei Kuo, Bin Zhang, Patrick Pirrotte, Le Xuan Truong Nguyen, Guido Marcucci
Journal: Leukemia (2024)
The developmental timing of spinal touch processing alterations predicts behavioral changes in genetic mouse models of autism spectrum disorders
Authors: Aniqa Tasnim, Ilayda Alkislar, Richard Hakim, Josef Turecek, Amira Abdelaziz, Lauren L. Orefice, David D. Ginty
Journal: Nature Neuroscience (2024)

Abstract Altered somatosensory reactivity is frequently observed among individuals with autism spectrum disorders (ASDs). Here, we report that although multiple mouse models of ASD exhibit aberrant somatosensory behaviors in adulthood, some models exhibit altered tactile reactivity as early as embryonic development, whereas in others, altered reactivity emerges later in life. Additionally, tactile overreactivity during neonatal development is associated with anxiety-like behaviors and social behavior deficits in adulthood, whereas tactile overreactivity that emerges later in life is not. The locus of circuit disruption dictates the timing of aberrant tactile behaviors, as altered feedback or presynaptic inhibition of peripheral mechanosensory neurons leads to abnormal tactile reactivity during neonatal development, whereas disruptions in feedforward inhibition in the spinal cord lead to touch reactivity alterations that manifest later in life. Thus, the developmental timing of aberrant touch processing can predict the manifestation of ASD-associated behaviors in mouse models, and differential timing of sensory disturbance onset may contribute to phenotypic diversity across individuals with ASD.
Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms
Authors: Jing Guo, Klaudia Walter, Pedro M. Quiros, Muxin Gu, E. Joanna Baxter, John Danesh, Emanuele Di Angelantonio, David Roberts, Paola Guglielmelli, Claire N. Harrison, Anna L. Godfrey, Anthony R. Green, George S. Vassiliou, Dragana Vuckovic, Jyoti Nangalia, Nicole Soranzo
Journal: Nature Genetics (2024)

Abstract Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2 V617F , are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2 V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2 V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2 V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.