tbuckley/cabot-search huggingface dataset:
Clinical impact of mutated <scp>JAK2</scp> allele burden reduction in polycythemia vera and essential thrombocythemia
Authors: Paola Guglielmelli, Barbara Mora, Francesca Gesullo, Francesco Mannelli, Giuseppe Gaetano Loscocco, Leonardo Signori, Chiara Pessina, Ilaria Colugnat, Raffaela Aquila, Manjola Balliu, Chiara Maccari, Simone Romagnoli, Chiara Paoli, Elena Nacca, Lorenzo Fagiolo, Margherita Maffioli, Tiziano Barbui, Francesco Passamonti, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2024)

Abstract The variant allele frequency (VAF) of driver mutations ( JAK2, CALR ) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long‐term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%–99%) to 3.5% (0%–98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction &gt;50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis‐free, event‐free and progression‐free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF &lt;50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.
Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D
Authors: Tarik Asselah, Vladimir Chulanov, Pietro Lampertico, Heiner Wedemeyer, Adrian Streinu-Cercel, Victor Pântea, Stefan Lazar, Gheorghe Placinta, George S Gherlan, Pavel Bogomolov, Tatyana Stepanova, Viacheslav Morozov, Vladimir Syutkin, Olga Sagalova, Dmitry Manuilov, Renee-Claude Mercier, Lei Ye, Ben L Da, Grace Chee, Audrey H Lau, Anu Osinusi, Marc Bourliere, Vlad Ratziu, Stanislas Pol, Marie-Noëlle Hilleret, Fabien Zoulim
Journal: New England Journal of Medicine (2024)

In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.
Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF
Authors: Pooja Dewan, Li Shen, João Pedro Ferreira, Pardeep S. Jhund, Inder S. Anand, Alvin Chandra, Lu-May Chiang, Brian Claggett, Akshay S. Desai, Jianjian Gong, Carolyn S.P. Lam, Martin P. Lefkowitz, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Margaret M. Redfield, Jean L. Rouleau, Dirk J. van Veldhuisen, Faiez Zannad, Michael R. Zile, Scott D. Solomon, John J.V. McMurray
Journal: Circulation (2024)

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score &lt;24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score &lt;24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score &lt;24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.
The antisickling agent, 5‐hydroxymethyl‐2‐furfural: Other potential pharmacological applications
Authors: Piyusha P. Pagare, Mina McGinn, Mohini S. Ghatge, Vibha Shekhar, Rana T. Alhashimi, B. Daniel Pierce, Osheiza Abdulmalik, Yan Zhang, Martin K. Safo
Journal: Medicinal Research Reviews (2024)

Abstract For the last two decades, the aromatic aldehyde 5‐hydroxymethyl‐furfural (5‐HMF) has been the subject of several investigations for its pharmacologic potential. In 2004, the Safo group reported that 5‐HMF has potent antisickling activity by targeting and ameliorating the primary pathophysiology of hypoxia‐induced sickling of erythrocytes (red blood cells [RBC]). Following the encouraging outcome of the preclinical and phase I/II clinical studies of 5‐HMF for the treatment of sickle cell disease (SCD), there have been multiple studies suggesting 5‐HMF has several other biological or pharmacologic activities, including anti‐allergic, antioxidant, anti‐hypoxic, anti‐ischemic, cognitive improvement, anti‐tyrosinase, anti‐proliferation, cytoprotective, and anti‐inflammatory activities. The wide range of its effects makes 5‐HMF a potential candidate for treating a variety of diseases including cognitive disorders, gout, allergic disorders, anemia, hypoxia, cancers, ischemia, hemorrhagic shock, liver fibrosis, and oxidative injury. Several of these therapeutic claims are currently under investigation and, while promising, vary in terms of the strength of their evidence. This review presents the research regarding the therapeutic potential of 5‐HMF in addition to its sources, physicochemical properties, safety, absorption, distribution, metabolism, and excretion (ADME) profiles.
Sustained aviraemia despite anti-retroviral therapy non-adherence in male children following in utero hiv transmission
Authors: Nomonde Bengu, Gabriela Cromhout, Emily Adland, Katya Govender, Nicholas Herbert, Nicholas Lim, Rowena Fillis, Kenneth Sprenger, Vinicius Vieira, Samantha Kannie, Jeroen van Lobenstein, Kogielambal Chinniah, Constant Kapongo, Roopesh Bhoola, Malini Krishna, Noxolo Mchunu, Giuseppe Rubens Pascucci, Nicola Cotugno, Paolo Palma, Alfredo Tagarro, Pablo Rojo, Julia Roider, Maria C. Garcia-Guerrero, Christina Ochsenbauer, Andreas Groll, Kavidha Reddy, Carlo Giaquinto, Paolo Rossi, Seohyun Hong, Krista Dong, M. Azim Ansari, Maria C. Puertas, Thumbi Ndung’u, Edmund Capparelli, Mathias Lichterfeld, Javier Martinez-Picado, John C. Kappes, Moherndran Archary, Philip Goulder
Journal: Nature Medicine (2024)

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.
Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial
Authors: Yi-Bin Chen, Mohamad Mohty, Robert Zeiser, Takanori Teshima, Omer Jamy, Johan Maertens, Duncan Purtill, Jingjing Chen, Hong Cao, Guillermo Rossiter, Johan Jansson, Yngvar Fløisand
Journal: Nature Medicine (2024)

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α
Precision-guided treatment in high-risk pediatric cancers
Authors: Loretta M. S. Lau, Dong-Anh Khuong-Quang, Chelsea Mayoh, Marie Wong, Paulette Barahona, Pamela Ajuyah, Akanksha Senapati, Sumanth Nagabushan, Alexandra Sherstyuk, Ann-Kristin Altekoester, Noemi A. Fuentes-Bolanos, Veronica Yeung, Ashleigh Sullivan, Natacha Omer, Yonatan Diamond, Sophie Jessop, Lauren Battaglia, Nataliya Zhukova, Louise Cui, Angela Lin, Andrew J. Gifford, Emmy D. G. Fleuren, Luciano Dalla-Pozza, Andrew S. Moore, Seong-Lin Khaw, David D. Eisenstat, Nicholas G. Gottardo, Paul J. Wood, Heather Tapp, Frank Alvaro, Geoffrey McCowage, Wayne Nicholls, Jordan R. Hansford, Neevika Manoharan, Rishi S. Kotecha, Marion K. Mateos, Richard B. Lock, Vanessa Tyrrell, Michelle Haber, Toby N. Trahair, Mark J. Cowley, Paul G. Ekert, Glenn M. Marshall, David S. Ziegler
Journal: Nature Medicine (2024)

Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.
A cost-effectiveness analysis of early detection and bundled treatment of postpartum hemorrhage alongside the E-MOTIVE trial
Authors: Eleanor V. Williams, Ilias Goranitis, Raymond Oppong, Samuel J. Perry, Adam J. Devall, James T. Martin, Kristie-Marie Mammoliti, Leanne E. Beeson, Kulandaipalayam N. Sindhu, Hadiza Galadanci, Fadhlun Alwy Al‑beity, Zahida Qureshi, G. Justus Hofmeyr, Neil Moran, Sue Fawcus, Sibongile Mandondo, Lee Middleton, Karla Hemming, Olufemi T. Oladapo, Ioannis D. Gallos, Arri Coomarasamy, Tracy E. Roberts
Journal: Nature Medicine (2024)

Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide objective, accurate and early diagnosis of PPH, and a treatment bundle can address delays or inconsistencies in the use of effective interventions. Here we conducted an economic evaluation alongside the E-MOTIVE trial, an international, parallel cluster-randomized trial with a baseline control phase involving 210,132 women undergoing vaginal delivery across 78 secondary-level hospitals in Kenya, Nigeria, South Africa and Tanzania. We aimed to assess the cost-effectiveness of the E-MOTIVE intervention, which included a calibrated blood-collection drape for early detection of PPH and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination and escalation), compared with usual care. We used multilevel modeling to estimate incremental cost-effectiveness ratios from the perspective of the public healthcare system for outcomes of cost per severe PPH (blood loss ≥1,000 ml) avoided and cost per disability-adjusted life-year averted. Our findings suggest that the use of a calibrated blood-collection drape for early detection of PPH and bundled first-response treatment is cost-effective and should be perceived by decision-makers as a worthwhile use of healthcare budgets. ClinicalTrials.gov identifier: NCT04341662 .
DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts
Authors: Martina Rimoldi, Ning Wang, Jilin Zhang, Diego Villar, Duncan T. Odom, Jussi Taipale, Paul Flicek, Maša Roller
Journal: Genome biology (2024)

Abstract Background DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. Results Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. Conclusions Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.
Repeated Low-Level Red Light Therapy for Myopia Control in High Myopia Children and Adolescents
Authors: Yan Xu, Lipu Cui, Miao Kong, Qian Li, Xueliang Feng, Kehong Feng, Huang Zhu, Hongping Cui, Caiping Shi, Jian Zhang, Haidong Zou
Journal: Ophthalmology (2024)
iIMPACT: integrating image and molecular profiles for spatial transcriptomics analysis
Authors: Xi Jiang, Shidan Wang, Lei Guo, Bencong Zhu, Zhuoyu Wen, Liwei Jia, Lin Xu, Guanghua Xiao, Qiwei Li
Journal: Genome biology (2024)

Abstract Current clustering analysis of spatial transcriptomics data primarily relies on molecular information and fails to fully exploit the morphological features present in histology images, leading to compromised accuracy and interpretability. To overcome these limitations, we have developed a multi-stage statistical method called iIMPACT. It identifies and defines histology-based spatial domains based on AI-reconstructed histology images and spatial context of gene expression measurements, and detects domain-specific differentially expressed genes. Through multiple case studies, we demonstrate iIMPACT outperforms existing methods in accuracy and interpretability and provides insights into the cellular spatial organization and landscape of functional genes within spatial transcriptomics data.
Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance
Authors: Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H. Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei Wang, Yu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah-Maria Fendt, Peter Carmeliet, Abhishek D. Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone
Journal: Nature Cancer (2024)

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y
Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk
Authors: Tiange Wang, Zhun Shi, Huahui Ren, Min Xu, Jieli Lu, Fangming Yang, Chaojie Ye, Kui Wu, Mingling Chen, Xun Xu, Dong Liu, Lijie Kong, Ruizhi Zheng, Jie Zheng, Mian Li, Yu Xu, Zhiyun Zhao, Yuhong Chen, Huanming Yang, Jian Wang, Guang Ning, Junhua Li, Huanzi Zhong, Yufang Bi, Weiqing Wang
Journal: Nature Medicine (2024)
Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease
Authors: Henry E Wiley, Ramaprasad Srinivasan, Jodi K Maranchie, Jay Chhablani, Ane Bundsbæk Bøndergaard Iversen, Anders Kruse, Eric Jonasch, Dan S Gombos, Tobias Else, Hakan Demirci, Benjamin L Maughan, M Elizabeth Hartnett, Hanna R Coleman, Wei Fu, Rodolfo F Perini, Yanfang Liu, W Marston Linehan, Emily Y Chew
Journal: Ophthalmology (2024)
Structural variant landscapes reveal convergent signatures of evolution in sheep and goats
Authors: Ji Yang, Dong-Feng Wang, Jia-Hui Huang, Qiang-Hui Zhu, Ling-Yun Luo, Ran Lu, Xing-Long Xie, Hosein Salehian-Dehkordi, Ali Esmailizadeh, George E. Liu, Meng-Hua Li
Journal: Genome biology (2024)

Abstract Background Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. Results We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B , BMPR2 , RALYL , COL21A1 , and LRP1B ) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B , with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. Conclusions Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.
Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management
Authors: Daniela Esposito, Cesar Luiz Boguszewski, Annamaria Colao, Maria Fleseriu, Federico Gatto, Jens Otto Lunde Jørgensen, Oskar Ragnarsson, Diego Ferone, Gudmundur Johannsson
Journal: Nature Reviews Endocrinology (2024)
Five decades of natural killer cell discovery
Authors: Lewis L. Lanier
Journal: The Journal of Experimental Medicine (2024)

The first descriptions of “non-specific” killing of tumor cells by lymphocytes were reported in 1973, and subsequently, the mediators of the activity were named “natural killer” (NK) cells by Rolf Kiessling and colleagues at the Karolinska Institute in 1975. The activity was detected in mice, rats, and humans that had no prior exposure to the tumors, major histocompatibility complex (MHC) antigen matching of the effectors and tumor cells was not required, and the cells responsible were distinct from MHC-restricted, antigen-specific T cells. In the ensuing five decades, research by many labs has extended knowledge of NK cells beyond an in vitro curiosity to demonstrate their in vivo relevance in host defense against tumors and microbial pathogens and their role in regulation of the immune system. This brief Perspective highlights a timeline of a few selected advancements in NK cell biology from a personal perspective of being involved in this quest.
Is Suffering a Useless Concept?
Authors: Ryan H. Nelson, Brent Kious, Emily Largent, Bryanna Moore, Jennifer Blumenthal-Barby
Journal: The American Journal of Bioethics (2024)

"Suffering" is a central concept within bioethics and often a crucial consideration in medical decision making. As used in practice, however, the concept risks being uninformative, ambiguous, or even misleading. In this paper, we consider a series of cases in which "suffering" is invoked and analyze them in light of prominent theories of suffering. We then outline ethical hazards that arise as a result of imprecise usage of the concept and offer practical recommendations for avoiding them. Appeals to suffering are often getting at something ethically important. But this is where the work of ethics begins, not where it ends.