tbuckley/cabot-search huggingface dataset:
Ebola Outbreak Response in the DRC with rVSV-ZEBOV-GP Ring Vaccination
Authors: Jean-Jacques Muyembe, Hongchao Pan, Richard Peto, Abdourahamane Diallo, Alhassane Touré, Placide Mbala-Kingebene, Stéphane H Bateyi Mustafa, Ndjoloko Tambwe, Sabue Mulangu, Steve Ahuka-Mundeke, Elisabeth Mukamba Musenga, Godwin Enwere, Pierre-Stéphane Gsell, Ira M Longini, Ximena Riveros Balta, Chrissy H Roberts, Michael Marks, Michel N K Yao, Abdou Salam Gueye, Ibrahima-Soce Fall, Peter Salama, Michael J Ryan, Ana Maria Henao-Restrepo
Journal: New England Journal of Medicine (2024)

BackgroundAt the beginning of the 2018–2020 outbreak of Ebola virus disease (EVD) in eastern Democratic Republic of Congo (DRC), no vaccine had been licensed. However, cluster-randomized evidence from Guinea in 2015 had indicated that ring vaccination around new cases (targeting contacts and contacts-of-contacts) with the use of single-dose live-replicating rVSV-ZEBOV-GP vaccine reduced EVD rates starting 10 days after vaccination. Thus, ring vaccination was added to the standard control measures for that outbreak.MethodsIn this study, we evaluated the incidence of EVD within the first 9 days after vaccination (when little protection was expected from case isolation or ring vaccination), during days 10 to 29, and at later time periods. We established 1853 rings around new cases or clusters within 21 days after symptom onset in the index case and offered vaccination to the ring members. Vaccinees were monitored for EVD onset until the end of the outbreak in mid-2020.ResultsFrom August 8, 2018, to January 14, 2020, we vaccinated 265,183 participants. Of these vaccinees, 102,515 were monitored on days 0, 3, and 21 for safety. Among the contacts and contacts-of-contacts, 434 cases of EVD (0.2 per ring) were diagnosed, almost all within 0 to 9 days (380 cases) or 10 to 29 days (32 cases) after vaccination. An additional 22 cases were diagnosed after day 29 during an average of 170 more days of follow-up. The sooner that control measures (including ring vaccination) began after EVD onset in the index case, the sooner EVD rates fell among contacts. In each subgroup, EVD rates fell suddenly around day 10. Among the contacts and contacts-of-contacts who were still disease-free at day 10, the EVD onset rate during days 10 to 29 was 0.16 per 1000 (in 32 of 194,019 participants). This rate was much lower than the rate of 4.64 per 1000 (in 21 of 4528 participants) that had been seen among similarly defined ring members in Guinea, in whom standard control measures had been promptly initiated but vaccination was delayed until 21 days after ring formation (rate ratio, 0.04; 95% confidence interval, 0.02 to 0.06). No safety concerns with the vaccine were identified.ConclusionsNonrandomized evidence regarding standard EVD control measures plus ring vaccination in eastern DRC reinforces the earlier randomized evidence from Guinea of vaccine efficacy against EVD onset 10 or more days after vaccination.
Levofloxacin Preventive Therapy for Persons Exposed to MDR Tuberculosis
Authors: Susan E Dorman
Journal: New England Journal of Medicine (2024)

The use of preventive tuberculosis treatment after Mycobacterium tuberculosis infection, historically with isoniazid and more recently with shorter-duration rifamycin regimens, is a core component of tuberculosis control in the United States and is increasingly being used in some tuberculosis-endemic areas.1 However, multidrug-resistant (MDR) tuberculosis, which is caused by M. tuberculosis resistant to isoniazid and rifampin, threatens efforts to control tuberculosis. Worldwide, most initiatives to address MDR tuberculosis have focused on disease diagnosis and treatment, resulting in important successes in these areas.2-5 Less has been done in the domain of chemoprevention after exposure to a person with MDR tuberculosis, despite evidence . . .
Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder
Authors: Min Xue, Shaoying Wang, Changjiang Li, Yuewei Wang, Ming Liu, Xiaoshan Huang, Gan Wang, Qikai Yin, Dandan Xiao, Shuo Yang, Musan Yan, Liyuan Niu, Muhammad Awais, Chuanbin Shen, Jianxun Wang, Ren Lai, Heyu Ni, Xiaopeng Tang
Journal: Blood (2024)

Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in thrombosis patients. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, FXIa, and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or intravenous administration promoted coagulation and hemostasis and aggravated thrombosis whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 min, respectively, resembling uncontrollable bleeding and clotting disorder seen in Hemophilia mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the crosstalk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.
Case 40-2024: A 56-Year-Old Woman with End-Stage Liver Disease and Headache
Authors: Shoshana J Herzig, Benjamin M Kozak, Camille N Kotton, Annemarie E Fogerty, Sarah E Turbett
Journal: New England Journal of Medicine (2024)

A 56-year-old woman with liver disease was admitted with headache, confusion, and abdominal tenderness. On hospital day 5, blurred vision in the right eye occurred. A diagnosis was made.
Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer
Authors: Joan Jacob, Yasuaki Anami, Peyton C. High, Zhengdong Liang, Shraddha Subramanian, Sukhen C. Ghosh, Solmaz AghaAmiri, Cara Guernsey-Biddle, Ha Tran, Julie Rowe, Ali Azhdarinia, Kyoji Tsuchikama, Kendra S. Carmon
Journal: Cancer Research (2024)

As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.
Effects of amoxicillin dosage on cure rate, gut microbiota, and antibiotic resistome in vonoprazan and amoxicillin dual therapy for Helicobacter pylori: a multicentre, open-label, non-inferiority randomised controlled trial
Authors: Yi Hu, Zhen-Yu Zhang, Fen Wang, Kun Zhuang, Xin Xu, Dong-Sheng Liu, Hui-Zhen Fan, Li Yang, Kui Jiang, De-Kui Zhang, Long Xu, Jian-Hua Tang, Xue-Mei Liu, Cong He, Xu Shu, Yong Xie, James Y W Lau, Yin Zhu, Yi-Qi Du, David Y Graham, Nong-Hua Lu
Journal: The Lancet Microbe (2024)
CLK1 Activates YAP to Promote Intrahepatic Cholangiocarcinogenesis
Authors: Shuai Xue, Xiangzheng Chen, Guoteng Qiu, Haotian Liao, Zeyuan Qiang, Zheng Zhang, Xuping Feng, Lin Xu, Rui Xie, Hongyu Zhou, Jiwei Huang, Yong Zeng, Haichuan Wang
Journal: Cancer Research (2024)

Abstract Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiological processes and has been shown to contribute to multiple types of cancer. Here, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients with high expression of CLK1 demonstrated poor prognosis. In hydrodynamically transfected mouse models, CLK1 alone was insufficient to induce ICC, whereas CLK1 cooperated with AKT (AKT/CLK1) to trigger ICC initiation. In addition, overexpression of CLK1 in ICC cells facilitated proliferation in vitro and tumor growth in vivo, while loss of CLK1 elicited the opposite effects. Moreover, RNAseq analysis indicated that high levels of CLK1 corresponded with activation of the Hippo-YAP signaling pathway. Consistently, the AKT/CLK1 murine tumors displayed upregulation of YAP as well as its downstream targets. Furthermore, loss or pharmacological inhibition YAP in ICC cells inhibited CLK1-induced growth, and deletion of Yap completely retarded the induction of AKT/CLK1 tumors. Mechanistically, 4D-label free mass spectrometry and co-immunoprecipitation assays revealed WWC2 as a potential mediator of CLK1-YAP cascade. Collectively, the current findings identify a critical role for CLK1 in promoting ICC development and indicate that inhibiting YAP might be an effective approach for perturbing CLK1-mediated tumorigenesis.
Immune responses to SARS-CoV-2 in sub-Saharan Africa and western Europe: a retrospective, population-based, cross-sectional study
Authors: Moustapha Mbow, Dennis Hoving, Marouba Cisse, Ibrahima Diallo, Yabo J Honkpehedji, Wesley Huisman, Cilia R Pothast, Marlieke L M Jongsma, Marion H König, Alicia C de Kroon, Le Thi Kieu Linh, Shohreh Azimi, Tamar Tak, Yvonne C M Kruize, Farid Kurniawan, Yacine Amet Dia, Jaimie L H Zhang, Corine Prins, Anna H E Roukens, Jutte J C de Vries, Linda J Wammes, Hermelijn H Smits, Ayola A Adegnika, Mihaela Zlei, Taco W Kuijpers, Luuk Wieske, Alioune Dieye, Souleymane Mboup, Peter G Kremsner, Filip Eftimov, Thirumalaisamy P Velavan, Ilana Berlin, Mirjam H M Heemskerk, Maria Yazdanbakhsh, Simon P Jochems
Journal: The Lancet Microbe (2024)
SurgeryLLM: a retrieval-augmented generation large language model framework for surgical decision support and workflow enhancement
Authors: Chin Siang Ong, Nicholas T. Obey, Yanan Zheng, Arman Cohan, Eric B. Schneider
Journal: npj Digital Medicine (2024)

Abstract SurgeryLLM, a large language model framework using Retrieval Augmented Generation demonstrably incorporated domain-specific knowledge from current evidence-based surgical guidelines when presented with patient-specific data. The successful incorporation of guideline-based information represents a substantial step toward enabling greater surgeon efficiency, improving patient safety, and optimizing surgical outcomes.
Abemaciclib Plus Fulvestrant in Advanced Breast Cancer Following Progression on CDK4/6 Inhibition: Results from the Phase III postMONARCH Trial
Authors: Kevin Kalinsky, Giampaolo Bianchini, Erika Hamilton, Stephanie L. Graff, Kyong Hwa Park, Rinath Jeselsohn, Miguel Martin, Rachel M. Layman, Sara A. Hurvitz, Sarah Sammons, Peter A. Kaufman, Montserrat Muñoz, Jiun-I Lai, Holly Knoderer, Cynthia Sandoval, Aarti R. Chawla, Bastien Nguyen, Yanhong Zhou, Elizabeth Ravenberg, Lacey M. Litchfield, Lillian Smyth, Seth A. Wander
Journal: Journal of Clinical Oncology (2024)

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.
The unique roles of family, friend, and online support in the psychological adjustment of transgender young adults
Authors: Will Curth, Lara Mayeux
Journal: International Journal of Transgender Health (2024)

Background Transgender youth are more likely than cisgender youth to encounter risk, such as a lack of social support from families and offline friends, leading many to turn to online friendships for social support. Feeling supported is crucial for psychological adjustment, measured in positive outcomes such as pride, self-esteem, and belongingness and in negative outcomes such as internalized transphobia, depression, and loneliness.
Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer
Authors: Yan Hu, Ze-Rong Cai, Ren-Ze Huang, De-Shen Wang, Huai-Qiang Ju, Dong-Liang Chen
Journal: Molecular Cancer (2024)
Patterns of genomic instability in &gt; 2000 patients with ovarian cancer across six clinical trials evaluating olaparib
Authors: Alan Barnicle, Isabelle Ray-Coquard, Etienne Rouleau, Karen Cadoo, Fiona Simpkins, Carol Aghajanian, Alexandra Leary, Andrés Poveda, Stephanie Lheureux, Eric Pujade-Lauraine, Benoit You, Jonathan Ledermann, Ursula Matulonis, Charlie Gourley, Kirsten M. Timms, Zhongwu Lai, Darren R. Hodgson, Cathy E. Elks, Simon Dearden, Coumaran Egile, Pierre Lao-Sirieix, Elizabeth A. Harrington, Jessica S. Brown
Journal: Genome Medicine (2024)
The UFMylation pathway is impaired in Alzheimer’s disease
Authors: Tingxiang Yan, Michael G. Heckman, Emily C. Craver, Chia-Chen Liu, Bailey D. Rawlinson, Xue Wang, Melissa E. Murray, Dennis W. Dickson, Nilufer Ertekin-Taner, Zhenkun Lou, Guojun Bu, Wolfdieter Springer, Fabienne C. Fiesel
Journal: Molecular Neurodegeneration (2024)

Abstract Background Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. Methods Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. Results Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. Conclusions There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.
Corrigendum to ‘MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC’ [Journal of Thoracic Oncology 19 Issue 3 (2024) 434-450]
Authors: Naoki Haratake, Hiroki Ozawa, Yoshihiro Morimoto, Nami Yamashita, Tatsuaki Daimon, Atrayee Bhattacharya, Keyi Wang, Ayako Nakashoji, Hideko Isozaki, Mototsugu Shimokawa, Chie Kikutake, Mikita Suyama, Asato Hashinokuchi, Kazuki Takada, Tomoyoshi Takenaka, Tomoharu Yoshizumi, Tetsuya Mitsudomi, Aaron N Hata, Donald Kufe
Journal: Journal of Thoracic Oncology (2024)
Incidence, risk factors, and epidemiological trends of tracheal cancer: a global analysis
Authors: Junjie Huang, Mingtao Chen, Lin Zhang, Xu Lin, Don Eliseo Lucero-Prisno, Claire Chenwen Zhong, Wanghong Xu, Zhi-Jie Zheng, Mellissa Withers, Martin C. S. Wong
Journal: Molecular Cancer (2024)
Advances in the Delivery, Activation and Therapeutics Applications of Bioorthogonal Prodrugs
Authors: Zhou Zhou, Yuanjun Sun, Jing Pang, Ya‐Qiu Long
Journal: Medicinal Research Reviews (2024)

Traditional prodrug strategies have been leveraged to overcome many inherent drawbacks of active native drugs in the drug research and development. However, endogenous stimuli such as specific microenvironment or enzymes are relied on to achieve the prodrug activation, resulting in unintended drug release and systemic toxicity. Alternatively, bioorthogonal cleavage reaction-enabled bioorthogonal prodrugs activation via exogenous triggers has emerged as a valuable approach, featuring spatiotemporally controlled drug release. Such bioorthogonal prodrug strategies would ensure targeted drug delivery and/or in situ generation, further circumventing systemic toxicity or premature elimination of active drugs. In recent years, metal-free bioorthogonal cleavage reactions with fast kinetics have boomed in the bioorthogonal prodrug design. Meanwhile, transition-metal-catalyzed and photocatalytic deprotection reactions have also been developed to trigger prodrug activation in biological systems. Besides traditional small molecule prodrugs, gasotransmitters have been successfully delivered to specific organelles or cells via bioorthogonal reactions, and nanosystems have been devised into bioorthogonal triggers as well. Herein, we present an overview of the latest advances in these bioorthogonally-uncaged prodrugs, focused on the delivery, activation and therapeutics applications.
Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity
Authors: Vaishali Bhardwaj, Zhi-Zhang Yang, Shahrzad Jalali, Jose C. Villasboas, Rekha Mudappathi, Junwen Wang, Prithviraj Mukherjee, Jonas Paludo, Xinyi Tang, Hyo Jin Kim, Jordan E. Krull, Kerstin Wenzl, Anne J. Novak, Patrizia Mondello, Stephen M. Ansell
Journal: Blood Cancer Journal (2024)

The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRlowCD11b+CD33+ MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM.
Estimation of minimal data sets sizes for machine learning predictions in digital mental health interventions
Authors: Kirsten Zantvoort, Barbara Nacke, Dennis Görlich, Silvan Hornstein, Corinna Jacobi, Burkhardt Funk
Journal: npj Digital Medicine (2024)

Abstract Artificial intelligence promises to revolutionize mental health care, but small dataset sizes and lack of robust methods raise concerns about result generalizability. To provide insights on minimal necessary data set sizes, we explore domain-specific learning curves for digital intervention dropout predictions based on 3654 users from a single study (ISRCTN13716228, 26/02/2016). Prediction performance is analyzed based on dataset size ( N = 100–3654), feature groups (F = 2–129), and algorithm choice (from Naive Bayes to Neural Networks). The results substantiate the concern that small datasets ( N ≤ 300) overestimate predictive power. For uninformative feature groups, in-sample prediction performance was negatively correlated with dataset size. Sophisticated models overfitted in small datasets but maximized holdout test results in larger datasets. While N = 500 mitigated overfitting, performance did not converge until N = 750–1500. Consequently, we propose minimum dataset sizes of N = 500–1000. As such, this study offers an empirical reference for researchers designing or interpreting AI studies on Digital Mental Health Intervention data.
Rapid and sustained response of stubborn guttate psoriasis to ustekinumab: A 52-week, two-center, one-arm, observational study
Authors: Liuyu Chen, Minjia Tan, Tao Li, Laiqiang Zhu, Changxu Han, Leying Liu, Zhenying Zhang
Journal: British Journal of Dermatology (2024)

Ustekinumab showed significant and prolonged efficacy in treating stubborn GP patients, particularly for those patients with SDD. The CARD14: rs11652075C>T may serve as a predictor of favorable treatment response.