tbuckley/cabot-search huggingface dataset:
Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer
Authors: Matthew D. Galsky, Xiangnan Guan, Deepali Rishipathak, Aaron S. Rapaport, Hesham M. Shehata, Romain Banchereau, Kobe Yuen, Eugene Varfolomeev, Ruozhen Hu, Chia-Jung Han, Haocheng Li, Yuxin Liang, Domagoj Vucic, Li Wang, Jun Zhu, Haocheng Yu, Rebecca H. Herbst, Emma Hajaj, Evgeny Kiner, Aristotelis Bamias, Maria De Santis, Ian D. Davis, José Ángel Arranz, Eiji Kikuchi, Sandrine Bernhard, Patrick Williams, Chooi Lee, Ira Mellman, Shomyseh Sanjabi, Robert Johnston, Peter C. Black, Enrique Grande, Sanjeev Mariathasan
Journal: Cell Reports Medicine (2024)

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.
Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study
Authors: Hajime Yamazaki, Samantha A. Streicher, Lang Wu, Shunichi Fukuhara, Róbert Wagner, Martin Heni, Steven R. Grossman, Heinz-Josef Lenz, Veronica Wendy Setiawan, Loïc Le Marchand, Brian Z. Huang
Journal: Cell Reports Medicine (2024)

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60–7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10−8) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38–4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidence for a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.
New advances in type 1 diabetes
Authors: Savitha Subramanian, Farah Khan, Irl B Hirsch
Journal: BMJ (2024)

ABSTRACT Type 1 diabetes is an autoimmune condition resulting in insulin deficiency and eventual loss of pancreatic β cell function requiring lifelong insulin therapy. Since the discovery of insulin more than 100 years ago, vast advances in treatments have improved care for many people with type 1 diabetes. Ongoing research on the genetics and immunology of type 1 diabetes and on interventions to modify disease course and preserve β cell function have expanded our broad understanding of this condition. Biomarkers of type 1 diabetes are detectable months to years before development of overt disease, and three stages of diabetes are now recognized. The advent of continuous glucose monitoring and the newer automated insulin delivery systems have changed the landscape of type 1 diabetes management and are associated with improved glycated hemoglobin and decreased hypoglycemia. Adjunctive therapies such as sodium glucose cotransporter-1 inhibitors and glucagon-like peptide 1 receptor agonists may find use in management in the future. Despite these rapid advances in the field, people living in under-resourced parts of the world struggle to obtain necessities such as insulin, syringes, and blood glucose monitoring essential for managing this condition. This review covers recent developments in diagnosis and treatment and future directions in the broad field of type 1 diabetes.
Lineage and ecology define liver tumor evolution in response to treatment
Authors: Mahler Revsine, Limin Wang, Marshonna Forgues, Shay Behrens, Amanda J. Craig, Meng Liu, Bao Tran, Michael Kelly, Anuradha Budhu, Cecilia Monge, Changqing Xie, Jonathan M. Hernandez, Tim F. Greten, Xin Wei Wang, Lichun Ma
Journal: Cell Reports Medicine (2024)

A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.
Virological characteristics of the SARS-CoV-2 BA.2.86 variant
Authors: Tomokazu Tamura, Keita Mizuma, Hesham Nasser, Sayaka Deguchi, Miguel Padilla-Blanco, Yoshitaka Oda, Keiya Uriu, Jarel E.M. Tolentino, Shuhei Tsujino, Rigel Suzuki, Isshu Kojima, Naganori Nao, Ryo Shimizu, Lei Wang, Masumi Tsuda, Michael Jonathan, Yusuke Kosugi, Ziyi Guo, Alfredo A. Hinay, Olivia Putri, Yoonjin Kim, Yuri L. Tanaka, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Akatsuki Saito, Jumpei Ito, Takashi Irie, Shinya Tanaka, Jiri Zahradnik, Terumasa Ikeda, Kazuo Takayama, Keita Matsuno, Takasuke Fukuhara, Kei Sato
Journal: Cell Host & Microbe (2024)

In late 2023, several SARS-CoV-2 XBB descendants, notably EG.5.1, were predominant worldwide. However, a distinct SARS-CoV-2 lineage, the BA.2.86 variant, also emerged. BA.2.86 is phylogenetically distinct from other Omicron sublineages, accumulating over 30 amino acid mutations in its spike protein. Here, we examined the virological characteristics of the BA.2.86 variant. Our epidemic dynamics modeling suggested that the relative reproduction number of BA.2.86 is significantly higher than that of EG.5.1. Additionally, four clinically available antivirals were effective against BA.2.86. Although the fusogenicity of BA.2.86 spike is similar to that of the parental BA.2 spike, the intrinsic pathogenicity of BA.2.86 in hamsters was significantly lower than that of BA.2. Since the growth kinetics of BA.2.86 are significantly lower than those of BA.2 both in vitro and in vivo, the attenuated pathogenicity of BA.2.86 is likely due to its decreased replication capacity. These findings uncover the features of BA.2.86, providing insights for control and treatment.
Monoclonal antibody therapy protects nonhuman primates against mucosal exposure to Lassa virus
Authors: Robert W. Cross, Karla A. Fenton, Courtney Woolsey, Abhishek N. Prasad, Viktoriya Borisevich, Krystle N. Agans, Daniel J. Deer, Natalie S. Dobias, Alyssa C. Fears, Megan L. Heinrich, Joan B. Geisbert, Robert F. Garry, Luis M. Branco, Thomas W. Geisbert
Journal: Cell Reports Medicine (2024)

Lassa fever (LF) is an acute viral illness that causes thousands of deaths annually in West Africa. There are currently no Lassa virus (LASV) vaccines or antivirals approved for human use. Recently, we showed that combinations of broadly neutralizing human monoclonal antibodies (BNhuMAbs) known as Arevirumab-2 or Arevirumab-3 protected up to 100% of cynomolgus macaques against challenge with diverse lineages of LASV when treatment was initiated at advanced stages of disease. This previous work assessed efficacy against parenteral exposure. However, transmission of LASV to humans occurs primarily by mucosal exposure to virus shed from Mastomys rodents. Here, we describe the development of a lethal intranasal exposure macaque model of LF. This model is employed to show that Arevirumab cocktails rescue 100% of macaques from lethal LASV infection when treatment is initiated 8 days after LASV exposure. Our work demonstrates BNhuMAbs have utility in treating LASV infection acquired through mucosal exposure.
Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk
Authors: Takumi Nakamura, Junko Ueda, Shota Mizuno, Kurara Honda, An-a Kazuno, Hirona Yamamoto, Tomonori Hara, Atsushi Takata
Journal: Cell Genomics (2024)

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.
Error in Byline
Journal: JAMA (2024)

Charles L. Raison, MD; Gerard Sanacora, MD, PhD; Joshua Woolley, MD, PhD; Keith Heinzerling, MD; Boadie W. Dunlop, MD, MS; Randall T. Brown, MD, PhD; Rishi Kakar, MD; Michael Hassman, DO; Rupal P. Trivedi, MD; Reid Robison, MD; Natalie Gukasyan, MD; Sandeep M. Nayak, MD; Xiaojue Hu, MD; Kelley C. O’Donnell, MD, PhD; Benjamin Kelmendi, MD; Jordan Sloshower, MD, MSc; Andrew D. Penn, RN, MS, NP; Ellen Bradley, MD; Daniel F. Kelly, MD; Tanja Mletzko, MA; Christopher R. Nicholas, PhD; Paul R. Hutson, PharmD; Gary Tarpley, PhD; Malynn Utzinger, MD; Kelsey Lenoch, BS; Kasia Warchol, BS; Theraysa Gapasin, MS, aMFT; Mike C. Davis, MD, PhD; Courtney Nelson-Douthit, BS; Steffanie Wilson, PhD; Carrie Brown, MA; William Linton, BS; Matthew W. Johnson, PhD; Stephen Ross, MD; Roland R. Griffiths, PhD
Reducing Barriers and Improving Motivations of Students Enrolled in Summer Health Professions Exposure Programs
Authors: Leila Amiri, Will Ross
Journal: JAMA Network Open (2024)

Patricia Xirau-Probert, PhD; Tram Lai, BS, BA; Erik Black, PHD, MPH; Dany Fanfan, PhD, MSN, RN; Amy Blue, PhD; Caronne C. Rush, MSM, MEd, EdS; Rachel Powers, BA, BEd; Jeanne-Marie R. Stacciarini, RN, PhD
Pan-Cancer Comparative and Integrative Analyses of Driver Alterations Using Japanese and International Genomic Databases
Authors: Sara Horie, Yuki Saito, Yasunori Kogure, Kota Mizuno, Yuta Ito, Mariko Tabata, Takanori Kanai, Koichi Murakami, Junji Koya, Keisuke Kataoka
Journal: Cancer Discovery (2024)

Abstract Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with White patients in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asian patients across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data reveals many cooccurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently cooccur with PI3K pathway molecules. Furthermore, we found significant cooccurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations of not only the same but also different epigenetic drivers. Our analyses dissect various genetic properties and provide valuable resources for precision medicine in cancer. Significance: We present a genetic landscape of 26 principal cancer types/subtypes, including Asian-prevalent ones, in Japanese patients. Multicohort data integration unveils numerous cooccurring and exclusive relationships between driver mutations, identifying cooccurrence of multiple mutations in epigenetic regulators, which coordinately cause transcriptional and phenotypic changes. These findings provide insights into epigenetic regulator–driven oncogenesis. This article is featured in Selected Articles from This Issue, p. 695
Metal natural product complex Ru-procyanidins with quadruple enzymatic activity combat infections from drug-resistant bacteria
Authors: Jie Shan, Xu Jin, Cong Zhang, Muchen Huang, Jianghao Xing, Qingrong Li, Yuyu Cui, Qiang Niu, Xu Lin Chen, Xianwen Wang
Journal: Acta Pharmaceutica Sinica B (2024)

Bacterial infection hampers wound repair by impeding the healing process. Concurrently, inflammation at the wound site triggers the production of reactive oxygen species (ROS), causing oxidative stress and damage to proteins and cells. This can lead to chronic wounds, posing severe risks. Therefore, eliminating bacterial infection and reducing ROS levels are crucial for effective wound healing. Nanozymes, possessing enzyme-like catalytic activity, can convert endogenous substances into highly toxic substances, such as ROS, to combat bacteria and biofilms without inducing drug resistance. However, the current nanozyme model with single enzyme activity falls short of meeting the complex requirements of antimicrobial therapy. Thus, developing nanozymes with multiple enzymatic activities is essential. Herein, we engineered a novel metalloenzyme called Ru-procyanidin nanoparticles (Ru-PC NPs) with diverse enzymatic activities to aid wound healing and combat bacterial infections. Under acidic conditions, due to their glutathione (GSH) depletion and peroxidase (POD)-like activity, Ru-PC NPs combined with H2O2 exhibit excellent antibacterial effects. However, in a neutral environment, the Ru-PC NPs, with catalase (CAT) activity, decompose H2O2 to O2, alleviating hypoxia and ensuring a sufficient oxygen supply. Furthermore, Ru-PC NPs possess exceptional antioxidant capacity through their superior superoxide dismutase (SOD) enzyme activity, effectively scavenging excess ROS and reactive nitrogen species (RNS) in a neutral environment. This maintains the balance of the antioxidant system and prevents inflammation. Ru-PC NPs also promote the polarization of macrophages from M1 to M2, facilitating wound healing. More importantly, Ru-PC NPs show good biosafety with negligible toxicity. In vivo wound infection models have confirmed the efficacy of Ru-PC NPs in inhibiting bacterial infection and promoting wound healing. The focus of this work highlights the quadruple enzymatic activity of Ru-PC NPs and its potential to reduce inflammation and promote bacteria-infected wound healing.
SRT-Server: powering the analysis of spatial transcriptomic data
Authors: Sheng Yang, Xiang Zhou
Journal: Genome Medicine (2024)

Abstract Background Spatial resolved transcriptomics (SRT) encompasses a rapidly developing set of technologies that enable the measurement of gene expression in tissue while retaining spatial localization information. SRT technologies and the enabled SRT studies have provided unprecedent insights into the structural and functional underpinnings of complex tissues. As SRT technologies have advanced and an increasing number of SRT studies have emerged, numerous sophisticated statistical and computational methods have been developed to facilitate the analysis and interpretation of SRT data. However, despite the growing popularity of SRT studies and the widespread availability of SRT analysis methods, analysis of large-scale and complex SRT datasets remains challenging and not easily accessible to researchers with limited statistical and computational backgrounds. Results Here, we present SRT-Server, the first webserver designed to carry out comprehensive SRT analyses for a wide variety of SRT technologies while requiring minimal prior computational knowledge. Implemented with cutting-edge web development technologies, SRT-Server is user-friendly and features multiple analytic modules that can perform a range of SRT analyses. With a flowchart-style interface, these different analytic modules on the SRT-Server can be dragged into the main panel and connected to each other to create custom analytic pipelines. SRT-Server then automatically executes the desired analyses, generates corresponding figures, and outputs results—all without requiring prior programming knowledge. We demonstrate the advantages of SRT-Server through three case studies utilizing SRT data collected from two common platforms, highlighting its versatility and values to researchers with varying analytic expertise. Conclusions Overall, SRT-Server presents a user-friendly, efficient, effective, secure, and expandable solution for SRT data analysis, opening new doors for researchers in the field. SRT-Server is freely available at https://spatialtranscriptomicsanalysis.com/ .
Self‐Assembled Nanocomposite Hydrogels as Carriers for Demineralized Bone Matrix Particles and Enhanced Bone Repair
Authors: Chen Chen, Zhi Li, Changlu Xu, Minjee Kang, Chung‐Sung Lee, Tara Aghaloo, Min Lee
Journal: Advanced Healthcare Materials (2024)

Demineralized bone matrix (DBM) has been widely used as an allogeneic alternative to autologous bone graft for bone repair. However, more extensive use of DBM is limited due to its particulate nature after demineralization and rapid particle dispersion following irrigation, resulting in unpredictable osteoinductivity. Here, a new design of injectable hydrogel carriers for DBM that combine self-healing ability and osteogenic properties based on the self-assembly of guanidinylated hyaluronic acid and silica-rich nanoclays is reported. The nanoclays serve as reversible linkages to form a dynamic hydrogel network with the guanidine moieties on the polymer chains. Gelation kinetics and mechanical properties can be controlled by altering nanoclay content in the hydrogel. The resulting hydrogel exerts self-healing ability due to its dynamic crosslinks and well retains its overall performance with high DBM loading. The hydrogel exhibits great cytocompatibility and osteogenic effects mediated by the nanoclays. In vivo delivery of DBM using the nanocomposite hydrogel further demonstrates robust bone regeneration in a mouse calvarial defect model in comparison to DBM delivered with aqueous HA. This work suggests a promising hydrogel platform for many applications including therapeutic delivery and tissue engineering.
Authors’ response: Added value of backward contact tracing for COVID-19
Authors: Timo Louis Boelsums, Maaike Buskermolen
Journal: Eurosurveillance (2024)

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Re-emergence of human leishmaniasis in northern Italy, 2004 to 2022: a retrospective analysis
Authors: Renato Todeschini, Muriel Assunta Musti, Paolo Pandolfi, Mattea Troncatti, Morena Baldini, Davide Resi, Silvano Natalini, Federica Bergamini, Giorgio Galletti, Annalisa Santi, Arianna Rossi, Gianluca Rugna, Bianca Granozzi, Luciano Attard, Valeria Gaspari, Giovanna Liguori, Margherita Ortalli, Stefania Varani
Journal: Eurosurveillance (2024)

Background Human leishmaniasis is a protozoan disease transmitted by sand flies and endemic in the Mediterranean region. In Italy, leishmaniasis is present in the south and the western coastal regions, with an epidemic peak detected in northern Italy in the early 1970s. Aim To examine temporal trends, and demographic, clinical, geographical and environmental features of human leishmaniasis cases recorded by the local health unit (LHU) of Bologna, northern Italy. Methods In this retrospective observational study, we analysed human leishmaniasis cases recorded from 2004 to 2022 within the Bologna LHU. We also conducted serological investigations for canine leishmaniasis in owned dogs living near the place of infection of human cases. Results In total, 173 cases of human leishmaniasis were detected, and 154 cases were considered autochthonous. An increase of human cases was observed since 2004, with incidence peaks above 2 cases/100,000 inhabitants in 2013, 2018 and 2022; epidemic peaks were preceded by dry summers. Most cases lived in the plain and hilly areas less than 400 m above sea level and many resided in isolated housing, in city outskirts, and/or near uncultivated areas, watercourses and railway sections. The incidence of canine leishmaniasis did not increase in the study period. Conclusion An epidemic of human leishmaniasis with fluctuating annual numbers of cases, probably related to environmental and climatic factors, was identified in the Bologna LHU. Understanding the risk factors and the environmental characteristics related to places of infection is crucial to evaluate the public health implications of leishmaniasis.
Letter to the editor: Added value of backward contact tracing for COVID-19
Authors: Graham Fraser, Gareth Hughes, Simon Packer, Obaghe Edeghere, Isabel Oliver
Journal: Eurosurveillance (2024)

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Increased incidence of Mycoplasma pneumoniae infections and hospital admissions in the Netherlands, November to December 2023
Authors: Dita C Bolluyt, Sjoerd M Euser, Dennis Souverein, Annemarie MC van Rossum, Jayant Kalpoe, Mireille van Westreenen, Marco Goeijenbier, Dominic Snijders, Dirk Eggink, Femke Jongenotter, Steven FL van Lelyveld, Marlies A van Houten
Journal: Eurosurveillance (2024)

Mycoplasma pneumoniae is an important cause of pneumonia and extra-pulmonary manifestations. We observed a rise in admissions due to M. pneumoniae infections starting October 2023 in a regional hospital in the Netherlands and an increased incidence in national surveillance data. The incidence in the Netherlands has not been that high since 2011. The patients had a lower median age compared with 2019 and 2020 (28 vs 40 years). M. pneumoniae should be considered in patients with respiratory symptoms, especially children.