tbuckley/cabot-search huggingface dataset:
pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy
Authors: Jianhua Zou, Zheng Li, Yang Zhu, Yucen Tao, Qing You, Fangfang Cao, Qinghe Wu, Min Wu, Junjie Cheng, Jianwei Zhu, Xiaoyuan Chen
Journal: Bioactive Materials (2024)

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O
Perinatal Depression and Risk of Suicidal Behavior
Authors: Hang Yu, Qing Shen, Emma Bränn, Yihui Yang, Anna Sara Oberg, Unnur Anna Valdimarsdóttir, Donghao Lu
Journal: JAMA Network Open (2024)

Suicidal ideation is common among women with perinatal depression (PND). However, prospective data are limited on the risk, particularly long-term risk, of suicidal behavior (suicide attempt and completed suicide) among women with perinatal depression.
Effect of Risk Mitigation Guidance for opioid and stimulant dispensations on mortality and acute care visits during dual public health emergencies: retrospective cohort study
Authors: Amanda Slaunwhite, Jeong Eun Min, Heather Palis, Karen Urbanoski, Bernie Pauly, Brittany Barker, Alexis Crabtree, Paxton Bach, Emmanuel Krebs, Laura Dale, Louise Meilleur, Bohdan Nosyk
Journal: BMJ (2024)

Abstract Objective To determine the effect of opioid and stimulant Risk Mitigation Guidance (RMG) dispensations on mortality and acute care visits during the dual public health emergencies of overdose and covid-19. Design Population based retrospective cohort study. Setting British Columbia, Canada. Participants 5882 people with opioid or stimulant use disorder who received RMG prescriptions for opioids (n=5356) and/or stimulants (n=1061) (535 received both) from 27 March 2020 to 31 August 2021. Main outcome measures All cause and overdose specific mortality and acute care visits in the week after RMG opioid or stimulant dispensation. RMG recipients were matched 1:1 with controls through use of high dimensional propensity score matching. Marginal structural models, executed on weekly time steps, were used to measure the effect of dispensations on outcomes. Results RMG opioid dispensations of one day or more were associated with reduced all cause mortality (adjusted hazard ratio 0.39, 95% confidence interval 0.25 to 0.60) and overdose related mortality (0.45, 0.27 to 0.75) in the subsequent week. Dispensations of RMG stimulants (≥1 days) were not significantly associated with reduced all cause mortality (adjusted hazard ratio 0.50, 0.20 to 1.23) or overdose related mortality (0.53, 0.18 to 1.56). The protective effect of RMG opioid dispensations increased with the number of days the medications were dispensed in a given week. People who received four or more days of RMG opioid dispensations had reduced all cause mortality (adjusted hazard ratio 0.09, 0.04 to 0.21) and overdose related mortality (0.11, 0.04 to 0.32) compared with the control group. Opioid RMG dispensations did not significantly modify the odds of all cause or overdose related acute care visits. Dispensations of RMG stimulants were associated with a significant decrease in the odds of acute care visits for any cause but did not affect the odds of overdose related acute care visits. Conclusions RMG opioid dispensations were associated with reduced overdose related and all cause mortality among a sample of people with opioid use disorder. Pharmaceutical alternatives to the illegal drug supply are promising interventions to reduce mortality in people with opioid use disorder.
Undisclosed financial conflicts of interest in DSM-5-TR: cross sectional analysis
Authors: Lauren C Davis, Alexa T Diianni, Sydney R Drumheller, Noha N Elansary, Gianna N D’Ambrozio, Farahdeba Herrawi, Brian J Piper, Lisa Cosgrove
Journal: BMJ (2024)

Abstract Objective To assess the extent and types of financial ties to industry of panel and task force members of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders , fifth edition, text revision (DSM-5-TR), published in 2022. Design Cross sectional analysis. Setting Open Payments database, USA. Participants 92 physicians based in the US who served as members of either a panel (n=86) or task force (n=6) on the DSM-5-TR with information recorded in the Centers for Medicare and Medicaid Services Open Payments database during 2016-19. This period was chosen to include the year that development of the DSM-5-TR began and the three years preceding, a time consistent with previous research on conflicts of interest and consistent with the American Psychiatric Association’s disclosure requirements for the fifth revision (DSM-5) of the manual. Main outcome measures Type and amount of compensation the panel and task force members of DSM-5-TR received during 2016-19. Results After duplicate names had been removed, 168 individuals were identified who served as either panel or task force members of the DSM-5-TR. 92 met the inclusion criteria of being a physician who was based in the US and therefore could be included in Open Payments. Of these 92 individuals, 55 (60%) received payments from industry. Collectively, these panel members received a total of $14.2m (£11.2m; €13m). One third (33.3%) of the task force members had payments reported in Open Payments. Conclusions Conflicts of interest among panel members of DSM-5-TR were prevalent. Because of the enormous influence of diagnostic and treatment guidelines, the standards for participation on a guideline development panel should be high. A rebuttable presumption should exist for the Diagnostic and Statistical Manual of Mental Disorders to prohibit conflicts of interest among its panel and task force members. When no independent individuals with the requisite expertise are available, individuals with associations to industry could consult to the panels, but they should not have decision making authority on revisions or the inclusion of new disorders.
Efficacy of three benznidazole dosing strategies for adults living with chronic Chagas disease (MULTIBENZ): an international, randomised, double-blind, phase 2b trial
Authors: Pau Bosch-Nicolau, Marisa L Fernández, Elena Sulleiro, Juan Carlos Villar, José A Perez-Molina, Rodrigo Correa-Oliveira, Sergio Sosa-Estani, Adrián Sánchez-Montalvá, Maria del Carmen Bangher, Otacilio C Moreira, Fernando Salvador, Ariela Mota Ferreira, Silvana Maria Eloi-Santos, Núria Serre-Delcor, Juan Carlos Ramírez, Aroa Silgado, Inés Oliveira, Oihane Martín, Maria Luisa Aznar, Antonio Luiz P Ribeiro, Paulo Emilio Clementino Almeida, Sandra Chamorro-Tojeiro, Juan Espinosa-Pereiro, Alfredo Mauricio Batista de Paula, Eliana Váquiro-Herrera, Carmen Tur, Israel Molina
Journal: The Lancet Infectious Diseases (2024)
Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial
Authors: Maria-Jesus Pinazo, Colin Forsyth, Irene Losada, Elena Trigo Esteban, Magdalena García-Rodríguez, Maria Luz Villegas, Israel Molina, Clara Crespillo-Andújar, Montserrat Gállego, Cristina Ballart, Juan Carlos Ramirez, Tilman Aden, Achim Hoerauf, Kenneth Pfarr, Michel Vaillant, Tayná Marques, Jayme Fernandes, Bethania Blum, Isabela Ribeiro, Sergio Sosa-Estani, Fabiana Barreira, Joaquim Gascón
Journal: The Lancet Infectious Diseases (2024)
Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme
Authors: Alona Sosinsky, John Ambrose, William Cross, Clare Turnbull, Shirley Henderson, Louise Jones, Angela Hamblin, Prabhu Arumugam, Georgia Chan, Daniel Chubb, Boris Noyvert, Jonathan Mitchell, Susan Walker, Katy Bowman, Dorota Pasko, Marianna Buongermino Pereira, Nadezda Volkova, Antonio Rueda-Martin, Daniel Perez-Gil, Javier Lopez, John Pullinger, Afshan Siddiq, Tala Zainy, Tasnim Choudhury, Olena Yavorska, Tom Fowler, David Bentley, Clare Kingsley, Sandra Hing, Zandra Deans, Augusto Rendon, Sue Hill, Mark Caulfield, Nirupa Murugaesu
Journal: Nature Medicine (2024)

Abstract The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.
Improved prediction of bacterial CRISPRi guide efficiency from depletion screens through mixed-effect machine learning and data integration
Authors: Yanying Yu, Sandra Gawlitt, Lisa Barros de Andrade e Sousa, Erinc Merdivan, Marie Piraud, Chase L. Beisel, Lars Barquist
Journal: Genome biology (2024)

Abstract CRISPR interference (CRISPRi) is the leading technique to silence gene expression in bacteria; however, design rules remain poorly defined. We develop a best-in-class prediction algorithm for guide silencing efficiency by systematically investigating factors influencing guide depletion in genome-wide essentiality screens, with the surprising discovery that gene-specific features substantially impact prediction. We develop a mixed-effect random forest regression model that provides better estimates of guide efficiency. We further apply methods from explainable AI to extract interpretable design rules from the model. This study provides a blueprint for predictive models for CRISPR technologies where only indirect measurements of guide activity are available.
Synthetic Particulate Subunit Vaccines for the Prevention of Q Fever
Authors: Gayathri Sam, Karren Plain, Shuxiong Chen, Aminul Islam, Mark E. Westman, Ian Marsh, John Stenos, Stephen R. Graves, Bernd H. A. Rehm
Journal: Advanced Healthcare Materials (2024)

Coxiella burnetti is an intracellular bacterium that causes Q fever, a disease of worldwide importance. Q-VAX
Perinatal depression and risk of mortality: nationwide, register based study in Sweden
Authors: Naela Hagatulah, Emma Bränn, Anna Sara Oberg, Unnur A Valdimarsdóttir, Qing Shen, Donghao Lu
Journal: BMJ (2024)

To determine whether women with perinatal depression are at an increased risk of death compared with women who did not develop the disorder, and compared with full sisters.
Artificial intelligence-based models enabling accurate diagnosis of ovarian cancer using laboratory tests in China: a multicentre, retrospective cohort study
Authors: Guangyao Cai, Fangjun Huang, Yue Gao, Xiao Li, Jianhua Chi, Jincheng Xie, Linghong Zhou, Yanling Feng, He Huang, Ting Deng, Yun Zhou, Chuyao Zhang, Xiaolin Luo, Xing Xie, Qinglei Gao, Xin Zhen, Jihong Liu
Journal: The Lancet Digital Health (2024)

Ovarian cancer is the most lethal gynecological malignancy. Timely diagnosis of ovarian cancer is difficult due to the lack of effective biomarkers. Laboratory tests are widely applied in clinical practice, and some have shown diagnostic and prognostic relevance to ovarian cancer. We aimed to systematically evaluate the value of routine laboratory tests on the prediction of ovarian cancer, and develop a robust and generalisable ensemble artificial intelligence (AI) model to assist in identifying patients with ovarian cancer.
Bioengineering and vascularization strategies for islet organoids: advancing toward diabetes therapy
Authors: Jing Yang, Yuxin Yan, Xiya Yin, Xiangqi Liu, Igor V. Reshetov, Pavel A. Karalkin, Qingfeng Li, Ru-Lin Huang
Journal: Metabolism (2024)

Diabetes presents a pressing healthcare crisis, necessitating innovative solutions. Organoid technologies have rapidly advanced, leading to the emergence of bioengineering islet organoids as an unlimited source of insulin-producing cells for treating insulin-dependent diabetes. This advancement surpasses the need for cadaveric islet transplantation. However, clinical translation of this approach faces two major limitations: immature endocrine function and the absence of a perfusable vasculature compared to primary human islets. In this review, we summarize the latest developments in bioengineering functional islet organoids in vitro and promoting vascularization of organoid grafts before and after transplantation. We highlight the crucial roles of the vasculature in ensuring long-term survival, maturation, and functionality of islet organoids. Additionally, we discuss key considerations that must be addressed before clinical translation of islet organoid-based therapy, including functional immaturity, undesired heterogeneity, and potential tumorigenic risks.
Insights into Targeted and Stimulus‐Responsive Nanocarriers for Brain Cancer Treatment
Authors: Zahra Abousalman‐Rezvani, Ahmed Refaat, Pouya Dehghankelishadi, Hossein Roghani‐Mamaqani, Lars Esser, Nicolas H. Voelcker
Journal: Advanced Healthcare Materials (2024)

Abstract Brain cancers, especially glioblastoma multiforme, are associated with poor prognosis due to the limited efficacy of current therapies. Nanomedicine has emerged as a versatile technology to treat various diseases, including cancers, and has played an indispensable role in combatting the COVID‐19 pandemic as evidenced by the role that lipid nanocarrier‐based vaccines have played. The tunability of nanocarrier physicochemical properties —including size, shape, surface chemistry, and drug release kinetics— has resulted in the development of a wide range of nanocarriers for brain cancer treatment. These nanocarriers can improve the pharmacokinetics of drugs, increase blood‐brain barrier transfer efficiency, and specifically target brain cancer cells. These unique features would potentially allow for more efficient treatment of brain cancer with fewer side effects and better therapeutic outcomes. This review provides an overview of brain cancers, current therapeutic options, and challenges to efficient brain cancer treatment. The latest advances in nanomedicine strategies are investigated with an emphasis on targeted and stimulus‐responsive nanocarriers and their potential for clinical translation.
Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study
Authors: Mike M Sathekge, Ismaheel O Lawal, Chandrasekhar Bal, Frank Bruchertseifer, Sajana Ballal, Giuseppe Cardaci, Cindy Davis, Mathias Eiber, Türkay Hekimsoy, Otto Knoesen, Clemens Kratochwil, Nat P Lenzo, Johncy Mahapane, Letjie C Maserumule, Amanda H Mdlophane, Kgomotso M G Mokoala, Honest Ndlovu, Vineet Pant, Hendrik Rathke, Janet Reed, Ishita B Sen, Aviral Singh, Ashwani Sood, Robert Tauber, Parul Thakral, Madhav Prasad Yadav, Alfred Morgenstern
Journal: The Lancet Oncology (2024)
High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT
Authors: Lang Bu, Zhengkun Zhang, Jianwen Chen, Yizeng Fan, Jinhe Guo, Yaqing Su, Huan Wang, Xiaomei Zhang, Xueji Wu, Qiwei Jiang, Bing Gao, Lei Wang, Kunpeng Hu, Xiang Zhang, Wei Xie, Wenyi Wei, Ming Kuang, Jianping Guo
Journal: Gut (2024)

Objective Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. Design Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1 C77S and AKT1 C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1 C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. Results By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. Conclusions Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
A comparison of 1550-nm fractional photothermolysis versus intense focused ultrasound for treatment of periorbital wrinkles: a randomized control trial
Authors: Eric Koza, Melissa S. Ma, Areeba Ahmed, Misha Haq, Victoria J. Shi, Dennis Whiting, Kapila Paghdal, Alexandra Weil, Nataya Voravutinon, Wanjarus Roongpisuthipong, Emily Poon, Murad Alam
Journal: Journal of the American Academy of Dermatology (2024)
Abstract B019: BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response
Authors: Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Aravind Krishnan, Youngho Kwon, Patrick Sung, Roger Greenberg
Journal: Cancer Research (2024)

Abstract Alternative Lengthening of Telomeres (ALT) is a homology-directed repair (HDR) mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. ALT cells exhibit more endogenous replication stress and DNA damage at the telomere compared to ALT-negative cells. The Bloom Syndrome helicase (BLM) is critical for ALT and promotes replication stress and DNA damage specifically at telomeres in ALT cells. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication stress-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2 commensurate with the appearance of telomere C-strand specific single-stranded DNA. Moreover, DNA2 nuclease deficiency increased 5’-flap formation in a BLM-dependent manner, and BLM promoted ALT in response to telomere C-strand, but not G-strand, nicks. These findings define the seminal events in the ALT DNA damage response, linking aberrant lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers (Jiang et al. submitted). These findings will be discussed and how BLM activity is a key determinant of the specific vulnerability of ALT cells to FANCM inhibition, which is currently being developed to target ALT-dependent cancers. Citation Format: Haoyang Jiang, Tianpeng Zhang, Hardeep Kaur, Tao Shi, Aravind Krishnan, Youngho Kwon, Patrick Sung, Roger Greenberg. BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B019.
Opportunities and limitations of genomics for diagnosing bedaquiline-resistant tuberculosis: a systematic review and individual isolate meta-analysis
Authors: Camus Nimmo, Neda Bionghi, Matthew J Cummings, Rubeshan Perumal, Madeleine Hopson, Shamim Al Jubaer, Kogieleum Naidoo, Allison Wolf, Barun Mathema, Michelle H Larsen, Max O’Donnell
Journal: The Lancet Microbe (2024)

BackgroundClinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship with phenotypic Mycobacterium tuberculosis resistance. We did a systematic review to assess the maximal sensitivity of sequencing bedaquiline resistance-associated genes and evaluate the association between RAVs and phenotypic resistance, using traditional and machine-based learning techniques.MethodsWe screened public databases for articles published from database inception until Oct 31, 2022. Eligible studies performed sequencing of at least mmpR5 and atpE on clinically sourced M tuberculosis isolates and measured bedaquiline minimum inhibitory concentrations (MICs). A bias risk scoring tool was used to identify bias. Individual genetic mutations and corresponding MICs were aggregated, and odds ratios calculated to determine association of mutations with resistance. Machine-based learning methods were used to define test characteristics of parsimonious sets of diagnostic RAVs, and mmpR5 mutations were mapped to the protein structure to highlight mechanisms of resistance. This study was registered in the PROSPERO database (CRD42022346547).Findings18 eligible studies were identified, comprising 975 M tuberculosis isolates containing at least one potential RAV (mutation in mmpR5, atpE, atpB, or pepQ), with 201 (20·6%) showing phenotypic bedaquiline resistance. 84 (29·5%) of 285 resistant isolates had no candidate gene mutation. Sensitivity and positive predictive value of taking an any mutation approach was 69% and 14%, respectively. 13 mutations, all in mmpR5, had a significant association with a resistant MIC (adjusted p<0·05). Gradient-boosted machine classifier models for predicting intermediate or resistant and resistant phenotypes both had receiver operator characteristic c statistic of 0·73 (95% CI 0·70–0·76). Frameshift mutations clustered in the α1 helix DNA-binding domain, and substitutions in the α2 and α3 helix hinge region and in the α4 helix-binding domain.InterpretationSequencing candidate genes is insufficiently sensitive to diagnose clinical bedaquiline resistance, but where identified, some mutations should be assumed to be associated with resistance. Genomic tools are most likely to be effective in combination with rapid phenotypic diagnostics. This study was limited by selective sampling in contributing studies and only considering single genetic loci as causative of resistance.FundingFrancis Crick Institute and National Institute of Allergy and Infectious Diseases at the National Institutes of Health.