tbuckley/cabot-search huggingface dataset:
Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression
Authors: Yingyong Zhou, Zhihong Bai, Wenchao Zhang, Shouyu Xu, Yunfei Feng, Qiuwen Li, Lishan Li, Anqi Ping, Liang Chen, Saiying Wang, Kaiming Duan
Journal: JAMA Network Open (2024)

Importance Postpartum depression (PPD) is emerging as a major public health problem worldwide. Although the particular period and context in which PPD occurs provides an opportunity for preventive interventions, there is still a lack of pharmacologic prevention strategies for PPD. Objective To assess the efficacy and safety of dexmedetomidine for prevention of PPD among women with prenatal depression undergoing cesarean delivery. Design, Setting, and Participants This randomized clinical trial enrolled 338 women who screened positive for prenatal depression at 2 hospitals in Hunan, China from March 28, 2022, to April 16, 2023. Women with an Edinburgh Postnatal Depression Scale score of more than 9 who were 18 years of age or older and were scheduled for elective cesarean delivery were eligible. Interventions Eligible participants were randomly assigned in a 1:1 ratio to either the dexmedetomidine group or the control group via centrally computer-generated group randomization. Dexmedetomidine, 0.5 μg/kg and 0.9% saline were intravenously infused for 10 minutes after delivery in the dexmedetomidine and control groups, respectively. After infusion, sufentanil or dexmedetomidine plus sufentanil was administered via patient-controlled intravenous analgesia for 48 hours in the control group and dexmedetomidine group, respectively. Main Outcomes and Measures The primary outcome was positive PPD screening results at 7 and 42 days post partum, defined as a postpartum Edinburgh Postnatal Depression Scale score of more than 9. Analysis was on an intention-to-treat basis. Results All 338 participants were female, with a mean (SD) age of 31.5 (4.1) years. Positive PPD screening incidence at 7 and 42 days post partum in the dexmedetomidine group vs the control group was significantly decreased (day 7, 21 of 167 [12.6%] vs 53 of 165 [32.1%]; risk ratio, 0.39 [95% CI, 0.25-0.62]; P &amp;amp;lt; .001; day 42, 19 of 167 [11.4%] vs 50 of 165 [30.3%]; risk ratio, 0.38 [95% CI, 0.23-0.61]; P &amp;amp;lt; .001). The dexmedetomidine group showed no significant difference in adverse events vs the control group (46 of 169 [27.2%] vs 33 of 169 [19.5%]; P = .10), but the incidence of hypotension increased (31 of 169 [18.3%] vs 16 of 169 [9.5%]; risk ratio, 2.15 [95% CI, 1.13-4.10]; P = .02). Conclusions and Relevance Dexmedetomidine administration in the early postpartum period significantly reduced the incidence of a positive PPD screening and maintained a favorable safety profile. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200057213
Human tumor-associated macrophages and neutrophils regulate anti-tumor antibody efficacy through lethal and sublethal trogocytosis
Authors: Sunil Singhal, Abhishek S. Rao, Jason Stadanlick, Kyle Bruns, Neil T. Sullivan, Andres Bermudez, Adam Honig-Frand, Ryan Krouse, Sachinthani Arambepola, Emily Guo, Edmund K. Moon, George Georgiou, Thomas Valerius, Steven M. Albelda, Evgeniy B. Eruslanov
Journal: Cancer Research (2024)

Abstract The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells “nibbled off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy. Significance: The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.
Subclonal Cancer Driver Mutations are Prevalent in the Unresected Peritumoral Edema of Adult Diffuse Gliomas
Authors: Hunter R. Underhill, Michael Karsy, Christian J. Davidson, Sabine Hellwig, Samuel Stevenson, Eric A. Goold, Sydney Vincenti, Drew L. Sellers, Charlie Dean, Brion E. Harrison, Mary P. Bronner, Howard Colman, Randy L. Jensen
Journal: Cancer Research (2024)

Abstract Adult diffuse gliomas commonly recur regardless of therapy. As recurrence typically arises from the peritumoral edema adjacent to the resected bulk tumor, the profiling of somatic mutations from infiltrative malignant cells within this critical, unresected region could provide important insights into residual disease. A key obstacle has been the inability to distinguish between next-generation sequencing (NGS) noise and the true but weak signal from tumor cells hidden among the noncancerous brain tissue of the peritumoral edema. Here, we developed and validated True2 sequencing to reduce NGS-associated errors to &amp;lt;1 false positive/100 kb panel positions while detecting 97.6% of somatic mutations with an allele frequency ≥0.1%. True2 was then used to study the tumor and peritumoral edema of 22 adult diffuse gliomas including glioblastoma, astrocytoma, oligodendroglioma, and NF1-related low-grade neuroglioma. The tumor and peritumoral edema displayed a similar mutation burden, indicating that surgery debulks these cancers physically but not molecularly. Moreover, variants in the peritumoral edema included unique cancer driver mutations absent in the bulk tumor. Finally, analysis of multiple samples from each patient revealed multiple subclones with unique mutations in the same gene in 17 of 22 patients, supporting the occurrence of convergent evolution in response to patient-specific selective pressures in the tumor microenvironment that may form the molecular foundation of recurrent disease. Collectively, True2 enables the detection of ultralow frequency mutations during molecular analyses of adult diffuse gliomas, which is necessary to understand cancer evolution, recurrence, and individual response to therapy. Significance: True2 is a next-generation sequencing workflow that facilitates unbiased discovery of somatic mutations across the full range of variant allele frequencies, which could help identify residual disease vulnerabilities for targeted adjuvant therapies.
In situ tissue profile of rat trigeminal nerve in trigeminal neuralgia using spatial transcriptome sequencing
Authors: Wenbin Wei, Yuemin Liu, Yifen Shen, Tao Yang, Yabing Dong, Zixiang Han, Yiwen Wang, Zhiyang Liu, Ying Chai, Mengjie Zhang, Hanshao Wang, Hao Shen, Yihang Shen, Minjie Chen
Journal: International Journal of Surgery (2024)

Background: Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses. Objective: The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN. Methods: TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on weighted gene coexpression network analysis and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand–receptor interactions was analyzed using CellPhoneDB analysis. Results: The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand–receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells. Conclusions: This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development.
Disparities in Diagnostic Timeliness and Outcomes of Pediatric Appendicitis
Authors: Kenneth A. Michelson, Richard G. Bachur, Shawn J. Rangel, Jonathan A. Finkelstein, Michael C. Monuteaux, Monika K. Goyal
Journal: JAMA Network Open (2024)

This cohort study compares rates of delayed diagnosis and complications of appendicitis by race and ethnicity and Child Opportunity Index among children in 8 states.
Investigation of Genetic Alterations Associated With Interval Breast Cancer
Authors: Juan Rodriguez, Felix Grassmann, Qingyang Xiao, Mikael Eriksson, Xinhe Mao, Svetlana Bajalica-Lagercrantz, Per Hall, Kamila Czene
Journal: JAMA Oncology (2024)

Importance Breast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied. Objective To evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density. Design, Setting, and Participants This population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022. Exposure Germline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing. Main Outcomes and Measures Odds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression. Results All 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05). This association was primarily influenced by BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination. Conclusions and Relevance The results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.
Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors
Authors: Tista Roy Chaudhuri, Qingxiang Lin, Ewa K. Stachowiak, Spencer R. Rosario, Joseph A. Spernyak, Wen Wee Ma, Michal K. Stachowiak, Michelle K. Greene, Gerard P. Quinn, Simon S. McDade, Martin Clynes, Christopher J. Scott, Robert M. Straubinger
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) “primes” PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial–mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. Experimental Design: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key “nodes” responsible for EMT induction. Results: Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusions: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical–translational requirement for patient stratification.
Advances in Extracellular Vesicle Research Over the Past Decade: Source and Isolation Method are Connected with Cargo and Function
Authors: Rodolphe Poupardin, Martin Wolf, Nicole Maeding, Liliia Paniushkina, Sven Geissler, Paolo Bergese, Kenneth W. Witwer, Katharina Schallmoser, Gregor Fuhrmann, Dirk Strunk
Journal: Advanced Healthcare Materials (2024)

Abstract The evolution of extracellular vesicle (EV) research has introduced nanotechnology into biomedical cell communication science while recognizing what is formerly considered cell “dust” as constituting an entirely new universe of cell signaling particles. To display the global EV research landscape, a systematic review of 20 364 original research articles selected from all 40 684 EV‐related records identified in PubMed 2013–2022 is performed. Machine‐learning is used to categorize the high‐dimensional data and further dissected significant associations between EV source, isolation method, cargo, and function. Unexpected correlations between these four categories indicate prevalent experimental strategies based on cargo connectivity with function of interest being associated with certain EV sources or isolation strategies. Conceptually relevant association of size‐based EV isolation with protein cargo and uptake function will guide strategic conclusions enhancing future EV research and product development. Based on this study, an open‐source database is built to facilitate further analysis with conventional or AI tools to identify additional causative associations of interest.
Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes
Authors: Simon Heeke, Carl M. Gay, Marcos R. Estecio, Hai Tran, Benjamin B. Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M. Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I. Vokes, Monique B. Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A. Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I. Wistuba, Lauren A. Byers, John V. Heymach
Journal: Cancer Cell (2024)

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.
Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions
Authors: Yanjing Zhu, Shijie Tang, Qiuyue Yuan, Jing Fu, Juan He, Zhuang Liu, Xiaofang Zhao, Yunguang Li, Yan Zhao, Yani Zhang, Xiaoyu Zhang, Yangqianwen Zhang, Yiqin Zhu, Wenwen Wang, Bo Zheng, Rui Wu, Tong Wu, Shuai Yang, Xinyao Qiu, Siyun Shen, Ji Hu, Luonan Chen, Yong Wang, Hongyang Wang, Dong Gao, Lei Chen
Journal: Cell Reports Medicine (2024)

Despite considerable efforts to identify human liver cancer genomic alterations that might unveil druggable targets, the systematic translation of multiomics data remains challenging. Here, we report success in long-term culture of 64 patient-derived hepatobiliary tumor organoids (PDHOs) from a Chinese population. A divergent response to 265 metabolism- and epigenetics-related chemicals and 36 anti-cancer drugs is observed. Integration of the whole genome, transcriptome, chromatin accessibility profiles, and drug sensitivity results of 64 clinically relevant drugs defines over 32,000 genome-drug interactions. RUNX1 promoter mutation is associated with an increase in chromatin accessibility and a concomitant gene expression increase, promoting a cluster of drugs preferentially sensitive in hepatobiliary tumors. These results not only provide an annotated PDHO biobank of human liver cancer but also suggest a systematic approach for obtaining a comprehensive understanding of the gene-regulatory network of liver cancer, advancing the applications of potential personalized medicine.
The BMJ Appeal 2023-24: IMF austerity policies are strangling healthcare systems in the Global South
Authors: Natalia Rodriguez Malagon
Journal: BMJ (2024)

A typical day for volunteer nurse Martha, one of only two healthcare workers at a public health unit in Mbundorbu, Sierra Leone, involves seeing anywhere between 40 and 150 patients."Most of the time we overwork ourselves, and it is demanding on both our bodies and minds," the 24 year old told ActionAid. 1 Martha qualified in maternal and child health aid four years ago but has yet to secure a job.
Glutamate inputs send prediction error of reward, but not negative value of aversive stimuli, to dopamine neurons
Authors: Ryunosuke Amo, Naoshige Uchida, Mitsuko Watabe-Uchida
Journal: Neuron (2024)

Midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), but the mechanisms underlying RPE computation, particularly the contributions of different neurotransmitters, remain poorly understood. Here, we used a genetically encoded glutamate sensor to examine the pattern of glutamate inputs to dopamine neurons in mice. We found that glutamate inputs exhibit virtually all of the characteristics of RPE rather than conveying a specific component of RPE computation, such as reward or expectation. Notably, whereas glutamate inputs were transiently inhibited by reward omission, they were excited by aversive stimuli. Opioid analgesics altered dopamine negative responses to aversive stimuli into more positive responses, whereas excitatory responses of glutamate inputs remained unchanged. Our findings uncover previously unknown synaptic mechanisms underlying RPE computations; dopamine responses are shaped by both synergistic and competitive interactions between glutamatergic and GABAergic inputs to dopamine neurons depending on valences, with competitive interactions playing a role in responses to aversive stimuli.
<i>Notes from the Field:</i> Nontuberculous Mycobacteria Infections After Cosmetic Surgery Procedures in Florida — Nine States, 2022–2023
Authors: Katharine E. Saunders, Juliana M. Reyes, Lorrie Cyril, Molly Mitchell, Stephanie Colter, Jalysa Erskine, Kiara X. McNamara, Jennifer C. Hunter, Kiran M. Perkins, Argentina Charles
Journal: MMWR Morbidity and Mortality Weekly Report (2024)