tbuckley/cabot-search huggingface dataset:
Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis
Authors: Hui Xiao, Huiyao Chen, Xiang Chen, Yulan Lu, Bingbing Wu, Huijun Wang, Yun Cao, Liyuan Hu, Xinran Dong, Wenhao Zhou, Lin Yang
Journal: Genome Medicine (2023)

Abstract Background In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. Methods A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children’s Hospital of Fudan University, Shanghai, China. Results Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P =0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P =0.012). We filtered out 3 genes ( ITGB4 , TXNRD2 , RRM2B ) as potential causative genes for SGA and 1 gene ( ADIPOQ ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84–0.96] vs. AUC=0.74 [0.64–0.84]; P =0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6–0.93] vs. AUC=0.53[0.29–0.76]; P =0.0117). Conclusion SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction.
Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Authors: S. Loibl, F. André, T. Bachelot, C.H. Barrios, J. Bergh, H.J. Burstein, M.J. Cardoso, L.A. Carey, S. Dawood, L. Del Mastro, C. Denkert, E.M. Fallenberg, P.A. Francis, H. Gamal-Eldin, K. Gelmon, C.E. Geyer, M. Gnant, V. Guarneri, S. Gupta, S.B. Kim, D. Krug, M. Martin, I. Meattini, M. Morrow, W. Janni, S. Paluch-Shimon, A. Partridge, P. Poortmans, L. Pusztai, M.M. Regan, J. Sparano, T. Spanic, S. Swain, S. Tjulandin, M. Toi, D. Trapani, A. Tutt, B. Xu, G. Curigliano, N. Harbeck
Journal: Annals of Oncology (2023)
Transdermal Blood Sampling for C-Peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes
Authors: Rachel E.J. Besser, Anna E. Long, Katharine R. Owen, Rebecca Law, Jacqueline S. Birks, Olivia Pearce, Claire L. Williams, Claire L. Scudder, Timothy J. McDonald, John A. Todd
Journal: Diabetes Care (2023)

OBJECTIVE C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. RESEARCH DESIGN AND METHODS Ninety-one individuals (71 with type 1 diabetes, 20 control; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1–17.1], diabetes duration 4.0 years [1.5–7.7]; control individuals: 42.2 years [38.0–52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire. RESULTS Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40–50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) &amp;lt;35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] – TCB ln[C-peptide] = 0.008, 95% CI [−0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided). CONCLUSIONS Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment.
Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA
Authors: Hao-Jie Zhong, Si-Qi Wang, Ruo-Xin Zhang, Yu-Pei Zhuang, Longyan Li, Shuo-Zhao Yi, Ying Li, Lei Wu, Yu Ding, Jumei Zhang, Xinqiang Xie, Xing-Xiang He, Qingping Wu
Journal: Translational Neurodegeneration (2023)

The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the "enteric nervous system-vagus nerve-brain" axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure.
Hsa_circ_0136666 stimulates gastric cancer progression and tumor immune escape by regulating the miR-375/PRKDC Axis and PD-L1 phosphorylation
Authors: Zhenyan Miao, Jifei Li, Yu Wang, Mingqin Shi, Xiao Gu, Xuanqi Zhang, Fang Wei, Xinying Tang, Lufeng Zheng, Yingying Xing
Journal: Molecular Cancer (2023)

Abstract Background Targeted drugs are not quite effective for prolonging the survival of patients with gastric cancer due to off-target effects as well as tumor immune escape mechanisms. Circular RNAs widely exist in tumor regions as biomarkers and can be developed as effective drug targets. Methods Western blot, QRT-PCR, fluorescence in situ hybridization, and flow cytometry were used to investigate the function of hsa_circ_0136666 in promoting the proliferation of gastric cancer cells. Tissue immunofluorescence, enzyme-linked immunosorbent assay (ELISA), as well as flow cytometric analysis, was conducted to explore the process of tumor immune evasion in tumor-bearing mice. The differences of circRNA expression in clinical samples were analyzed through tissue microarray FISH. The effect of siRNA on improving the efficacy of anti-PDL1 drugs and suppressing the immune microenvironment was evaluated by the coadministration model. Results We demonstrated that hsa_circ_0136666 was widely and highly expressed in gastric cancer tissues and cells. Functionally, hsa_circ_0136666 promoted gastric cancer tumor proliferation and tumor microenvironment formation, leading to tumorigenesis immune escape, and this effect was dependent on CD8 + T cells. Mechanistically, we confirmed that hsa_circ_0136666 competitively upregulated PRKDC expression by sponging miR-375-3p, regulating immune checkpoint proteins, prompting phosphorylation of PD-L1 to preventing its degradation, driving PD-L1 aggregation and suppressing immune function, thereby impairing cancer immune responses. In terms of application, we found that LNP-siRNA effectively improved anti-PDL1 drug efficacy and inhibited immune escape. Conclusion Our results reveal an oncogenic role played by hsa_circ_0136666 in gastric cancer, driving PD-L1 phosphorylation via the miR-375/PRKDC signaling axis, prompting immune escape. This work proposes a completely new pathogenic mechanism of gastric cancer, uncovers a novel role for hsa_circ_0136666 as an immune target, and provides a rationale for enhancing the efficacy of anti-PD-L1 therapy for gastric cancer.
A Mobile Health Application Integrated in the Electronic Health Record for Rheumatoid Arthritis <scp>Patient–Reported</scp> Outcomes: A Controlled Interrupted <scp>Time‐Series</scp> Analysis of Impact on Visit Efficiency
Authors: Daniel H. Solomon, Hallie Altwies, Leah Santacroce, Jack Ellrodt, Tammy Pham, Jacklyn Stratton, Adam Landman, Anuj Dalal, Jamie Collins, Robert S. Rudin
Journal: Arthritis & Rheumatology (2023)

Objective Patient‐reported outcome (PRO) collection between visits for rheumatoid arthritis (RA) could improve visit efficiency, reducing in‐person visits for patients with stable symptoms while facilitating access for those with symptoms. We examined whether a mobile health PRO application integrated in the electronic health record (EHR) could reduce visit volume for those with RA. Methods We developed an application for RA that prompted patients every other day to complete brief PRO questionnaires. Results of the application were integrated into the EHR. We tested the application in a controlled interrupted time‐series analysis between 2020 and 2023. Rheumatologists received EHR‐based messages based on PRO results recommending the patient receive a visit earlier or later than scheduled. The primary outcome was monthly visit volume during the year before versus the year after initiation. Results A total of 150 patients with RA consented and used the application. The median age was 62 years, 83% were female, 7% had fewer than 2 years of disease, and 50% were seropositive; 150 controls were well matched. Among those in the application cohort, the estimated monthly median visit volume in the year before use of the application was 31.2 (95% confidence interval [95% CI] 28.0–34.3); in controls, this was 30.4 (95% CI 27.3–33.6). In the year using the application, the estimated monthly visit volume was 36.8 (95% CI 33.4–40.3) compared to 38.7 (95% CI 35.2–42.3) in controls. The difference in the differences between the cohorts was not statistically significant (−2.7 visits, 95% CI −9.3 to 4.0). No differences were noted in flare rates or visit delays. Conclusion In this initial trial of a PRO application intervention to improve visit efficiency, we found no association with reduced visit volume. image
USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity
Authors: Juntae Kwon, Jinmin Zhang, Boram Mok, Samuel Allsup, Chul Kim, Jeffrey Toretsky, Cecil Han
Journal: Molecular Cancer (2023)

Abstract Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on Kras G12D/+; Trp53 flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors such as NKX2-1 and SOX2 in club cells of the airway and reinforced the fate of club cells to squamous carcinoma development. We showed a strong molecular association between USP13 and c-MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate that USP13 is a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of LUSC. Graphical Abstract
Extracellular vesicles remodel tumor environment for cancer immunotherapy
Authors: Ming Yue, Shengyun Hu, Haifeng Sun, Baojing Tuo, Bin Jia, Chen Chen, Wenkang Wang, Jinbo Liu, Yang Liu, Zhenqiang Sun, Junhong Hu
Journal: Molecular Cancer (2023)

Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles including exosomes have emerged as therapeutic agents actively involved in a diverse range of pathological conditions. Mounting evidence suggests that alterations in the quantity and composition of extracellular vesicles (EVs) contribute to the remodeling of the immune-suppressive tumor microenvironment (TME), thereby influencing the efficacy of immunotherapy. This revelation has sparked clinical interest in utilizing EVs for immune sensitization. In this perspective article, we present a comprehensive overview of the origins, generation, and interplay among various components of EVs within the TME. Furthermore, we discuss the pivotal role of EVs in reshaping the TME during tumorigenesis and their specific cargo, such as PD-1 and non-coding RNA, which influence the phenotypes of critical immune cells within the TME. Additionally, we summarize the applications of EVs in different anti-tumor therapies, the latest advancements in engineering EVs for cancer immunotherapy, and the challenges encountered in clinical translation. In light of these findings, we advocate for a broader understanding of the impact of EVs on the TME, as this will unveil overlooked therapeutic vulnerabilities and potentially enhance the efficacy of existing cancer immunotherapies.
<i>Akkermansia muciniphila</i> protects the intestine from irradiation-induced injury by secretion of propionic acid
Authors: Kai-Yue He, Xin-Yuan Lei, Dan-Hui Wu, Lei Zhang, Jun-Qi Li, Qiu-Tong Li, Wei-Tao Yin, Zi-Long Zhao, Huai Liu, Xiong-Yan Xiang, Ling-Jun Zhu, Cui-Yun Cui, Ke-Ke Wang, Jin-Hua Wang, Lin Lv, Qian-Hui Sun, Guo-Long Liu, Zhi-Xiang Xu, Yong-Ping Jian
Journal: Gut Microbes (2023)

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.
The impact of aging-induced gut microbiome dysbiosis on dendritic cells and lung diseases
Authors: Jonaid Ahmad Malik, Mohammad Adeel Zafar, Taruna Lamba, Sidhanta Nanda, Mohammad Affan Khan, Javed Naim Agrewala
Journal: Gut Microbes (2023)

Aging is an inevitable natural process that impacts every individual, and understanding its effect on the gut microbiome and dendritic cell (DC) functionality in elderly subjects is crucial. DCs are vital antigen-presenting cells (APCs) that orchestrate the immune response, maintaining immune tolerance to self-antigens and bridging innate and adaptive immunity. With aging, there is a shift toward nonspecific innate immunity, resulting in a decline in adaptive immune responses. This alteration raises significant concerns about managing the health of an elderly population. However, the precise impact of aging and microbiome changes on DC function and their implications in lung-associated diseases remain relatively understudied. To illuminate this subject, we will discuss recent advancements in understanding the connections between aging, gut dysbiosis, DCs, and lung diseases. Emphasizing the key concepts linking age-related gut microbiome changes and DC functions, we will focus on their relevance to overall health and immune response in elderly individuals. This article aims to improve our understanding of the intricate relationship between aging, gut microbiome, and DCs, potentially benefiting the management of age-associated diseases and promoting healthy aging.
Discovery of U2AF1 neoantigens in myeloid neoplasms
Authors: Melinda Ann Biernacki, Jessica Lok, Ralph Graeme Black, Kimberly A Foster, Carrie Cummings, Kyle B Woodward, Tim Monahan, Vivian G Oehler, Derek L Stirewalt, David Wu, Anthony Rongvaux, Hans Joachim Deeg, Marie Bleakley
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Myelodysplastic syndromes (MDS) arise from somatic mutations acquired in hematopoietic stem and progenitor cells, causing cytopenias and predisposing to transformation into secondary acute myeloid leukemia (sAML). Recurrent mutations in spliceosome genes, including U2AF1 , are attractive therapeutic targets as they are prevalent in MDS and sAML, arise early in neoplastic cells, and are generally absent from normal cells, including normal hematopoietic cells. MDS and sAML are susceptible to T cell-mediated killing, and thus engineered T-cell immunotherapies hold promise for their treatment. We hypothesized that targeting spliceosome mutation-derived neoantigens with transgenic T-cell receptor (TCR) T cells would selectively eradicate malignant cells in MDS and sAML. Methods We identified candidate neoantigen epitopes from recurrent protein-coding mutations in the spliceosome genes SRSF2 and U2AF1 using a multistep in silico process. Candidate epitopes predicted to bind human leukocyte antigen (HLA) class I, be processed and presented from the parent protein, and not to be subject to tolerance then underwent in vitro immunogenicity screening. CD8 + T cells recognizing immunogenic neoantigen epitopes were evaluated in in vitro assays to assess functional avidity, confirm the predicted HLA restriction, the potential for recognition of similar peptides, and the ability to kill neoplastic cells in an antigen-specific manner. Neoantigen-specific TCR were sequenced, cloned into lentiviral vectors, and transduced into third-party T cells after knock-out of endogenous TCR, then tested in vitro for specificity and ability to kill neoplastic myeloid cells presenting the neoantigen. The efficacy of neoantigen-specific T cells was evaluated in vivo in a murine cell line-derived xenograft model. Results We identified two neoantigens created from a recurrent mutation in U2AF1 , isolated CD8 + T cells specific for the neoantigens, and demonstrated that transferring their TCR to third-party CD8 + T cells is feasible and confers specificity for the U2AF1 neoantigens. Finally, we showed that these neoantigen-specific TCR-T cells do not recognize normal hematopoietic cells but efficiently kill malignant myeloid cells bearing the specific U2AF1 mutation, including primary cells, in vitro and in vivo. Conclusions These data serve as proof-of-concept for developing precision medicine approaches that use neoantigen-directed T-cell receptor-transduced T cells to treat MDS and sAML.
XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer
Authors: Kurt A Jenkins, Miso Park, Magali Pederzoli-Ribeil, Ugur Eskiocak, Parker Johnson, Wilson Guzman, Megan McLaughlin, Deborah Moore-Lai, Caitlin O’Toole, Zhen Liu, Benjamin Nicholson, Veronica Flesch, Huawei Qiu, Tim Clackson, Ronan C O’Hagan, Ulrich Rodeck, Margaret Karow, Jennifer O’Neil, John C Williams
Journal: Journal for ImmunoTherapy of Cancer (2023)

Introduction The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb. Methods XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity. Results Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system. Conclusions These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies.