tbuckley/cabot-search huggingface dataset:
Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T Cell Pyrimidine Synthesis
Authors: David Allard, Jeanne Cormery, Salma Bricha, Camille Fuselier, Farnoosh Abbas Aghababazadeh, Lucie Giraud, Emma Skora, Benjamin Haibe-Kains, John Stagg
Journal: Cancer Research (2024)

Abstract Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α, and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T cell responses.
Butyrate-producing<i>Faecalibacterium prausnitzii</i>suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway
Authors: Zhuangzhuang Shi, Min Li, Chen Zhang, Hongwen Li, Yue Zhang, Lei Zhang, Xin Li, Ling Li, Xinhua Wang, Xiaorui Fu, Zhenchang Sun, Xudong Zhang, Li Tian, Mingzhi Zhang, Wei-Hua Chen, Zhaoming Li
Journal: Gut (2024)

Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes. To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL. This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms. We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in Faecalibacterium prausnitzii which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of F. prausnitzii in NKTCL mouse models. Furthermore, F. prausnitzii culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1. These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of F. prausnitzii to ameliorate this malignancy.
Plasma cell-free DNA chromatin immunoprecipitation profiling depicts phenotypic and clinical heterogeneity in advanced prostate cancer
Authors: Joonatan Sipola, Aslı D. Munzur, Edmond M. Kwan, Clara C. Y. Seo, Benjamin J. Hauk, Karan Parekh, Yi Jou (Ruby) Liao, Cecily Q. Bernales, Gráinne Donnellan, Ingrid Bloise, Emily Fung, Sarah W.S. Ng, Gang Wang, Gillian Vandekerkhove, Matti Nykter, Matti Annala, Corinne Maurice-Dror, Kim N. Chi, Cameron Herberts, Alexander W. Wyatt, David Y. Takeda
Journal: Cancer Research (2024)

Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction-demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.
GLP-1RAs attenuated obesity and reversed leptin resistance partly via activating the microbiome-derived inosine/A2A pathway
Authors: Chunyan Dong, Bailing Zhou, Binyan Zhao, Ke Lin, Yaomei Tian, Rui Zhang, Daoyuan Xie, Siwen Wu, Li Yang
Journal: Acta Pharmaceutica Sinica B (2024)

Extensive evidence has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorate obesity. Our previous studies revealed that (Ex-4)2-Fc, a long-acting GLP-1RA we developed, depends on the leptin pathway to treat obesity. However, the mechanisms linking (Ex-4)2-Fc and leptin resistance remain largely unclear. To address this question, we explored the mechanism of GLP-1RAs from the perspective of the gut microbiota, as increasing evidence indicates an important link between the gut microbiota and obesity. This study aimed to explore the potential role of the gut microbiota in the treatment of GLP-1RAs. We found that (Ex-4)2-Fc treatment reshaped obesity-induced gut microbiota disturbances and substantially increased the abundance of Akkermansia muciniphila (Am). In addition, (Ex-4)2-Fc did not respond well in antibiotic-treated (ATB) Obese mice. Subsequent studies have shown that this defect can be overcome by gavage with Am. In addition, we found that Am enhanced (Ex-4)2-Fc therapy by producing the metabolite inosine. Inosine regulates the macrophage adenosine A2A receptor (A2A) pathway to indirectly reduce leptin levels in adipocytes Thus, elucidating the role of metabolites in regulating the leptin pathway will provide new insights into GLP-1RAs therapy and may lead to more effective strategies for guiding the clinical use of antidiabetic agents.
Booster vaccination and post COVID-19 condition during the Omicron variant-dominant wave: A large population-based study
Authors: Arisa Iba, Mariko Hosozawa, Miyuki Hori, Yoko Muto, Tomomi Kihara, Isao Muraki, Rie Masuda, Nanako Tamiya, Hiroyasu Iso
Journal: Clinical Microbiology and Infection (2024)
Procalcitonin-guided use of antibiotic in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease: a randomized clinical trial
Authors: Weili Sheng, Lixue Huang, Xiaoying Gu, Yeming Wang, Mingyan Jiang, Chao Hu, Jingya Li, Chunxue Ran, Hongxu Zhang, Na Wang, Yuling Wang, Xiaowei Qi, Lijun Suo, Bo Liu, Guangsheng Pei, Zhiyi He, Jinxiang Wang, Bin Cao
Journal: Clinical Microbiology and Infection (2024)
Learning from Post COVID-19 condition for epidemic preparedness: a variable catalogue for future Post-Acute Infection Syndromes
Authors: A Górska, L M Canziani, E Rinaldi, Z D Pana, S Beale, F Bai, B M Boxma-de Klerk, S de Bruijn, D Donà, M B Ekkelenkamp, F Incardona, P Mallon, G C Marchetti, M Puhan, A Riva, V C Simensen, M Vaillant, M M van der Zalm, S M J van Kuijk, S van Wingerden, A Judd, E Tacconelli, J L Peñalvo
Journal: Clinical Microbiology and Infection (2024)
Differential HBV RNA and HBcrAg patterns in untreated patients with chronic hepatitis delta
Authors: Elisabetta Degasperi, Caroline Scholtes, Barbara Testoni, Sara Uceda Renteria, Maria Paola Anolli, Caroline Charre, Floriana Facchetti, Marie-Laure Plissonnier, Dana Sambarino, Riccardo Perbellini, Sara Monico, Annapaola Callegaro, Ester García-Pras, Sabela Lens, Maria Francesca Cortese, Xavier Forns, Sofía Pérez-Del-Pulgar, Marintha Heil, Massimo Levrero, Fabien Zoulim, Pietro Lampertico
Journal: Journal of Hepatology (2024)
Authors' Reply: Using VNtyper from Whole Exome Sequencing Data to Detect Pathogenic Variants in the MUC1 Gene
Authors: Ilias Bensouna, Thomas Robert, Xavier Vanhoye, Laurent Mesnard
Journal: Journal of the American Society of Nephrology (2024)

We appreciate the feedback on our JASN article, "Systematic Screening of Autosomal Dominant Tubulointerstitial Kidney Disease–MUC1 27dupC Pathogenic Variant through Exome Sequencing,"1 which has provided us the opportunity to clarify our approach and address the concerns raised by Saei et al.2 The original VNtyper paper demonstrated its effectiveness on high-depth targeted sequencing panels, achieving coverage above 500×, as shown in Figure S6C of their study.3 However, in our study, we have shown that SharkVNTyper performs well on exome sequencing data with significantly lower coverage.1 Exome sequencing is widely used in clinical genomics, and achieving comparable diagnostic accuracy at lower coverage is essential for broader applicability and scalability. The Shark tool enabled us to significantly reduce processing times, from several hours per patient (as seen in Figure S6A of the VNtyper study) to just 10 minutes per patient. This improvement is significant for large clinical cohorts, as detailed in the supplemental material of our paper. In their letter, Saei et al. recommend using binary alignment map (BAM) files as input; however, generating BAM files from FASTQ files is time consuming and should be considered when making comparisons with SharkVNTyper.4 We advocate for the use of raw FASTQ files, which allows diagnoses to be achieved within minutes. We also chose to work with raw FASTQ files instead of BAM files to avoid alignment-related biases. To illustrate this, we converted 27 FASTQ exome files from our positive control cohort into BAM files (mean coverage=132×). When these BAM files were input into VNtyper, only one positive result was obtained (4% sensitivity). By contrast, applying Shark to the same FASTQ files resulted in 96% sensitivity, with 26 out of 27 samples testing positive. Therefore, using FASTQ files as input is essential for maximizing sensitivity at lower coverage levels. In addition, we ran VNtyper on five BAM files provided by Saei et al. (https://github.com/hassansaei/VNtyper) and confirmed that reduced coverage negatively affected sensitivity. All samples tested positive at 404× coverage, but sensitivity dropped to 80% at 240×, 60% at 158×, and 40% at 142×. In many laboratories, BAM files are not stored long term, and regenerating them from archived FASTQ data can be resource intensive, especially for large retrospective cohort analyses.5 This further supports our decision to use FASTQ files for efficiency. In conclusion, we believe that our work successfully extends the application of VNtyper to exome sequencing, making it more accessible for clinical use. The integration of Shark not only improves processing times but also enables workflows to scale for large datasets with lower coverage. We appreciate the opportunity to engage in this discussion and contribute to the evolving field of nephrogenomics.
Using VNtyper from Whole Exome Sequencing Data to Detect Pathogenic Variants in the MUC1 Gene
Authors: Hassan Saei, Cécile Masson, Vincent Morinière, Jessica Kachmar, Laurence Heidet, Olivier Gribouval, Corinne Antignac, Guillaume Dorval
Journal: Journal of the American Society of Nephrology (2024)

We have carefully and interestingly read the manuscript by Bensouna et al., recently published in JASN, in which the authors used our tool, VNtyper (github.com/hassansaei/Vntyper), to detect pathogenic variants in the MUC1 gene.1 We are pleased to see that VNtyper enabled a genetic diagnosis in patients with CKD, with roughly similar diagnostic yields in their cohort as in ours, whether VNtyper was used on exome or targeted panel, respectively. We believe that our initial article may have been misinterpreted in the present study, leading to statements or conclusions about it that are either inaccurate or require more nuance to avoid over- or underdiagnosis. First, the authors state that the VNtyper tool requires considerable processing time, justifying the addition of the Shark tool to reduce computational time. It seems important to point out that the limited analysis of the MUC1 region is already incorporated in VNtyper v1.2.0. Consequently, when used from binary alignment map files (data already aligned on the genome of reference) as recommended, VNtyper's processing time is not 6–12 hours per patient, but approximately 6–10 minutes for exome and 10–16 minutes for high coverage panel >500×. Only the use of FASTQ files (not aligned raw data) as primary data may need the addition of the Shark tool. Therefore, for prospective analysis, we strongly recommend using binary alignment map files to expedite the genotyping process, as outlined on our GitHub release page and in the welcome message displayed when running VNtyper. Second, and most importantly, it is incorrectly stated that VNtyper was developed to detect variants "when average coverage is above 500×." In reality, VNtyper was designed to be applied to MUC1 short-read sequencing data, regardless the coverage (meaning the number of times a region is sequenced), and we are pleased to see that the authors finally showed the usefulness of VNtyper on exome sequencing data. However, our data showed that results became less accurate when MUC1 coverage decreases. In this vein, coverage information (affected by both capture and sequencing strategy) must be considered, especially in case of negative results. That is why VNtyper labels each result as low/high precision. Ignoring this factor may lead to false negative or positive results, making confirmation by other methods necessary. We believe sequencing results with low coverage should be interpreted cautiously and strongly recommend integrating these data in the final diagnosis report as in the study by Saei et al. even in a screening strategy to limit false-negative patients.2
A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway
Authors: Ying Hou, Bingling Zhong, Lin Zhao, Heng Wang, Yanyan Zhu, Xianzhe Wang, Haoyi Zheng, Jie Yu, Guokai Liu, Xin Wang, Jose M Martin-Garcia, Xiuping Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Human NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoenzyme expressed at high levels in multiple solid tumors, making it an attractive target for anticancer drugs. Bioactivatable drugs targeting NQO1, such as β-lapachone (β-lap), are currently in clinical trials for the treatment of cancer. β-Lap selectively kills NQO1-positive (NQO1+) cancer cells by inducing reactive oxygen species (ROS) via catalytic activation of NQO1. In this study, we demonstrated that cryptotanshinone (CTS), a naturally occurring compound, induces NQO1-dependent necrosis without affecting NQO1 activity. CTS selectively kills NQO1+ cancer cells by inducing NQO1-dependent necrosis. Interestingly, CTS directly binds to NQO1 but does not activate its catalytic activity. In addition, CTS enables activation of JNK1/2 and PARP, accumulation of iron and Ca2+, and depletion of ATP and NAD+. Furthermore, CTS selectively suppressed tumor growth in the NQO1+ xenograft models, which was reversed by NQO1 inhibitor and NQO1 shRNA. In conclusion, CTS induces NQO1-dependent necrosis via the JNK1/2/iron/PARP/NAD+/Ca2+ signaling pathway. This study demonstrates the non-enzymatic function of NQO1 in inducing cell death and provides new avenues for the design and development of NQO1-targeted anticancer drugs.
Cancer care for transgender and gender‐diverse people: Practical, literature‐driven recommendations from the Multinational Association of Supportive Care in Cancer
Authors: Elizabeth J. Cathcart‐Rake, Alexandre Chan, Alvaro Menendez, Denise Markstrom, Carla Schnitzlein, Yee Won Chong, Don S. Dizon
Journal: CA A Cancer Journal for Clinicians (2024)

In the United States, over 2 million individuals openly identify with a gender that differs from their sex assigned at birth. A cancer diagnosis is physically and psychologically taxing-and, in some, traumatic. However, for transgender and gender-diverse (TGD) people, many of whom have experienced discrimination in myriad health care settings, the challenges may be even greater. These recommendations focus on how best to deliver quality cancer care to transgender men (individuals who identify as men but were assigned female sex at birth), transgender women (individuals who identify as women but were assigned male sex at birth), and people who identify somewhere beyond this gender spectrum as nonbinary or using other terms, based on the available, albeit sparse, literature. This review broaches: (1) the epidemiology of cancer in TGD individuals, including the incidence of cancer and cancer-related mortality; (2) cancer center practices that are welcoming and affirming to TGD patients; (3) the need for awareness and intentionality in the spaces of diagnosis and treatment for cancer; (4) the inevitable conclusion that gender differences exist but much more needs to be learned about the impact of gender-affirming therapy, consisting of gender-affirming surgeries and gender-affirming hormone therapy, on cancer therapy; and (5) the efficacy and perceived safety of antineoplastic therapy and gender-affirming hormone therapy.
Organic anion transporting polypeptides (OATPs/SLCOs): Pharmacology, toxicology, structure, and transport mechanisms
Authors: Bruno Hagenbuch, Bruno Stieger, Kaspar P Locher
Journal: Pharmacological Reviews (2024)

Organic anion transporting polypeptides (OATPs) are membrane proteins that mediate the uptake of a wide range of substrates across the plasma membrane of various cells and tissues. They are classified into 6 subfamilies, OATP1 through OATP6. Humans contain 12 OATPs encoded by 11 solute carrier of organic anion transporting polypeptide (SLCO) genes: OATP1A2, OATP1B1, OATP1B3, the splice variant OATP1B3-1B7, OATP1C1, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP4C1, OATP5A1, and OATP6A1. Most of these proteins are expressed in epithelial cells, where they mediate the uptake of structurally unrelated organic anions, cations, and even neutral compounds into the cytoplasm. The best-characterized members are OATP1B1 and OATP1B3, which have an important role in drug metabolism by mediating drug uptake into the liver and are involved in drug-drug interactions. In this review, we aimed to (1) provide a historical perspective on the identification of OATPs and their nomenclature and discuss their phylogenic relationships and molecular characteristics; (2) review the current knowledge of the broad substrate specificity and their role in drug disposition and drug-drug interactions, with a special emphasis on human hepatic OATPs; (3) summarize the different experimental systems that are used to study the function of OATPs and discuss their advantages and disadvantages; (4) review the available experimental 3-dimensional structures and examine how they can help elucidate the transport mechanisms of OATPs; and (5) finally, summarize the current knowledge of the regulation of OATP expression, discuss clinically important single-nucleotide polymorphisms, and outline challenges of physiologically based pharmacokinetic modeling and in vitro to in vivo extrapolation. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are a family of 12 uptake transporters in the solute carrier superfamily. Several members, particularly the liver-expressed OATP1B1 and OATP1B3, are important drug transporters. They mediate the uptake of several endobiotics and xenobiotics, including statins and numerous other drugs, into hepatocytes, and their inhibition by other drugs or reduced expression due to single-nucleotide polymorphisms can lead to adverse drug effects. Their recently solved 3-dimensional structures should help to elucidate their transport mechanisms and broad substrate specificities.