tbuckley/cabot-search huggingface dataset:
How does the microbiota control systemic innate immunity?
Authors: Christine K.I. Jordan, Thomas B. Clarke
Journal: Trends in Immunology (2024)

The intestinal microbiota has a pervasive influence on mammalian innate immunity fortifying defenses to infection in tissues throughout the host. How intestinal microbes control innate defenses in systemic tissues is, however, poorly defined. In our opinion, there are three core challenges that need addressing to advance our understanding of how the intestinal microbiota controls innate immunity systemically: first, deciphering how signals from intestinal microbes are transmitted to distal tissues; second, unraveling how intestinal microbes prime systemic innate immunity without inducing widespread immunopathology; and third, identifying which intestinal microbes control systemic immunity. Here, we propose answers to these problems which provide a framework for understanding how microbes in the intestine can regulate innate immunity systemically.
Abstract IA005: PET imaging predictors of response to chemoradiotherapy in cervical cancer
Authors: Julie K. Schwarz
Journal: Cancer Research (2024)

Abstract Although HPV transformed tumors are presumed to be radiation sensitive, approximately one third of locally advanced cervical cancer patients fail the current standard of care (concurrent cisplatin and radiation therapy). Work in our laboratory has combined the results of functional imaging with 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging together with bioinformatic analyses of associated translational correlates to define new predictors of resistance to DNA damaging therapies. Results of this work demonstrate that cervical tumors with increased FDG uptake on pretreatment FDG-PET imaging are characterized by myeloid predominant inflammatory infiltrates, including immature monocytes and macrophages. Co-culture of cervical tumor cells with macrophages is associated with increased glucose uptake and pro-survival signaling in tumor cells mediated through macrophage derived IL-6 and signaling through the JAK-STAT pathway. We are currently using a combination of single cell sequencing and spatially resolved approaches to further define PET associated and chemoradiation induced changes in cervix tumor cell metabolism and the immune tumor microenvironment with the goal of defining new targets for personalized therapies. Importantly, cervical cancers retain and transcribe portions of the HPV genome. At the end of the talk, we will review recent work in our lab that highlights the impact of HPV associated gene expression, including splice variants, on the response to DNA damaging agents. Citation Format: Julie K. Schwarz. PET imaging predictors of response to chemoradiotherapy in cervical cancer [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 IA005.
Emerging health implications of climate change: dengue outbreaks and beyond in Bangladesh
Authors: Yusha Araf, Marjana Akter, Jingbo Zhai, Chunfu Zheng, Md Golzar Hossain
Journal: The Lancet Microbe (2024)

The combination of the sharp spike in the number of dengue cases in Bangladesh in 2023 and the undeniably altering climate patterns clearly elucidates the intricate nexus between environmental changes and public health ramifications. As of Oct 28, 2023, the nation recorded 1327 dengue-induced fatalities, with a staggering 265 862 individuals grappling with the infection,1 thereby positioning this year as the most disastrous since the report of the epidemic in 2000 (appendix).2 To contextualise the severity, the death toll from dengue in the country in 2023 starkly eclipsed the preceding year's count, registering approximately four times the dengue-related fatalities reported in 2022 (ie, 281 fatalities).
Transcriptional signals of transformation in human cancer
Authors: Gerda Kildisiute, Maria Kalyva, Rasa Elmentaite, Stijn van Dongen, Christine Thevanesan, Alice Piapi, Kirsty Ambridge, Elena Prigmore, Muzlifah Haniffa, Sarah A. Teichmann, Karin Straathof, Isidro Cortés-Ciriano, Sam Behjati, Matthew D. Young
Journal: Genome Medicine (2024)

As normal cells transform into cancers, their cell state changes, which may drive cancer cells into a stem-like or more primordial, foetal, or embryonic cell state. The transcriptomic profile of this final state may encode information about cancer's origin and how cancers relate to their normal cell counterparts. Here, we used single-cell atlases to study cancer transformation in transcriptional terms. We utilised bulk transcriptomes across a wide spectrum of adult and childhood cancers, using a previously established method to interrogate their relationship to normal cell states. We extend and validate these findings using single-cell cancer transcriptomes and organ-specific atlases of colorectal and liver cancer. Our bulk transcriptomic data reveals that adult cancers rarely return to an embryonic state, but that a foetal state is a near-universal feature of childhood cancers. This finding was confirmed with single-cell cancer transcriptomes. Our findings provide a nuanced picture of transformation in human cancer, indicating cancer-specific rather than universal patterns of transformation pervade adult epithelial cancers.
Abstract B028: Preclinical effects of Tumor Treating Fields (TTFields) applied with cisplatin for treatment of cervical cancer
Authors: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg Palmer, Angeles A. Secord
Journal: Cancer Research (2024)

Abstract Introduction: Though largely preventable, cervical cancer remains a significant health issue. Treatment of early-stage disease usually involves surgery; while systemic therapy is often required for advanced, recurrent, or metastatic cases. Most patients with advanced disease receive cisplatin-containing chemotherapy combinations in the first-line setting. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Concomitant treatment with TTFields and cisplatin has shown benefit in other tumor types. This in vitro study assessed the effects of TTFields in cervical cancer cells and explored their efficacy together with cisplatin. Methods: Cervical cancer cell lines were exposed to TTFields (0.5 V/cm for Ca Ski cells, 1 V/cm RMS for HeLa and SiHa cells; 72 h) at varying frequencies (100-400 kHz) followed by cell count assays. TTFields (200 kHz) were then applied with a range of cisplatin doses, and cell count, colony formation, and apoptosis were evaluated. Overall effect was calculated as the product of the relative reductions in cell count and colony formation. TTFields-treated cells were also examined for formation of γH2AX (a DNA damage marker) using fluorescent microscopy and for the expression of Fanconi Anemia (FA)-BRCA pathway proteins involved in repairing cisplatin-induced DNA damage via Western blot. Results: TTFields treatment reduced cell count in all cervical cancer cell lines tested. A frequency of 200 kHz was determined effective and used for all experiments. Cisplatin exhibited dose-response effects, which were augmented when TTFields were co-applied. TTFields also induced DNA damage in the cells and downregulated the expression of FA-BRCA pathway proteins. Conclusions: These preclinical findings suggest that TTFields should be explored as a potential treatment for cervical cancer. TTFields-induced downregulation of the FA-BRCA pathway creates a conditional vulnerability that may account for the enhanced efficacy seen when TTFields are applied together with cisplatin, providing mechanistic insight. Citation Format: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg Palmer, Angeles A. Secord. Preclinical effects of Tumor Treating Fields (TTFields) applied with cisplatin for treatment of cervical cancer [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 B028.
Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts
Authors: Leo L. Wang, Spencer Tuohy, Karen L. Xu, Arben Nace, Ruifeng Yang, Ying Zheng, Jason A. Burdick, George Cotsarelis
Journal: Advanced Healthcare Materials (2024)

Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile-containing baricitinib for drug tethering, which is confirmed with
Increase Attention to Computed Tomography Findings of Emphysema without Airflow Limitation: Small Airway Disease Is Already There
Authors: Naoya Tanabe
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Increase Attention to CT Emphysema without Airflow Limitation: Small Airway Disease Is Already There." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
UNC93B1 variants underlie TLR7-dependent autoimmunity
Authors: Christine Wolf, Ee Lyn Lim, Mohammad Mokhtari, Barbara Kind, Alexandru Odainic, Eusebia Lara-Villacanas, Sarah Koss, Simon Mages, Katharina Menzel, Kerstin Engel, Gregor Dückers, Benedikt Bernbeck, Dominik T. Schneider, Kathrin Siepermann, Tim Niehues, Carl Christoph Goetzke, Pawel Durek, Kirsten Minden, Thomas Dörner, Anna Stittrich, Franziska Szelinski, Gabriela Maria Guerra, Mona Massoud, Markus Bieringer, Carina C. de Oliveira Mann, Eduardo Beltrán, Tilmann Kallinich, Mir-Farzin Mashreghi, Susanne V. Schmidt, Eicke Latz, Johanna Klughammer, Olivia Majer, Min Ae Lee-Kirsch
Journal: Science Immunology (2024)

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.
Endobronchial Optical Coherence Tomography as a Novel Method for <i>In Vivo</i> Microscopic Assessment of Interstitial Lung Abnormalities
Authors: Lida P Hariri, Amita Sharma, Sreyankar Nandy, Sarita R. Berigei, Satomi Yamamoto, Rebecca A Raphaely, Bess M. Flashner, Ashok Muniappan, Hugh G. Auchincloss, Michael Lanuti, Robert W Hallowell, Barry S Shea, Colleen M. Keyes
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Endobronchial Optical Coherence Tomography as a Novel Method for In Vivo Microscopic Assessment of Interstitial Lung Abnormalities ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Disrupted degradative sorting of TLR7 is associated with human lupus
Authors: Harshita Mishra, Claire Schlack-Leigers, Ee Lyn Lim, Oliver Thieck, Thomas Magg, Johannes Raedler, Christine Wolf, Christoph Klein, Helge Ewers, Min Ae Lee-Kirsch, David Meierhofer, Fabian Hauck, Olivia Majer
Journal: Science Immunology (2024)

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.
Severe Pulmonary and Nasopharyngeal <i>Candida krusei</i> Infection in Cocaine-induced Vasculopathy
Authors: Driss Laghlam, Frederique Giraud, Sarah Benghanem
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Keywords: cocaine-induced vasculopathy; fungal infection; Severe candida pneumonia; immunosuppression
Endoscopic submucosal dissection of Barrett’s neoplasia using adaptive multipolar traction combined with line: report of two cases
Authors: Jean Grimaldi, Louis-Jean Masgnaux, Alexandru Lupu, Timothée Wallenhorst, Jérôme Rivory, Jérémie Jacques, Mathieu Pioche
Journal: Endoscopy (2024)

Endoscopic submucosal dissection (ESD) is the gold standard for the resection of visible lesions of >15 mm in Barrett's neoplasia [1]. Recently, the "tunnel + traction with a line" strategy has shown encouraging results in terms of safety and efficacy [2] [3]. However, the traction with a line technique has the disadvantage of exerting a traction force that is quasi-tangential to the plane of the submucosa. We believed that combining this with the ATRACT 2+2 adaptive multitraction device ([Fig. 1]) [4] [5] would enable a 90° traction force to be exerted, which could also be increased during the procedure.
Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes
Authors: Stephen M. Humphries, Devlin Thieke, David Baraghoshi, Matthew J. Strand, Jeffrey J. Swigris, Kum Ju Chae, Hye Jeon Hwang, Andrea S. Oh, Kevin R. Flaherty, Ayodeji Adegunsoye, Renea Jablonski, Cathryn T. Lee, Aliya N. Husain, Jonathan H. Chung, Mary E. Strek, David A. Lynch
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained a MIL algorithm using a pooled dataset (n=2,143) and tested it in three independent populations: data from a prior publication (n=127), a single-institution clinical cohort (n=239), and a national registry of patients with pulmonary fibrosis (n=979). We tested UIP classification performance using receiver operating characteristic (ROC) analysis with histologic UIP as ground truth. Cox proportional hazards and linear mixed effects models were used to examine associations between MIL predictions and survival or longitudinal forced vital capacity (FVC). Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve [AUC] 0.77 [n=127] and 0.79 [n=239]) compared to visual assessment (AUC 0.65 and 0.71). In cohorts with survival data, MIL UIP classifications were significant for mortality ([n=239, mortality to April 2021] unadjusted hazard ratio 3.1 95% confidence interval [CI] [1.96, 4.91] p<0.001, and [n=979, mortality to July 2022] 3.64 95% CI [2.66, 4.97] p<0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/year versus -45 ml/year, n=979 p<0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.
Guidewire-assisted piecemeal resection of a giant gastric tumor
Authors: Jixiang Ao, Silin Huang, Suhuan Liao, Longbin Huang, Erzhen Zhong, Pengcheng Zhao, Dongfang Wang
Journal: Endoscopy (2024)

A 55-year-old woman underwent esophagogastroduodenoscopy, which revealed a large subepithelial lesion located at the gastroesophageal junction, presenting a "horseshoe" morphology ([Fig. 1]). A subsequent computed tomography (CT) scan and endoscopic ultrasonography indicated the lesion was a solid mass protruding into the lumen. The patient then underwent endoscopic submucosal resection, resulting in complete excision of the lesion. Due to the considerable size of the tumor, traditional snare-based extraction was unfeasible. Therefore, an innovative slicing technique was employed ([Video 1]).
Abstract A006: Targeting SETD2 in combination with radiotherapy in rectal cancer
Authors: Lokesh Akana, Henrique Rodrigues, Oscar Zuniga, Adam R. Wolfe
Journal: Cancer Research (2024)

Abstract Purpose: Tri-methyl-histone H3 (Lys36) is a modification of histone H3 involved in gene regulation and chromatin organization. It plays a crucial role in cell response to ionizing radiation and affects DNA damage repair, with altered levels linked to decreased radiation sensitivity. We hypothesize that targeting SETD2, the histone methyltransferase responsible for adding the tri-methyl group to Lys36 of histone H3, may enhance radiosensitivity in rectal cancer cells. Methods: To understand the role of Tri-Methyl-Histone H3 (Lys36) in response to ionizing radiation (IR), clonogenic assays, γH2aX foci staining, and western blot analysis of DNA damage response proteins and histones were performed on two established human rectal cancer cell lines following either RNA inhibition (RNAi) or drug targeting of SETD2, EPZ-719. Results: After treating two colorectal cancer cell lines (LS123 and LoVo) with IR (5 Gy) in vitro, Tri-Methyl-Histone H3 (Lys36) levels increased. When combined with IR, SETD2 RNAi reduced Tri-Methyl-Histone H3 (Lys36) and decreased clonogenic survival and cell proliferation. In vitro treatment with a novel SETD2 inhibitor, EPZ-719, increased DNA damage following IR (5 Gy) as measured by γH2aX foci staining. The treatment with EPZ-719 showed an enhancement in radiosensitization with a 0.37 improvement in the dose enhancement ratio. Conclusion: Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys36) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients. Citation Format: Lokesh Akana, Henrique Rodrigues, Oscar Zuniga, Adam R. Wolfe. Targeting SETD2 in combination with radiotherapy in rectal cancer [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 A006.
Abstract A015: 53BP1 loss mediated PARP inhibitor resistance in BRCA1-deficient pancreatic cancer is overcome with immune checkpoint blockade
Authors: Jeffrey Patterson-Fortin, Yajie Sun, Sen Han, Zhe Li, Zuzanna Nowicka, Yuna Hirohashi, Susan Kilgas, Jae Kyo Yi, Alexander Spektor, Wojciech Fendler, Panagiotis Konstantinopoulos, Alan D. D'Andrea, Dipanjan Chowdhury
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by the presence of mutations in homologous recombination (HR) repair genes, including BRCA1 and BRCA2, in approximately 20% of diagnosed cases. 53BP1 (tumor protein p53 binding protein 1) nucleates the anti-end resection machinery at DNA double strand break (DSB)s thereby countering BRCA1 activity. Importantly, BRCA1-deficient PDACs that are typically sensitive to poly-ADP ribose polymerase inhibitors (PARPi) become resistant in the absence of 53BP1. Here, we demonstrate that loss of 53BP1 results in enhanced DNA end-resection, increased micronuclei, and cytoplasmic dsDNA, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, activating pro-inflammatory signaling. This not only enhances CD8+ T cell infiltration but also activates macrophages and natural killer (NK) cells culminating in tumor growth inhibition. Loss of 53BP1 correlates with response to immune checkpoint blockade (ICB) and improved overall survival. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Taken together, our findings provide a rationale for combining PARPi with ICB to overcome PARPi-resistance in BRCA1-deficient pancreatic cancers. Citation Format: Jeffrey Patterson-Fortin, Yajie Sun, Sen Han, Zhe Li, Zuzanna Nowicka, Yuna Hirohashi, Susan Kilgas, Jae Kyo Yi, Alexander Spektor, Wojciech Fendler, Panagiotis Konstantinopoulos, Alan D. D'Andrea, Dipanjan Chowdhury. 53BP1 loss mediated PARP inhibitor resistance in BRCA1-deficient pancreatic cancer is overcome with immune checkpoint blockade [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 A015.