tbuckley/cabot-search huggingface dataset:
Abstract 2438: Genetic activation of JUN fuels the core regulatory circuitry of de-differentiated liposarcoma
Authors: Ye Chen, Pushkar Dakle, Tuan Zea Tan, Ruby Yu-Tong Lin, Mark E. Puhaindran, Sigal Gery, Liang Xu, Phillip H. Koeffler
Journal: Cancer Research (2021)

Abstract Background: As a high-grade neoplasm of connective tissues, de-differentiated liposarcoma (DDLPS) is featured by genomic amplification of MDM2, CDK4 and JUN. Super-enhancer-driven master transcription factors (RUNX1, FOSL2 and MYC) establish a core feed-forward transcriptional circuit underpinning the DDLPS malignancy. However, an important question remains unanswered: how do genomic insults interact with epigenetic dysregulation in this disease? Methods: We performed ChIP-seq analysis to map loading of transcription factors and histone marks on chromatin in DDLPS cells. Functional assays following genetic manipulation of target genes were conducted to explore their disease relevance. Results: Genomic activation of JUN represents a promising prognostic marker for DDLPS. Meanwhile, JUN locus engaged excessive H3K27ac signals in both DDLPS tissues and cells, while a markedly lower level of H3K27ac deposition was observed in normal adipose tissues, adipocytes and MSCs. JUN formed a complex with FOSL2 and other co-factors in active chromatin, especially super-enhancers. Silencing of either JUN or its co-factors disrupted the core regulatory circuitry, which was accompanied by strong deleterious impacts on both cell viability and tumorigenicity. As BET bromodomain proteins dictate transcriptionally active chromatin, targeted degradation of BET proteins by PROTAC compounds exerted potent inhibitory effects on both JUN cistrome and DDLPS development. Conclusion: Our study reveals that amplification and overexpression of JUN contribute to DDLPS development. DDLPS-associated genomic abnormalities collaborate with BET proteins to fuel disease-driving core regulatory circuitry. Citation Format: Ye Chen, Pushkar Dakle, Tuan Zea Tan, Ruby Yu-Tong Lin, Mark E. Puhaindran, Sigal Gery, Liang Xu, Phillip H. Koeffler. Genetic activation of JUN fuels the core regulatory circuitry of de-differentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2438.
Sutureless purely off-clamp robotic partial nephrectomy: Surgical technique and outcomes
Authors: A. Brassetti, U. Anceschi, A. Bove, M. Costantini, M. Ferriero, S. Guaglianone, R. Mastroianni, G. Tuderti, M. Gallucci, G. Simone
Journal: European Urology (2021)
ミトコンドリア分裂は,飽和脂肪酸(SFA)誘発in vitroミトコンドリアインシュリン抵抗性モデルにおける耐糖能異常と関連している
Authors: Watanabe Tomoyuki, Saotome Masao, Nobuhara Mamoru, Urushida Tsuyoshi, Katoh Hideki, Satoh Hiroshi, Hayashi Hideharu
Journal: Circulation (2012)
Autoimmunity to annexin A2 predicts mortality among hospitalised COVID-19 patients
Authors: Marisol Zuniga, Claudia Gomes, Steven E. Carsons, Michael T. Bender, Paolo Cotzia, Qing Robert Miao, David C. Lee, Ana Rodriguez
Journal: European Respiratory Journal (2021)

<b>Levels of anti-annexin A2 antibodies at admission strongly predicted mortality among hospitalised COVID-19 patients. Given its critical protective function in the lung, annexin A2 antagonism may play an important role in the pathophysiology of COVID-19.</b>https://bit.ly/2UMPr9w
Abstract 81: Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms
Authors: Tanya Ivanova Stoyanova, En-Chi Hsu, Shiqin Liu, Fernando Jose Garcia Marques, Abel Bermudez, Merve Aslan, Michelle Shen, Sharon Pitteri, James D. Brooks
Journal: Cancer Research (2021)

Abstract Background: The first line of treatment for men with advanced prostate cancer is androgen deprivation therapy. Although initial responses are observed, prostate cancer commonly relapses in its lethal metastatic form referred to as castration resistant prostate cancer (CRPC) with 1-2 years mean survival time. Neuroendocrine prostate cancer (NEPC) is highly aggressive, AR independent subtype and usually emerges post castration resistance. We recently identified that the cell surface receptor, Trop2, is a new driver of NEPC. Moreover, we demonstrated that Trop2 regulates prostate cancer growth and metastasis. In this study, we set out to delineate the molecular mechanisms through which Trop2 regulates prostate cancer growth and metastasis. Methods: Proximity-dependent Biotin Identification (BioID) followed by mass spectrometry was performed to identify Trop2 interactome. Lentiviral infection was used to generate prostate cancer cell lines with over-expression of Trop2 and knock-down of NOTCH1, SLC4A7, PLEC, and OCLN shRNA to modulate gene expression levels. In vitro functional assays were performed including colony formation, and Matrigel drop 3D cell invasion assays. Results: The Trop2 membrane interactome was identified utilizing Proximity-dependent Biotin Identification (BioID) in living cells and uncovered that Trop2-mediated prostate cancer growth and metastasis are orchestrated by distinct downstream pathways including Notch signaling (NOTCH1), control of intracellular pH (SLC4A7), exosome secretion (PLEC), and tight junctions (OCLN). Interaction of Trop2 binding partners including NOTCH1, SLC4A7, PLEC and OCLN with Trop2 were further validated by fluorescence resonance energy transfer (FRET) using confocal microscopy. Moreover, knocking down the Trop2 interacting partners in Trop2 over-expressing prostate cancer cells suppressed Trop2-driven growth and invasion ability. Conclusions: In a previous study, we identified cell surface receptor, Trop2, as a novel driver of metastatic NEPC. Herein, our new findings reveal that Trop2 interacts with NOTCH1, SLC4A7, PLEC, and OCLN, which may highlight novel biological functions of Trop2 in prostate tumorigenesis and provide new understanding of the potential mechanism of neuroendocrine differentiation and metastasis to provide new therapeutic strategy for metastatic CRPC with neuroendocrine features. Citation Format: Tanya Ivanova Stoyanova, En-Chi Hsu, Shiqin Liu, Fernando Jose Garcia Marques, Abel Bermudez, Merve Aslan, Michelle Shen, Sharon Pitteri, James D. Brooks. Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 81.
Abstract 1963: High expression of Cyclin D1 is an independent marker for favorable prognosis in Middle Eastern breast cancer
Authors: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Sarah Siraj, Saud Azam, Padmanaban Annaiyappanaidu, Maria Angelita Sabido, Mark Ranier Diaz
Journal: Cancer Research (2021)

Abstract Cyclin D1 protein regulates cell cycle progression which is mediated by its interactions with cyclin-dependent kinases. Over-expression of Cyclin D1 has been observed in several human cancers. This study was conducted to evaluate Cyclin D1 expression in a large cohort of Middle Eastern breast cancers and determine its prognostic significance. Cyclin D1 expression was assessed immunohistochemically and its association with clinico-pathological parameters was analyzed. Cyclin D1 was over-expressed in 59.4% (596/1003) of cases and significantly associated with a subset of breast cancers having favorable prognostic features such as low grade (p &amp;lt; 0.0001), low stage (p = 0.0276), estrogen receptor positive (p &amp;lt; 0.0001) and progesterone receptor positive (p &amp;lt; 0.0001) tumors. An inverse association was found with triple negative breast cancers (p &amp;lt; 0.0001). More importantly, Cyclin D1 expression was an independent predictor of favorable overall survival in our cohort (Hazard ratio = 0.69; 955 confidence interval = 0.48 - 0.98; p = 0.0405). Also, tumors that highly expressed cyclin D1 had a longer recurrence free survival. However, recurrence free survival was only significant in univariate analysis. In conclusion, our results reinforced the role of cyclin D1 in breast cancer pathology and revealed its expression as a valuable independent prognostic indicator for breast cancer from Middle Eastern ethnicity. Citation Format: Khawla S. Al-Kuraya, Abdul K. Siraj, Sandeep K. Parvathareddy, Sarah Siraj, Saud Azam, Padmanaban Annaiyappanaidu, Maria Angelita Sabido, Mark Ranier Diaz. High expression of Cyclin D1 is an independent marker for favorable prognosis in Middle Eastern breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1963.
Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity
Authors: Jun Ye, Yue Gao, Ming Ji, Yanfang Yang, Zhaohui Wang, Baolian Wang, Jing Jin, Ling Li, Hongliang Wang, Xiaoyan Xu, Hengfeng Liao, Chunfang Lian, Yaqi Xu, Renjie Li, Tong Sun, Lili Gao, Yan Li, Xiaoguang Chen, Yuling Liu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Mesenteric lymph nodes (MLNs) are critical draining lymph nodes of the immune system that accommodate more than half of the body’s lymphocytes, suggesting their potential value as a cancer immunotherapy target. Therefore, efficient delivery of immunomodulators to the MLNs holds great potential for activating immune responses and enhancing the efficacy of antitumor immunotherapy. Self-microemulsifying drug delivery systems (SMEDDS) have attracted increasing attention to improving oral bioavailability by taking advantage of the intestinal lymphatic transport pathway. Relatively little focus has been given to the lymphatic transport advantage of SMEDDS for efficient immunomodulators delivery to the MLNs. In the present study, we aimed to change the intestinal lymphatic transport paradigm from increasing bioavailability to delivering high concentrations of immunomodulators to the MLNs. Methods Chlorogenic acid (CHA)-encapsulated SMEDDS (CHA-SME) were developed for targeted delivery of CHA to the MLNs. The intestinal lymphatic transport, immunoregulatory effects on immune cells, and overall antitumor immune efficacy of CHA-SME were investigated through in vitro and in vivo experiments. Results CHA-SME enhanced drug permeation through intestinal epithelial cells and promoted drug accumulation within the MLNs via the lymphatic transport pathway. Furthermore, CHA-SME inhibited tumor growth in subcutaneous and orthotopic glioma models by promoting dendritic cell maturation, priming the naive T cells into effector T cells, and inhibiting the immunosuppressive component. Notably, CHA-SME induced a long-term immune memory effect for immunotherapy. Conclusions These findings indicate that CHA-SME have great potential to enhance the immunotherapeutic efficacy of CHA by activating antitumor immune responses.
Abstract 2833: Mesothelin expression in human tumor types: a tissue microarray study on more than 13,000 tumor samples
Authors: Sören Weidemann, Natalia Gorbokon, Doris Höflmayer, Katharina Möller, David Dum, Andreas Luebke, Martina Kluth, Claudia Hube-Magg, Niclas Blessin, Guido Sauter, Jakob Izbicki, Ronald Simon, Stefan Steurer, Andreas Marx, Till Krech, Kristina Jansen, Maximilian Lennartz
Journal: Cancer Research (2021)

Abstract Mesothelin is a glycoprotein which is normally expressed in only few non-vital tissues. Due to its membranous location and expression in various cancer types, it represents an attractive molecule for target-specific cancer therapies. To examine, what tumor types might benefit most from anti-mesothelin therapies, a set of tissue microarrays containing samples from 13,298 tumors from 122 different tumor types and 608 samples from 76 different normal tissue categories were analyzed for mesothelin expression by immunohistochemistry. Sixty-six (54%) of these 122 tumor types and subtypes showed at least occasional weak staining, including 49 tumor types with at least one strongly positive sample. Tumor types with highest prevalence of mesothelin positivity included ovarian cancers (serous 97%, clear cell 83%, endometroid 77%, mucinous 71%, Müllerian mixed tumors 65%), pancreatic adenocarcinoma (81%), endometrial cancers (clear cell 71%, serous 57%, Müllerian mixed tumors 50%, endometroid 45%), malignant mesothelioma (71%), and lung adenocarcinoma (55%). Mesothelin positivity was particularly rare or absent in urothelial carcinoma (10% positive out of 925), breast cancer (6% of 1,285), renal cell cancer (7% of 1,049), adenocarcinoma of the prostate (0 of 498), thyroid carcinomas (0 of 238), and soft tissue tumors (0 of 920). Significant associations with patient outcome or parameters of malignancy were not observed in 1,072 breast cancers of no special type, 925 urinary bladder cancers, 386 serous ovarian cancers, 266 lung cancers or 373 stomach cancers. Taken together, our systematic and highly standardized analysis identified numerous clinically important cancer types with frequent and high level mesothelin expression. These tumor types might benefit most from future anti-mesothelin therapies. The prognostic relevance of mesothelin appears to be low in the analyzed tumor types. Citation Format: Sören Weidemann, Natalia Gorbokon, Doris Höflmayer, Katharina Möller, David Dum, Andreas Luebke, Martina Kluth, Claudia Hube-Magg, Niclas Blessin, Guido Sauter, Jakob Izbicki, Ronald Simon, Stefan Steurer, Andreas Marx, Till Krech, Kristina Jansen, Maximilian Lennartz. Mesothelin expression in human tumor types: a tissue microarray study on more than 13,000 tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2833.
Abstract 397: <i>ECM2</i> mutation can serve as a potential efficacious predictor of immunotherapy in melanoma patients
Authors: Qitao Yu, Aiping Zeng, Yun Zhao, Xiaochun Huang, Wenzhuan Xie, Mengli Huang, Ting Bei
Journal: Cancer Research (2021)

Abstract Background: Epithelial-mesenchymal transition (EMT) has been reported to play a pivotal role in tumor immunosuppression and immune evasion. In multiple solid tumors, PD-L1 expression was much higher in “mesenchymal” compared with that in “epithelial”, indicating patients with mesenchymal phenotypes are more likely to benefit from PD-1/PD-L1 immunotherapy. ECM2 encodes a putative extracellular matrix protein, which involves in cell-cell and/or cell ECM recognition processes, thereby may affecting EMT. However, the predictive value of ECM2 in cancer immunotherapy has not been revealed. Method: Seven independent public cohorts of NSCLC, melanoma, and pan-cancer, including Rizvi, Van Allen, MSKCC, OAK/POPLAR, Miao, and Samstein cohorts were used to investigate the correlation between ECM2 mutation and clinical events, such as objective response rate (ORR), overall survival (OS), and progression free survival (PFS). Result: Across all the analyzed cancer types, ECM2 mutation has a strong connection with better outcomes to immune checkpoint inhibitors only in melanoma cancer. ECM2-mutated group was significantly associated with higher ORR (75.0% vs 13.9%, P = 0.013), longer OS (35.9 months vs 8.5 months, 95% CI, 0.02-1.09, P = 0.032) than ECM2-wide-type group. PFS between these two groups was comparable (8.15 months vs 2.8 months, 95% CI, P = 0.25). Furthermore, melanoma patients harboring ECM2 mutation exhibited significantly higher TMB compared with ECM2-wide-type patients in Van Allen cohort (1279.5 mut/Mb vs 125.5 mut/Mb, P = 0.0056). Conclusion: This study demonstrated that ECM2 mutation can serve as a potential predictor for a favorable response to ICIs in melanoma patients. Citation Format: Qitao Yu, Aiping Zeng, Yun Zhao, Xiaochun Huang, Wenzhuan Xie, Mengli Huang, Ting Bei. ECM2 mutation can serve as a potential efficacious predictor of immunotherapy in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 397.
Abstract 2402: Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression
Authors: Ching-Wen Chang, Yu-Syuan Chen, Jeng-Fan Lo, Xin Wei Wang
Journal: Cancer Research (2021)

Abstract Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor to drive hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation, meanwhile; sequentially developed fatty liver, NASH, and cirrhosis/HCC in a Diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 mRNA expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that plays a key mechanism involved in the NASH-dependent HCC development. Overall, we established a new mouse model developing NASH-dependent HCC and provided a promising approach for improving the treatment. Citation Format: Ching-Wen Chang, Yu-Syuan Chen, Jeng-Fan Lo, Xin Wei Wang. Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2402.
Abstract 23: Validation of a 27-gene immuno-oncology algorithm in metastatic urothelial carcinoma treated with an immune checkpoint inhibitor
Authors: Robert S. Seitz, Douglas T. Ross, Tyler J. Nielsen, David R. Hout, Brock L. Schweitzer
Journal: Cancer Research (2021)

Abstract Background Prognosis for patients with metastatic urothelial carcinoma (mUC) remains poor with fewer than 10% of patients surviving two years after diagnosis. The IMvigor210 was a multicenter, single-arm, phase 2 trial in patients with mUC treated by the immune checkpoint inhibitor (ICI) atezolizumab. RNA expression, overall survival, tumor mutation burden (TMB), and PD-L1 IHC data from this trial are publicly available.The 27-gene immuno-oncology (IO) algorithm has previously demonstrated significant association with ICI response in NSCLC and TNBC using three different ICI agents. Importantly, the algorithm and threshold for positivity was established prior to testing in ICI treated cohorts. Methods The prospectively defined 27-gene IO algorithm and threshold (IO Score) were applied to classify patients as likely responders or non-responders using available RNA expression data from 348 patients in the IMvigor210 trial. Cox proportional hazard models for overall survival was performed and the coefficient for the IO Score was determined in both a univariate and a multivariate equation with PD-L1 IHC and TMB. Results In total, 142 patients were positive by the IO Score (41%). Positivity was significantly associated with response (HR=0.61; 95% CI = 0.46 to 0.80; p &amp;lt; 0.001) and was significant in multivariate analysis with PD-L1 and TMB (HR=0.64; 95% CI = 0.45 to 0.92; p &amp;lt; 0.02). While both PD-L1 IHC staining and TMB were significant in univariate analysis, only TMB maintained significance in the multivariate equation. Conclusions These data demonstrate the association of the 27-gene IO algorithm and binary IO Score with response to ICI treatment in a third tissue indication (TNBC, NSCLC, and mUC) including four different ICI agents (two anti-PD-L1 and two anti-PD1). The algorithm and classification threshold were established prior to testing in all three studies and was not changed between the different tissue indications. Furthermore, in all three indications, only the IO Score consistently maintained significance in multivariate analysis with PD-L1 IHC and TMB. Taken together, these data begin to establish the 27-gene IO signature as a pan-cancer predictor of response to ICI therapy. Citation Format: Robert S. Seitz, Douglas T. Ross, Tyler J. Nielsen, David R. Hout, Brock L. Schweitzer. Validation of a 27-gene immuno-oncology algorithm in metastatic urothelial carcinoma treated with an immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 23.
The effect of early probiotic exposure on the preterm infant gut microbiome development
Authors: Yan Hui, Birgitte Smith, Martin Steen Mortensen, Lukasz Krych, Søren J. Sørensen, Gorm Greisen, Karen Angeliki Krogfelt, Dennis Sandris Nielsen
Journal: Gut Microbes (2021)

Premature birth, especially if born before week 32 of gestation, is associated with increased risk of neonatal morbidity and mortality. Prophylactic use of probiotics has been suggested to protect preterm infants via supporting a healthy gut microbiota (GM) development, but the suggested strains and doses vary between studies. In this study, we profiled the GM of 5, 10 and 30-day fecal samples from two cohorts of preterm neonates (born <30 weeks of gestation) recruited in the same neonatal intensive care unit. One cohort (n = 165) was recruited from September 2006 to January 2009 before probiotics were introduced in the clinic. The second cohort (n = 87) was recruited from May 2010 to October 2011 after introducing Lacticaseibacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis BB-12 supplementation policy. Through V3-V4 region 16S rRNA gene amplicon sequencing, a distinct increase of L. rhamnosus and B. animalis was found in the fecal samples of neonates supplemented with probiotics. During the first 30 days of life, the preterm GM went through similarly patterned progression of bacterial populations. Staphylococcus and Weissella dominated in early samples, but was gradually overtaken by Veillonella, Enterococcus and Enterobacteriaceae. Probiotic supplementation was associated with pronounced reduction of Weissella, Veillonella spp. and the opportunistic pathogen Klebsiella. Potential nosocomial pathogens Citrobacter and Chryseobacterium species also gradually phased out. In conclusion, probiotic supplementation to preterm neonates affected gut colonization by certain bacteria, but did not change the overall longitudinal bacterial progression in the neonatal period.Abbreviations: GM: Gut microbiota; ASV: Amplicon sequence variant; NEC: Necrotizing enterocolitis; DOL: Days of life; NICU: Neonatal intensive care unit; ESPGHAN: European Society for Pediatric Gastroenterology, Hepatology and Nutrition; Db-RDA: Distance-based redundancy analysis; PERMANOVA: Permutational multivariate analysis of variance; ANCOM: Analysis of compositions of microbiomes; LGG: Lacticaseibacillus (former Lactobacillus) rhamnosus GG; BB-12: Bifidobacterium animalis ssp. lactis BB-12; DGGE: Denaturing Gradient Gel Electrophoresis.