tbuckley/cabot-search huggingface dataset:
TXNIP/Redd1 signalling and excessive autophagy: a novel mechanism of myocardial ischaemia/reperfusion injury in mice
Authors: Chao Gao, Rutao Wang, Bing Li, Yongzhen Guo, Tao Yin, Yunlong Xia, Fuyang Zhang, Kun Lian, Yi Liu, Han Wang, Ling Zhang, Erhe Gao, Wenjun Yan, Ling Tao
Journal: Cardiovascular Research (2019)

Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the 'right-level' of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated.Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts.Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.
Dengue virus–elicited tryptase induces endothelial permeability and shock
Authors: Abhay P.S. Rathore, Chinmay Kumar Mantri, Siti A.B. Aman, Ayesa Syenina, Justin Ooi, Cyril J. Jagaraj, Chi Ching Goh, Hasitha Tissera, Annelies Wilder-Smith, Lai Guan Ng, Duane J. Gubler, Ashley L. St. John
Journal: Journal of Clinical Investigation (2019)

Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we identified that a MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection, through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in two independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.
Abstract 3199: Targeting LHRH-R to improve immune response in ovarian cancer
Authors: Mark S. Kim, Shaolin Ma, Carola Leuschner, Sanghoon Lee, Robert L. Coleman, Anil K. Sood
Journal: Cancer Research (2019)

Abstract Background: While immune checkpoint inhibitors have revolutionized the treatment of multiple cancers, such therapies have had limited efficacy in ovarian cancer. We hypothesized that a lytic peptide could stimulate local immune response and enhance efficacy of checkpoint blockade. Here, we tested the effects of a synthetic lytic peptide targeting the luteinizing hormone receptor (LHRH-R), EP-100, on immune therapy in ovarian cancer models. Methods: We carried out series of in vitro (MTT assay, immunoblot analysis, cytokine array, and immune profiling assay) and in vivo (orthotopic mouse model) experiments to determine the biological effects of EP-100 monotherapy and its combination with checkpoint blockade, α-PD-L1. Results: We found that LHRH-R positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. The in vivo syngeneic mouse models (ID8 and IG10) demonstrated that EP-100 reduced tumor volume, tumor weight, and ascites volume as a single agent. The greatest effects on tumor volume reduction and ascites volume were observed with the combination of EP-100 and α-PD-L1 antibody, indicating a potentially synergistic effect in vivo. Immune profiling of tumors showed that the population of CD8+ T cells, NK cells, dendritic cells, and macrophages were significantly increased in tumor and ascites treated with α-PD-L1, EP-100 and in the combination group. However, monocytic myeloid suppressor cells, B cells, and regulatory T cells were decreased in tumors treated with α-PD-L1, EP-100 and in the combination group. We found similar effects of EP-100 combination with α-PD-L1 antibody in ascites from each group. These data indicate that EP-100 promotes a tumor microenvironment that is favorable for immune response. In vitro cytokine arrays revealed that EP-100 induced IL-1α, IL-33, CCL20, VEGF, and LDLR secretion. Among them, we validated increasing Il-33 level following EP-100 treatment in vivo and in vitro and determined the specific biological role of CD8+ T cell activation with IL-33 gene silencing using siRNA and Cas9-CRISPR approaches. In addition, we found that CD8+ T cell expressed a low level of LHRH-R and had minimal direct effects from EP-100. Conclusion: These data demonstrate strong efficacy of EP-100 and checkpoint blockade therapy. Our results provide new directions to enhance the efficacy of immune therapies for ovarian cancer. Citation Format: Mark S. Kim, Shaolin Ma, Carola Leuschner, Sanghoon Lee, Robert L. Coleman, Anil K. Sood. Targeting LHRH-R to improve immune response in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3199.
Carfilzomib (K) in relapsed and refractory multiple myeloma (RRMM): Frailty subgroup analysis from phase III ASPIRE and ENDEAVOR.
Authors: Thierry Facon, Ruben Niesvizky, Katja Weisel, Sara Bringhen, P. Joy Ho, Mihaela Obreja, Zhao Yang, Zandra Karina Klippel, Julie Blaedel, Khalid Mezzi, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2019)

8028 Background: K-based regimens improved progression-free survival (PFS) and overall survival (OS) in RRMM patients (pts) in ASPIRE (K [27 mg/m 2 ]-lenalidomide-dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m 2 ]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). We assessed post hoc pt outcomes by frailty status. Methods: PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history-derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail. Results: Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K-based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment-emergent adverse events are summarized in the Table. Conclusions: Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit-risk profile of KRd and Kd56 regardless of frailty score. Clinical trial information: NCT01080391 and NCT01568866. [Table: see text]
Abstract 1797: Serum microRNAs as immune modulators and biomarkers of breast cancer recurrence
Authors: Lauren Chen, Mithil Soni
Journal: Cancer Research (2019)

Abstract MicroRNAs (microRNAs) are short sequences of RNA (about 22 nucleotides) that are involved in the regulation of gene expression. Previous studies have suggested that a number of microRNAs are recognized as new biomarkers for cancers. The aim of this study is to identify specific microRNAs in serum, which may serve as potential diagnostic and prognostic biomarkers and therapeutic targets for breast cancer. Quantitative real-time PCR (qRT-PCR) array analyses of microRNAs in sera from four pairs of recurrent and nonrecurrent breast cancer patients were performed. Those differentially expressed microRNAs were verified in serum samples from 42 breast cancer patients. The prognostic values of the selected microRNAs were statistically analyzed, determined by the correlation between microRNA expression and tumor parameters. High serum levels of miR-134 and miR-483-5p were found to be associated with some aggressive tumor behaviors. Kaplan-Meier analysis of four upregulated microRNAs (miR-134, miR-483-5p, miR-493-3p and miR-139-3p) indicated that serum level of miR-134 can predict tumor recurrence in breast cancer patients after primary treatment. Further functional analysis showed that overexpression of miR-134 has no significant effects on tumor growth but regulates macrophage M1/M2 polarization. Overall, our data suggested that serum microRNAs may promote tumor progression and recurrence via modulating inflammation and immune response and potentially serve as blood biomarkers for prediction of recurrence in breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Lauren Chen, Mithil Soni. Serum microRNAs as immune modulators and biomarkers of breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1797.
The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells
Authors: Katrin Mestermann, Theodoros Giavridis, Justus Weber, Julian Rydzek, Silke Frenz, Thomas Nerreter, Andreas Mades, Michel Sadelain, Hermann Einsele, Michael Hudecek
Journal: Science Translational Medicine (2019)

Dasatinib is a pharmacologic switch for CARs that enables physicians to control CAR T cell function in real time.
Abstract 3433: IL11 promotes the PhIP/DSS-induced colon carcinogenesis
Authors: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang
Journal: Cancer Research (2019)

Abstract Inflammation of the large intestine, such as colitis, is known to increase the risk of colorectal cancer in human. The colitis induced by dextran sodium sulfite (DSS) has been shown to promote carcinogen- and genetic-induced colon tumorigenesis in rodent models. In a CYP1A-humanized (hCYP1A) mouse colon cancer model that we developed to study dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), DSS-induced colitis was required for colon tumor development after the PhIP treatment. Nevertheless, the mechanism for DSS-induced colitis to promote carcinogenesis is not clear. To uncover the key cancer promotion factor induced by colitis is important in understanding the mechanism of colon cancer development. By investigating the gene expression profiles of PhIP/DSS-induced colon tumors and normal colon epithelium, we found that cytokine IL11 was significantly upregulated in all tumors. The elevated levels of IL11 are also found in the human colon cancer genomic data available in The Cancer Genome Atlas (TCGA), suggesting an important role of IL11 in human colon cancer. Consistently, the activation/phosphorylation of STAT3, a key downstream factor of IL11 signaling, was also positively identified in tumors but not the normal adjacent tissues. To investigate the role of IL11 signaling, we generated hCYP1A:IL11Rα1-/- mice for investigating the role of IL11 signaling in PhIP/DSS-induced carcinogenesis by crossing the IL11Rα1-/- mice with hCYP1A mice. These mice are infertile as the phenotype reported previously for the IL11Rα1 knockout mice, and need to be maintained through the breeding by the heterozygous. The experimental mice were maintained on the AIN93M diet. We found that the tumor incidence was reduced by 51.0% in hCYP1A:IL11Rα1+/- mice and 80.0% in hCYP1A:IL11Rα1-/- mice, suggesting that IL11 signaling plays critical roles in PhIP/DSS-induced colon carcinogenesis. By immunohistochemical staining for pSTAT3, we found the pSTAT3 staining in the colitis epithelial tissues induced by the DSS treatment in both heterozygous and homozygous mice were significantly reduced; whereas the tissues from the wildtype mice displayed strong positive staining in the nucleus. IL11 signaling could be a potential therapeutic target for colon cancer prevention. (supported by the John L. Colaizzi Chair Endowment Fund and GI Pilot Study from Rutgers Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720) Citation Format: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang. IL11 promotes the PhIP/DSS-induced colon carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3433.
Abstract 2934: AKT mutant allele-specific activation dictates pharmacologic sensitivities
Authors: Tripti Shrestha Bhattarai, Tambudzai Shamu, Swati Patel, Alexander Gorelick, Matthew T. Chang, Elena I. Gavrila, JianJong Gao, Mark T. Donoghue, Paul S. Gao, Tara Soumerai, Wassim Abida, Lilian M. Smyth, David M. Hyman, David B. Solit, Barry S. Taylor
Journal: Cancer Research (2019)

Abstract The objective of this study is to explore the biochemical characteristics and therapeutic sensitivity profiles of novel, non-E17K, less frequent AKT1 mutations, and thereby expand the biomarker of sensitivity to AKT inhibition in molecularly defined cancer patients. AKT is a critical signaling node that translates phosphoinositide 3-kinase (PI3K) pathway stimulation into diverse cellular effects. Gain of function AKT1 mutations arise in diverse human cancers, of which E17K is the most common. Presence of AKT1 E17K mutation renders these tumors susceptible to AKT inhibition. Nevertheless, the long tail of potentially activating mutations in AKT is largely uncharacterized, thereby limiting our ability to act clinically in prospectively sequenced advanced cancer patients. We performed a population-scale candidate driver mutation discovery analysis in AKT1, AKT2 and AKT3 in a cohort of 41,075 retrospectively and prospectively sequenced primary and metastatic cancers, and explored both their functional and biological impact as well as their therapeutic sensitivity. Our results demonstrated that some, but not all of the identified AKT missense mutations activated PI3K signaling in a growth factor-independent manner, and sensitized tumor cells to diverse AKT inhibitors. By contrast, we discovered a different class of small in-frame paralogous AKT duplication mutants that induced distinctive structural changes, leading to a far greater degree of membrane affinity, AKT activation, pathway dependence, and hyper-sensitivity to ATP-competitive AKT inhibitors, while conferring resistance to allosteric AKT inhibitors. Leveraging a co-clinical trial framework, we are now enrolling patients on the basis of these mutations in a basket study involving AKT alterations. One such case was that of a castration-resistant metastatic prostate cancer patient who harbored AKT2 duplication mutant, and subsequently responded to AKT inhibition. Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition. Citation Format: Tripti Shrestha Bhattarai, Tambudzai Shamu, Swati Patel, Alexander Gorelick, Matthew T. Chang, Elena I. Gavrila, JianJong Gao, Mark T. Donoghue, Paul S. Gao, Tara Soumerai, Wassim Abida, Lilian M. Smyth, David M. Hyman, David B. Solit, Barry S. Taylor. AKT mutant allele-specific activation dictates pharmacologic sensitivities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2934.
Strategies to Identify Women at High Risk of Advanced Breast Cancer During Routine Screening for Discussion of Supplemental Imaging
Authors: Karla Kerlikowske, Brian L. Sprague, Anna N. A. Tosteson, Karen J. Wernli, Garth H. Rauscher, Dianne Johnson, Diana S. M. Buist, Tracy Onega, Louise M. Henderson, Ellen S. O’Meara, Diana L. Miglioretti
Journal: JAMA Internal Medicine (2019)

Federal legislation proposes requiring that screening mammography reports to practitioners and women incorporate breast density information and that women with dense breasts discuss supplemental imaging with their practitioner given their increased risk of interval breast cancer. Instead of discussing supplemental imaging with all women with dense breasts, it may be more efficient to identify women at high risk of advanced breast cancer who may benefit most from supplemental imaging.To identify women at high risk of advanced breast cancer to target woman-practitioner discussions about the need for supplemental imaging.This prospective cohort study assessed 638 856 women aged 40 to 74 years who had 1 693 163 screening digital mammograms taken at Breast Cancer Surveillance Consortium (BCSC) imaging facilities from January 3, 2005, to December 31, 2014. Data analysis was performed from October 10, 2018, to March 20, 2019.Breast Imaging Reporting and Data System (BI-RADS) breast density and BCSC 5-year breast cancer risk.Advanced breast cancer (stage IIB or higher) within 12 months of screening mammography; high advanced cancer rates (≥0.61 cases per 1000 mammograms) defined as the top 25th percentile of advanced cancer rates, and discussions per potential advanced cancer prevented.A total of 638 856 women (mean [SD] age, 56.5 [8.9] years) were included in the study. Women with dense breasts (heterogeneously or extremely dense) accounted for 47.0% of screened women and 60.0% of advanced cancers. Low advanced cancer rates (<0.61 per 1000 mammograms) occurred in 34.5% of screened women with dense breasts. High advanced breast cancer rates occurred in women with heterogeneously dense breasts and a 5-year risk of 2.5% or higher (6.0% of screened women) and those with extremely dense breasts and a 5-year risk of 1.0% or higher (6.5% of screened women). Density-risk subgroups at high advanced cancer risk comprised 12.5% of screened women and 27.1% of advanced cancers. Density-risk subgroups had the fewest supplemental imaging discussions per potential advanced cancer prevented compared with a strategy based on dense breasts (1097 vs 1866 discussions). Women with heterogeneously dense breasts and a 5-year risk less than 1.67% (21.7% of screened women) had high rates of false-positive short-interval follow-up recommendation without undergoing supplemental imaging.The findings suggest that breast density notification should be combined with breast cancer risk so women at highest risk for advanced cancer are targeted for supplemental imaging discussions and women at low risk are not. BI-RADS breast density combined with BCSC 5-year risk may offer a more efficient strategy for supplemental imaging discussions than targeting all women with dense breasts.
Vaginal discharge—causes, diagnosis, and treatment
Authors: Helen Mitchell
Journal: BMJ (2004)

Vaginal discharge is a common presenting symptom seen by doctors in many services (primary care, gynaecology, family planning, and departments of genitourinary medicine). Vaginal discharge may be physiological or pathological. Although abnormal vaginal discharge often prompts women to seek screening for sexually transmitted infections (STIs), vaginal discharge is poorly predictive of the presence of an STI. This article focuses on the causes and diagnosis of vaginal discharge and treatment of the most common infective causes.

### Physiological discharge

Normal vaginal flora (lactobacilli) colonise the vaginal epithelium and may have a role in defence against infection. They maintain the normal vaginal pH between 3.8 and 4.4. The quality and quantity of vaginal discharge may alter in the same woman in cycles and over time; each woman has her own sense of normality and what is acceptable or excessive for her.

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What can influence physiological discharge?



### Pathological vaginal discharge

Vulvovaginal candidiasis is a common infective cause of vaginal discharge that affects about 75% of women at some time during their reproductive life, with 40-50% having two or more episodes. Bacterial vaginosis is one of the most common diagnoses in women attending genitourinary medicine clinics. As 50% of cases of bacterial vaginosis are asymptomatic, the true prevalence of this condition in the community is uncertain. Bacterial vaginosis is associated with a new sexual partner and frequent change of sexual partners. A reduced rate of bacterial vaginosis is seen among women in monogamous sexual relationships, but it can occur in virginal women. Increased rates of bacterial vaginosis occur in certain groups of women, such as black African women, lesbians, and smokers.

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Pathological vaginal discharge



Recurrence of bacterial vaginosis after treatment is common and can be increased by personal hygiene practices, such as vaginal douching, that disrupt the normal vaginal flora. Bacterial vaginosis may also be associated with concurrent STIs, commonly …
Pulmonary Atresia With Intact Ventricular Septum
Authors: P. E. F. Daubeney, G. K. Sharland, A. C. Cook, B. R. Keeton, R. H. Anderson, S. A. Webber
Journal: Circulation (1998)

Background —Fetal echocardiography is widely established in the United Kingdom for prenatal diagnosis of congenital heart disease. This may result in a substantial reduction in incidence at birth because of selected termination of pregnancy. The objective of this population-based study was to determine the incidence of pulmonary atresia with intact ventricular septum (PAIVS) at birth, the impact of fetal echocardiography on this incidence, and to compare the outcome of cases with and those without prenatal diagnosis. Methods and Results —From 1991 to 1995, all infants born with PAIVS and all fetal diagnoses in the United Kingdom and Eire were studied. There were 183 live births (incidence 4.5/100 000 live births). The incidence was 4.1 cases per 100 000 live births in England and Wales, 4.7 in Scotland, 6.8 in Eire, and 9.6 in Northern Ireland ( P =0.01). There were 86 fetal diagnoses made at a mean of 22.0 weeks of gestation leading to 53 terminations of pregnancy (61%), 4 intrauterine deaths (5%), and 29 live births (34%). The incidence at birth would be 5.6 per 100 000 births in England and Wales, 5.3 in Scotland, and unchanged in Eire and Northern Ireland, if there were no terminations of pregnancy and assuming no further spontaneous fetal deaths ( P =0.28). An initial diagnosis of critical pulmonary stenosis was made in 6 cases, at a mean of 22.3 weeks of gestation with progression to PAIVS by 31.4 weeks. Probability of survival at 1 year was 65% and was the same for live-born infants whether or not a fetal diagnosis had been made. Conclusions —PAIVS is rare, occurring in 1 in 22 000 live births in the United Kingdom and Eire. Termination of pregnancy has resulted in an important reduction in the live-born incidence in mainland Britain.