tbuckley/cabot-search huggingface dataset:
Abstract 15: PA28γ contributes to tumor angiogenesis through regulation of IL-6 and CCL2 in oral squamous cell carcinoma
Authors: Xin Zeng, Jing Li, Jiajia Liu, Ning Ji, Hui Feng, Qianming Chen
Journal: Cancer Research (2018)

Abstract Background: PA28γ has been shown to promote tumor development and progression. Although PA28γ has been suggested to play a role in tumor angiogenesis, direct evidence for the molecular mechanisms underlying this phenomenon have not been investigated. Methods: Oral squamous cell carcinoma (OSCC) stable cell lines with varying levels of PA28γ expression were constructed. EA.hy926 human endothelial cells were co-cultured with these lines to evaluate the influence of PA28γ on EA.hy926 cell proliferation, migration, invasion, and tube formation. Using a subcutaneous xenotransplantation tumor model of under-expressing PA28γ HSC-3 cells, we explored effects on tumor angiogenesis in nude mice. We performed screens of the different angiogenesis-related genes and cytokines being expressed using PCR and cytokine chips to identify candidates with the potential to affect tumor angiogenesis. Then, candidates were verified using Western blot, and neutralization tests immunohistochemistry. Finally human OSCC clinical cohort was used to validate. Results: PA28γ could enhance the ability of OSCC cells to interact with endothelial cells, thereby recruit endothelial cells and induce angiogenesis. Ablation of PA28γ inhibits tumor-induced angiogenesis in xenografts mice model in vivo. In vivo zebrafish model experiments showed that depleted PA28γ remarkably blocked the formation of intersegmental vessels in zebrafish embryos. Furthermore, Angiogenesis-related PCR, cytokine chips and Western blot analysis indicated that PA28γ through regulate IL-6 and CCL2 expression, thereby subsequent activation of the Stat3/VEGF and PI3K/MMP-1 axis to promote angiogenesis. Neutralization or block results IL-6 and CCL2 has an essential role in PA28γ-controlled promotes of angiogenesis. In addition, clinical OSCC cohort validate that PA28γ positively correlates with IL-6 or CCL2 expression. Conclusion: Collectively, our data show that PA28γ contributes to the tumor angiogenesis, by regulating IL-6 and CCL2. PA28γ thus represents a novel therapeutic target for treating PA28γ-positive OSCC cancers. Citation Format: Xin Zeng, Jing Li, Jiajia Liu, Ning Ji, Hui Feng, Qianming Chen. PA28γ contributes to tumor angiogenesis through regulation of IL-6 and CCL2 in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 15.
Phone Apps for Patients With Diabetes
Authors: Rita Rubin
Journal: JAMA (2018)

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Abstract 16236: The Majority of Laypersons Trained in CPR Do Not Maintain Current Certification or Training
Authors: Audrey L Blewer, Marion Leary, Daniel Ikeda, Lance B Becker, Benjamin S Abella
Journal: Circulation (2015)

Background: Recent work has demonstrated that U.S. CPR training rates are low, yet few studies have measured the overall prevalence of CPR education and whether individuals have maintained training over time. Furthermore, few studies have linked individual-level demographics with current maintenance of CPR training. Quantifying these variations could help inform future targeted education initiatives. Objectives: We hypothesized that current CPR training frequency is low in Southeastern Pennsylvania (SEPA). As a secondary analysis, we examined gender and racial variation among those who are currently trained. Methods: We administered validated survey questions to assess CPR training status through the Community Health Household Survey, a semi-annual survey of 50,000 households in SEPA. Participants were contacted via random-digit-dialing using stratified sampling methods. Analysis was performed using categorical methods. Results: From 12/2014-2/2015, 10,048 participants completed the regional health household survey. Subjects mean age was 44±23 and 55% were female. Overall, 61% identified taking a CPR training course at some point in time, while only 18% were trained within the past two years; 15% identified being CPR certified. Of those who were certified, 76% sought certification for their vocation. CPR training status varied by gender, with more females identified being trained in the past two years compared to males (61% vs 39%, p&lt;0.01). This gender distribution was similar among those who reported certification for their vocation (62% vs 38%, p&lt;0.01). Additionally, current CPR training status varied by race; among those trained within two years, 62% were White, 27% were Black, and 6% were Latino (p&lt;0.01). Conclusions: The overall prevalence of those currently trained or certified in CPR was low in SEPA. These data suggest that many individuals seek CPR training at some point, but few maintain current training or certification. Additionally, there was gender and racial variation among those currently trained within the past 2 years. These data suggest the need for programs to offer CPR skill refreshers among targeted layperson subpopulations. Future work may consider implementing a similar CPR training prevalence survey nationally.
Abstract 16740: Clinical Judgement Alone Challenges Evidence Based Clinical Predictive Rules When Diagnosing Cardiogenic Syncope
Authors: Marina Iskandir, Arismendy Nunez, Hemal Bhatt, Kaushik Patel, Soroori R Bahareh, David Beshai, Thomas Bustros
Journal: Circulation (2016)

Clinicians vary in their ability to classify patients presenting with syncope into cardiogenic or high risk and vasovagal or low risk categories. Several clinical prediction rules (CPRs) have been developed to assist clinicians in the decision to admit patients who present with syncope or discharge them home from the Emergency Department (ED). We hypothesized that CJ is better at predicting cardiac etiology of syncope and short term adverse outcomes than CPRs (OESIL and EGSYS).  Between January 2012 and August 2012 and January 2013 to August 2013 we reviewed all adult patients that presented to the ED with chief complaint of syncope. Syncope was defined by the presence of transient loss of consciousness with spontaneous return to baseline. Patients were interviewed in the ED and followed up via a phone 10 days after the visit for the presence of adverse outcomes. Both CPRs were applied to each one of the subjects. For CJ, we considered patients admitted to telemetry as high risk for adverse event and cardiac syncope and patients discharged from the ED as low risk.  645 patients were screened, 135 met inclusion criteria and 3 were lost to follow up. The remaining 132 subjects were enrolled in the study. The OESIL score had a sensitivity 80 % specificity 40% PPV 24% and NPV 90% for adverse outcomes and a sensitivity 91 % specificity 40% PPV 13% and NPV 98% for cardiac etiology. EGSYS had a sensitivity 32%, specificity 73%, PPV 21% and NPV 82% for adverse outcome and a sensitivity 67%, specificity 53%, PPV 13% and NPV 94% for cardiac etiology. CJ had a sensitivity of 96%, specificity of 25%, PPV 23% and NPV 96 for adverse outcome and sensitivity of 91%, specificity of 32%, PPV 12% and NPV 97 for cardiac etiology.  In conclusion, the results suggest that none of the studied CPR offers sufficient accuracy to be used as sole instrument to risk stratify patients presenting with syncope to the ED. However, In comparison with CJ the OESIL score shows a better specificity while maintaining similar sensitivity to predict cardiogenic syncope. It would have decreased the number of admissions to telemetry by 6% without a difference in the number of missed events. Regarding adverse outcomes neither of the CPR offers an improved predictive ability as compared with CJ.
pH-sensitive radiolabeled and superfluorinated ultra-small palladium nanosheet as a high-performance multimodal platform for tumor theranostics
Authors: Zhide Guo, Mei Chen, Chenyu Peng, Shiguang Mo, Changrong Shi, Guifeng Fu, Xuejun Wen, Rongqiang Zhuang, Xinhui Su, Ting Liu, Nanfeng Zheng, Xianzhong Zhang
Journal: Biomaterials (2018)
The Calcium-Dependent Protease Calpain-1 Links TRPC6 Activity to Podocyte Injury
Authors: Kim A.T. Verheijden, Ramon Sonneveld, Marinka Bakker-van Bebber, Jack F.M. Wetzels, Johan van der Vlag, Tom Nijenhuis
Journal: Journal of the American Society of Nephrology (2018)

Background The hallmark of podocytopathies, such as FSGS, is podocyte injury resulting in proteinuria. Transient receptor potential channel C6 (TRPC6) is a calcium-conducting ion channel expressed at the slit diaphragm. TRPC6 gain-of-function mutations and glomerular TRPC6 overexpression are associated with proteinuria. However, the pathways linking TRPC6 to podocyte injury, which is characterized by loss of the slit diaphragm protein nephrin, activation of several intracellular pathways (including calcineurin-NFAT signaling), and cytoskeletal rearrangement, remain elusive. Methods We tested whether the calcium-dependent protease calpain-1 mediates TRPC6-dependent podocyte injury in human and experimental FSGS and cultured podocytes. Results Compared with kidneys of healthy controls, kidneys of patients with FSGS had increased TRPC6 expression, increased calpain and calcineurin activity, and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability. In a rat model of human FSGS, increased glomerular and urinary calpain activity associated with reduced Talin-1 abundance, enhanced calcineurin activity, and increased proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects. In cultured podocytes, pharmacologic stimulation of TRPC6-dependent calcium influx increased calpain-1 and calcineurin activity and reduced Talin-1 expression, and knockdown of TRPC6 or calpain-1 prevented these effects. Conclusions We elucidated a novel mechanism that links TRPC6 activity to calpain-1 activation and through Talin-1 loss and possibly, calcineurin activation, the podocyte injury characterizing FSGS. Therefore, calpain-1 and/or TRPC6 inhibition could be future therapeutic options to treat patients with FSGS or other podocytopathies.
A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways
Authors: Donatella Romaniello, Luigi Mazzeo, Maicol Mancini, Ilaria Marrocco, Ashish Noronha, Matthew Kreitman, Swati Srivastava, Soma Ghosh, Moshit Lindzen, Tomer Meir Salame, Amir Onn, Jair Bar, Yosef Yarden
Journal: Clinical Cancer Research (2018)

Purpose: Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and in vitro an alternative therapeutic approach making use of antibodies.Experimental Design: An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed.Results: Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3.Conclusions: Our in vitro assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance. Clin Cancer Res; 24(22); 5610-21. ©2018 AACRSee related commentary by Fan and Yu, p. 5499.
Changes in computer extracted features of vessel tortuosity on CT scans post-treatment in responders compared to non-responders for non-small cell lung cancer on immunotherapy.
Authors: Vamsidhar Velcheti, Mehdi Alilou, Monica Khunger, Rajat Thawani, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

11518 Background: Immune-checkpoint blockade treatments demonstrate promising clinical efficacy in patients with non-small cell lung cancer (NSCLC). Nivolumab is a PD-1 inhibitor that is FDA approved for treatment of patients with chemotherapy refractory advanced NSCLC. The current standard clinical approach to evaluating tumor response is sub-optimal in defining clinical benefit from immunotherapy drugs. We sought to evaluate whether computer extracted measurements of vessel tortuosity significantly and differentially change post treatment between NSCLC patients who do and do not respond to immunotherapy. Methods: A total of 50 NSCLC patients including pre- and post- treatment CT scans were included in this study. The patients were either responders or non-responders to Nivolumab. Patients who did not receive Nivolumab after 2 cycles due to lack of response or progression as per RECIST were classified as ‘non-responders’. A total of 35 tortuosity features of the vessels around the lung nodules were investigated. In the training cohort (N = 25), the features were ranked based on the degree of change between pre- and post- treatment CT. The top 4 features were used for training a Support Vector Machine (SVM) classifier to identify which patients did and did not respond to immunotherapy on a validation cohort of N = 25 patients. Results: The top features identified were the ones associated with the curvature of the vessel branches. The AUC for the SVM classifier was 0.75 for the training and 0.79 for the test set. Conclusions: Changes in specific vessel tortuosity features between baseline and post-treatment CT scans following nivolumab were different between NSCLC patients who did and did not respond. Multi-site validation of the vessel tortuosity features is needed to establish it as a predictive biomarker for NSCLC patients treated with immunotherapy.
Abstract 4896: The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer
Authors: Catherine M. Sevigny, Surojeet Sengupta, Zhexun Luo, Lu Jin, Dominic Pearce, Robert Clarke
Journal: Cancer Research (2018)

Abstract Breast cancer is the leading cancer diagnosis for women in the United States. Endocrine therapies, such as tamoxifen and aromatase inhibitors, are used to treat the estrogen receptor-positive (ER+) breast cancers that comprise 70% of all new cases. Unfortunately, emergence of resistance to these therapies presents a major clinical challenge. Cancer cells can adapt to dysregulate the bioenergetics of cellular metabolism and evade cell death. Solute carrier family 7 member 5 (SLC7A5 or LAT1) is expressed across the cell membrane and is a transporter of large, neutral amino acids (such as leucine or tyrosine) supporting cell proliferation. Using LCC9 breast cancer cells that are resistant to tamoxifen and fulvestrant, we studied the role of LAT1 in endocrine therapy-resistant cells as compared to sensitive MCF7 breast cancer cells. SLC7A5 expression was upregulated by estrogen in MCF7 cells that was blocked in the presence of fulvestrant treatment. A significant 2.75-fold upregulation of SLC7A5 protein and 71-fold upregulation of SLC7A5 mRNA was found in LCC9 cells (as compared with MCF7 cells) without any estrogen regulation. Fulvestrant treatment did not significantly alter SLC7A5 mRNA or protein expression. These data suggest that higher levels of SLC7A5 in resistant cells may help in transporting key amino acids from their microenvironment to support cell growth. Inhibiting the functions of SLC7A5 using a pharmacologic inhibitor, JPH203, or depleting its expression by using siRNA led to significant growth suppression of LCC9 cells. Cell cycle analysis revealed that SLC7A5 depletion increased G1 phase of cell cycle and reduced S phase cells. In five publicly available data sets, of estrogen receptor-positive and tamoxifen-treated breast cancer patients, high expression of SLC7A5 was associated with worse prognosis. Endocrine therapy resistance is partly driven by autophagy in breast cancer cells. We depleted SLC7A5 expression in LCC9s to better understand the role of this transporter in autophagy. This study uncovers a novel adaptive mechanism in endocrine therapy-resistant breast cancer cells that is facilitated by increased SLC7A5 mediated transport of large neutral amino acids enabling them to supplement their increased metabolic needs and promoting cell growth. Therefore, blocking the functions of SLC7A5, perhaps in conjunction with inhibition of autophagy, may offer an avenue of potential therapeutic intervention in endocrine therapy-resistant breast cancers. Citation Format: Catherine M. Sevigny, Surojeet Sengupta, Zhexun Luo, Lu Jin, Dominic Pearce, Robert Clarke. The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4896.
Abstract 2338: XAV-939, a Wnt/beta-catenin pathway inhibitor, sensitizes liver cancer cells to sorafenib: Implications in sorafenib resistance
Authors: Kanchan Vishnoi, Rong Ke, Navin Vishwakarma, Ajay Rana, Basabi Rana
Journal: Cancer Research (2018)

Abstract Sorafenib is the only FDA-approved drug currently available for the treatment of advanced hepatocellular carcinoma (HCC). However, development of sorafenib-resistance in patients poses a major challenge to make this treatment successful in long-term. There is an urgent need to explore the mechanisms underlying sorafenib-resistance and to develop strategies towards overcoming sorafenib-resistance. Aberrant activation of Wnt/β-catenin signaling in HCC is suggested to maintain tumor initiating cells, drug-resistance, tumor progression, and metastasis. Combining β-catenin inhibitors with sorafenib might thus be an effective therapeutic strategy to target drug-resistant HCC. To explore this, we used wnt/β-catenin pathway inhibitor XAV-939 in combination with sorafenib to study their effect on the apoptotic potential of HCC cell lines Huh7, Hep3B and HepG2. XAV-939 was demonstrated to effectively reduce the expression of β-catenin in wild-type expressing Huh7 and Hep3B cells. Flow cytometric analysis of these cells pre-treated with XAV-939 followed by sorafenib treatment showed a significant increase in apoptosis in a time dependent manner. Furthermore, these cells revealed increased mitochondrial depolarization which was accompanied by a parallel increase in cytosolic cytochrome c release and downregulation of pro-survival protein Mcl-1. These effects of XAV-939 were further validated following knockdown of endogenous β-catenin, which showed a potentiation of sorafenib effects with β-catenin knockdown. Further, to understand the mechanism associated with sorafenib-resistance, we developed sorafenib-resistant HCC cells by repeated exposure to increasing concentration of sorafenib. To our surprise the combination of sorafenib and XAV-939 was ineffective in increasing the apoptotic potential of these resistant cells, suggesting a differential role of wnt/β-catenin axis in sorafenib-resistance. Taken together, these results suggested that combination of wnt/β-catenin pathway inhibitor and sorafenib could be effective in sensitizing HCC cells to apoptosis initially, but might be ineffective once these cells acquire sorafenib-resistance. Citation Format: Kanchan Vishnoi, Rong Ke, Navin Vishwakarma, Ajay Rana, Basabi Rana. XAV-939, a Wnt/beta-catenin pathway inhibitor, sensitizes liver cancer cells to sorafenib: Implications in sorafenib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2338.
Hypertensive Disorders of Pregnancy and Maternal Cardiovascular Disease Risk Factor Development
Authors: Jennifer J. Stuart, Lauren J. Tanz, Stacey A. Missmer, Eric B. Rimm, Donna Spiegelman, Tamarra M. James-Todd, Janet W. Rich-Edwards
Journal: Annals of Internal Medicine (2018)

Background: Women with a history of hypertensive disorders of pregnancy (HDP) are nearly twice as likely to develop cardiovascular disease (CVD) as those who are normotensive during pregnancy. However, the emergence of CVD risk factors after HDP is less well-understood. Objective: To identify associations between HDP and maternal CVD risk factors and chart the trajectory of risk factor development after pregnancy. Design: Observational cohort study. Setting: United States. Participants: 58 671 parous NHS II (Nurses' Health Study II) participants who did not have CVD or risk factors of interest at baseline. Measurements: Women were followed for self-reported physician diagnosis of chronic hypertension and hypercholesterolemia and confirmed type 2 diabetes mellitus (T2DM) from their first birth through 2013; mean follow-up ranged from 25 to 32 years across these end points. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs, with adjustment for prepregnancy confounders. Results: Compared with women who were normotensive during pregnancy, those with gestational hypertension (2.9%) or preeclampsia (6.3%) in their first pregnancy had increased rates of chronic hypertension (HRs, 2.8 [95% CI, 2.6 to 3.0] and 2.2 [CI, 2.1 to 2.3], respectively), T2DM (HRs, 1.7 [CI, 1.4 to 1.9] and 1.8 [CI, 1.6 to 1.9], respectively), and hypercholesterolemia (HRs, 1.4 [CI, 1.3 to 1.5] and 1.3 [CI, 1.3 to 1.4], respectively). Although these women were more likely to develop CVD risk factors throughout follow-up, the relative risk for chronic hypertension was strongest within 5 years after their first birth. Recurrence of HDP further elevated risks for all end points. Limitation: Participants self-reported HDP. Conclusion: Women with HDP in their first pregnancy had increased rates of chronic hypertension, T2DM, and hypercholesterolemia that persisted for several decades. These women may benefit from lifestyle intervention and early screening to reduce lifetime risk for CVD. Primary Funding Source: National Institutes of Health.