tbuckley/cabot-search huggingface dataset:
Abstract 4300: Overexpression of PARP is an independent prognostic marker for poor survival in Middle Eastern breast cancer and its inhibition can be enhanced with embelin co-treatment
Authors: Maqbool Ahmed, Abdul K. Siraj, Poyil Pratheeshkumar, Sandeep Parvathareddy, Sasidharan Padmaja Divya, Fouad Al-Dayel, Asma Tulbah, Dahish Ajarim, Khawla S. Al-Kuraya
Journal: Cancer Research (2019)

Abstract Patients with aggressive breast cancer (BC) subtypes usually don’t have favorable prognosis despite the improvement in treatment modalities. These cancers still remain a major cause of morbidity and mortality in females. This has fostered a major effort to discover actionable molecular targets to treat these patients. Poly ADP ribose polymerase (PARP) is one of these molecular targets that are under comprehensive investigation for treatment of such tumors. However, its role in the pathogenesis of BC from Middle Eastern ethnicity has not yet explored. Therefore, we examined the expression of PARP protein in a large cohort of over 1000 Middle Eastern BC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. Nuclear PARP overexpression was observed in 44.7% of all BC cases and was significantly associated with aggressive clinico-pathological markers. Interestingly nuclear PARP overexpression was an independent predictor of poor prognosis. PARP overexpression was also directly associated with XIAP overexpression, with PARP and XIAP co-expression in 15.8% (159/1008) of our cases. We showed that combined inhibition of PARP by olaparib and XIAP by embelin significantly and synergistically inhibited cell growth and induced apoptosis in BC cell lines. Finally, co-treatment of olaparib and embelin regressed BC xenograft tumor growth in nude mice. Our results revealed the role of PARP in Middle Eastern BC pathogenesis and prognosis. Furthermore, our data support the potential clinical development of combined inhibition of PARP and XIAP, which eventually could extend the utility of olaparib beyond BRCA deficient cancer. Citation Format: Maqbool Ahmed, Abdul K. Siraj, Poyil Pratheeshkumar, Sandeep Parvathareddy, Sasidharan Padmaja Divya, Fouad Al-Dayel, Asma Tulbah, Dahish Ajarim, Khawla S. Al-Kuraya. Overexpression of PARP is an independent prognostic marker for poor survival in Middle Eastern breast cancer and its inhibition can be enhanced with embelin co-treatment [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 4300.
Abstract 4751: Overcoming cisplatin resistance of esophageal squamous cell carcinoma by targeting RAC1-regulated Warburg effect
Authors: Ruijie Zeng, Chunwen Zheng, Jinge Gu, Liu Peng, Haixia Zhang, Pan Feng, Yang Chen, Xiue Xu, Liyan Xu, Enmin Li
Journal: Cancer Research (2019)

Abstract Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis. Despite treatment advances, development of chemo-resistance remains a major challenge in treating ESCC patients. Ras-related C3 botulinum toxin substrate 1 (RAC1) is essential in regulating cancer progression. However, its role in chemo-resistance of ESCC and the underlying mechanisms are still unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer disease-free survival (p=0.014) and overall survival (p=0.013) by immunohistochemistry in human ESCC samples (n=106). The over-expression of RAC1 was correlated with enhanced cell proliferation, migration, invasion and chemo-resistance in both KYSE150 and KYSE510 cells, while the knockdown of RAC1 produced the opposite results. The combination of RAC1 inhibitor EHop-016 with cisplatin significantly promoted cell viability reduction, cycle arrest at G2/M phase and apoptosis when compared with the single treatment. To examine the in vivo effects of RAC1 inhibition on chemo-resistance, we performed xenograft implantation studies in immunocompromised mice (n=10 per group). In the combination group, the tumor volume was significantly reduced to 21.4% (p&amp;lt;0.001) as compared to the single treatment groups (cisplatin: 62.7%, RAC1 inhibitor: 58.5%). Mechanistically, the RNA-Seq data indicated that the glycolytic pathway was significantly down-regulated in the EHop-016-treated group (p&amp;lt;0.001, Log2FC=1.86) and the combination group (p&amp;lt;0.001, Log2FC=1.76), as compared to the control group. Moreover, the qRT-PCR and western blot results confirmed that RAC1 inhibitor alone or the combination treatment suppressed Akt/FOXO signaling and resulted in inhibition of key enzymes such as PKM2, LDH-A, ALDOA and HK1 for the Warburg effect. Overall, our study suggests that inhibition of RAC1 overcomes cisplatin resistance in ESCC both in vitro and in vivo, and provides a novel mechanism of chemo-resistance in ESCC. Therefore, targeting RAC1 might be a promising and potent strategy for treating ESCC in clinical practice. Citation Format: Ruijie Zeng, Chunwen Zheng, Jinge Gu, Liu Peng, Haixia Zhang, Pan Feng, Yang Chen, Xiue Xu, Liyan Xu, Enmin Li. Overcoming cisplatin resistance of esophageal squamous cell carcinoma by targeting RAC1-regulated Warburg effect [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 4751.
Abstract 744: Clinically targetable genomic alterations in acral melanoma
Authors: Natasa Broit, Ken Dutton-Regester, Peter Johansson, Antonia L. Pritchard, Glen M. Boyle, Nicholas K. Hayward
Journal: Cancer Research (2019)

Abstract Background: Acral melanoma is a rare subtype of melanoma, which has a distinct genomic profile from cutaneous melanoma. While survival outcomes for late-stage cutaneous melanoma have significantly improved in the last decade, treatment options for acral melanoma remain limited. The purpose of this study was to assess therapeutically targetable genomic alterations in acral melanoma. Methods: The AACR project GENIE database was accessed via cBioPortal (http://cbioportal.org/genie/; version 3) to identify recurrent gene alterations in acral melanomas analyzed using the MSK-IMPACT oncopanel. These alterations were assessed through Cancer Genome Interpreter (http://cancergenomeinterpreter.org) to identify clinically actionable alterations. Results: Thirty-six patients with acral melanoma were identified from the cBioPortal-GENIE database. These patients were sequenced using three different versions of oncopanel, which included 341 (n = 6), 410 (n = 22) and 468 (n = 8) genes. Seventy-six genes were found to be somatically mutated in this cohort in at least one sample. The most commonly mutated genes were NF1 (n = 5), BRAF (n = 5), PTPRT (n = 4), NOTCH3, HRAS and KRAS (n = 3). Copy number variations greatly contributed to aberration burden, with 132 unique genes found to either carry an amplification or deletion event. The most commonly amplified genes were CDK4 (n = 9), CCND1 (n = 9), FGF19/FGF4 (n = 8), PAK1 (n = 8), MDM2 (n = 7) and FGF3 (n = 7). The most recurrently deleted genes included CDKN2A (n = 9) and CDKN2B (n = 8), and less commonly JAK2 and PTEN (n = 2). Some genes were altered by various mechanisms; for example, some tumors had KIT activated by amplification while other tumors carried missense mutations. BRAF exhibited two fusion events: BRAF-METTL2B (with concomitant amplification) and BRAF-KIAA1549. Cancer Genome Interpreter identified several therapeutic targets, some of which have been the focus of clinical trials in cutaneous melanoma and other solid tumors, e.g. CDK4/6 inhibitors to target amplified CDK4 and CCND1, or mTOR inhibitors for tumors with NF1 mutations. Conclusion: Several inhibitors are available which could show efficacy in a subset of acral melanomas with particular genomic alterations. Many of these inhibitors have yet to be tested in the context of acral melanoma and should be explored. Citation Format: Natasa Broit, Ken Dutton-Regester, Peter Johansson, Antonia L. Pritchard, Glen M. Boyle, Nicholas K. Hayward. Clinically targetable genomic alterations in acral melanoma [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 744.
Abstract P213: Psychological Distress and Low Health Locus of Control are Associated with Insulin Resistance
Authors: Maria C Eriksson, Margareta I Hellgren, Bledar Daka, Boo Johansson, Lennart Råstam, Ulf Lindblad, Charlotte A Larsson
Journal: Circulation (2016)

Introduction: Comorbidity of depression and type 2 diabetes is common. Less is known about metabolic impairment in association with milder forms of mental health issues, such as psychological distress (PD) and health locus of control (HLoC). Hypothesis: To cross-sectionally assess the hypothesis that PD and low HLoC are associated with insulin resistance in a Swedish population. Methods: In 2002-2005, a random sample of 2816 men and women aged 30-74 years participated (76%) in a survey in two municipalities in southwestern Sweden. Participants answered questionnaires, performed an OGTT and had anthropometric measurements taken. PD was measured by the validated 12-item General Health Questionnaire. HLoC was measured with the question ‘‘Do you believe that you can do anything yourself in order to preserve good health?”. PD and HLoC were both dichotomized and then combined into a risk score to indicate if the participants were positive for none of the factors, for either HLoC or PD , or for both . Insulin resistance was estimated by HOMA-ir. For the present study, 2714 subjects without previously known diabetes were included. Results: In general linear models, using none as reference (Table I), associations with HOMA-ir were seen for participants with either PD or HLoC, as well as for those with both . The strongest association was seen for both and this association remained, as did that for HLoC, when adjusting for multiple confounders. However, when adding physical activity to the model (Table I) the association was lost also for those positive solely for HLoC compared to those positive for none of the factors. In fact, a multiplicative effect on HOMA-ir was indicated with regard to having both factors (Table I). Conclusions: In the present study, a combination of psychological distress and low health locus of control was significantly associated with insulin resistance, highlighting the importance of further implementation of health psychology in primary care in order to prevent type 2 diabetes and ultimately cardiovascular disease.
Phospholipids in Biology and Medicine
Authors: Richard L. Jackson, Antonio M. Gotto
Journal: New England Journal of Medicine (1974)

Phospholipids and Plasma LipoproteinsAll the major plasma lipids, the free fatty acids, phospholipids, cholesterol, cholesteryl esters and triglycerides, are transported in association with proteins. The free fatty acids are primarily bound to albumin whereas the other lipids are carried as part of macromolecular complexes known as the plasma lipoproteins. The protein and phospholipid constituents serve as "solubilizers" to maintain the neutral lipids in a soluble form as they circulate in the blood. The lipoproteins are required for the transport of fat from the gut and liver into the lymph and the blood. Complete absence of three of the four . . .
Abstract 2912: The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal cancer
Authors: Sang Eun Yoon, Joon Young Hur, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim
Journal: Cancer Research (2019)

Abstract Recently, the sidedness of the primary tumor (right versus left) has been investigated for its ability to prognosticate and predict outcomes. We evaluated the effect of regorafenib based on KRAS mutation status and the sidedness of the primary tumor in patients with metastatic colorectal cancer (mCRC). We analyzed 135 patients with refractory metastatic colorectal cancer (mCRC) being treated with regorafenib at Samsung Medical Center, between January 2014 and January 2018. Primary tumors originating in the splenic flexure, descending colon, sigmoid colon, rectum, or proximal third of the transverse colon were defined as left-sided CRC (LC). Primary tumors originating in the appendix, cecum, ascending colon, hepatic flexure, or distal two-thirds of the transverse colon were defined as right-sided CRC (RC). Among all 135 patients, 100 (74.1%) had left sided colon cancer and 35 (25.9%) had right-sided colon cancer. No patients achieved a complete response, but four achieved a partial response, revealing a response rate (RR) of 3.0%. Thirty-seven patients had stable disease, yielding a disease control rate (DCR) of 30.4%. There was no difference in RR or DCR according to the location of the primary tumor (LC vs. RC). A significant difference in progression free survival (PFS) with regorafenib was observed between the LC and RC groups (2.6 months; 95% CI, 2.0 to 3.1 vs. 1.9 months; 95% CI, 1.6 to 2.3; P = 0.04, respectively). In a subpopulation with wild type KRAS, PFS with regorafenib was also significantly different between the LC and RC groups (2.9 months; 95% CI, 1.5 to 4.3 vs. 2.1 months; 95% CI, 0.6 to 3.6; P= 0.04). On multivariate analysis, the sidedness of the primary tumor (LC vs. RC) and the number of metastatic sites (≤1 vs. 2&amp;gt;) had a prognostic effect on PFS (P = 0.01 and P = 0.01, respectively). Regorafenib is a current standard treatment for CRC, but treatment outcomes may be improved if regorafenib is administered based on the appropriate biomarker. Citation Format: Sang Eun Yoon, Joon Young Hur, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim. The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal 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 2912.
Abstract 3452: hnRNPUL1 regulation by ATR in DNA damage response
Authors: Hui Zhang, PamelaSara E. Head, Duc M. Duong, Nicholas T. Seyfried, David S. Yu
Journal: Cancer Research (2019)

Abstract The DNA damage response (DDR) is a signaling network that recognizes damages to DNA and orchestrates a variety of DNA repair and cell cycle checkpoint pathways. The DDR is pivotal for cancer prevention. Ataxia Telangiectasia And Rad3-Related Protein (ATR), a protein kinase, functions as an essential transducer of the DDR signaling cascade. ATR primarily responds to single-stranded DNA (ssDNA) generated from double-strand break resection or at stalled replication forks. Depletion of ATR leads to cellular senescence and cancer related phenotypes. The mechanisms regarding how the ATR signal pathway is regulated, however, remain elusive. To discover novel DDR proteins regulated by ATR, we performed proteomic analysis to identify proteins that partner with ATR in response to DNA damage in cells. Our analysis revealed a network of proteins as potential ATR substrates, including Heterogeneous nuclear ribonucleoprotein U-like 1 (hnRPUL1), a protein functions in RNA metabolism. We validated that ATR interacts with hnRNPUL1. In addition, hnRPUL1 is phosphorylated on SQ/TQ sites in response to IR. ATR depletion suppresses the IR induced hnRPUL1 phosphorylation. Our results identify hnRNPUL1 as a novel ATR substrate, critical for the DNA damage response and provide insight into how DDR and RNA metabolism might work synergically in maintaining genomic stability and preventing cancer. Additionally, hnRNPUL1 phosphorylation by ATR may be targeted as an adjunct to improve the efficacy of ionizing radiation for cancer therapy. Citation Format: Hui Zhang, PamelaSara E. Head, Duc M. Duong, Nicholas T. Seyfried, David S. Yu. hnRNPUL1 regulation by ATR in DNA damage response [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 3452.
Abstract 2373: The mechanism study of propranolol in suppressing the genesis and development of gastrointestinal cancer through simultaneously activating autologous CD8+T cells and inhibiting tumor AKT/MAPK pathway
Authors: Ping Liao
Journal: Cancer Research (2019)

Abstract Background: Propranolol may exert the anti-tumor effect in cutaneous and acral melanoma by suppressing AKT and MAPK pathways. Reduced tumor growth following propranolol results from enhanced CD8+T-cell-mediated antitumor immune response. Objective: To clarify the efficacy and mechanism of propranolol in suppressing the genesis and development of gastrointestinal cancer through simultaneously activating autologous CD8+T cells and inhibiting tumor AKT/MAPK pathway. Methods: MTS assay was performed to detect gastrointestinal cancer cells viability, TUNEL staining was used to measure apoptosis in cell lines. IHC was used to detect the expressions of Ki67/p-AKT/p-MEK/p-ERK in tumor tissue. Flow cytometry was performed to explore the immune status of the tumor microenvironment. Clinical study has been performed by Case-control design. Subjects who had not been received neoadjuvant were randomly divided into propranolol or placebo group. Then the primary foci of gastrointestinal cancer subjects were removed by D2 gastrectomy. IHC was used to observe the immune status, tumor proliferation in tumor tissue. Results: We found propranolol reduced cell viability in CT26WT and MFC (mice derived melanoma cell line). Furthermore, propranolol could shrink the tumor size in CT26WT and MFC xenografts (P&amp;lt;0.0001). The frequency of CD3+CD8+ T cells in spleen was significantly elevated in propranolol-treated mice compared with controls. The IFNg and T-bet was significantly increased in the CD8+ T-cell population of propranolol treated mice tumor tissue. Propranolol reduced cell viability and induced apoptosis in AGS, HGC, SW480 and HCT116 cell line. But We did not observe differences in NCM460 cell line (human intestinal epithelial cells). Western Blot showed propranolol reduced the expression of p-AKT, p-MEK and p-ERK. In this prospective clinical study, the frequency of CD8+ was significantly elevated in tumor microenvironment. The expression of p-AKT, p-MEK and p-ERK was decreased in propranolol-treated subjects compared with controls. Conclusion: The potential of propranolol to suppress the genesis and development of gastrointestinal cancer through simultaneously activating autologous CD8+T cells and inhibiting tumor AKT/MAPK pathway. Note: This abstract was not presented at the meeting. Citation Format: Ping Liao. The mechanism study of propranolol in suppressing the genesis and development of gastrointestinal cancer through simultaneously activating autologous CD8+T cells and inhibiting tumor AKT/MAPK pathway [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 2373.
Analysis of Pathologic Complete Response 10 Weeks After Radiotherapy—A Radiobiological Sin
Authors: Todd J. Scarbrough
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
NK cells switch from granzyme B to death receptor–mediated cytotoxicity during serial killing
Authors: Isabel Prager, Clarissa Liesche, Hanna van Ooijen, Doris Urlaub, Quentin Verron, Niklas Sandström, Frank Fasbender, Maren Claus, Roland Eils, Joël Beaudouin, Björn Önfelt, Carsten Watzl
Journal: The Journal of Experimental Medicine (2019)

NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor–mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor–mediated cytotoxicity are differentially regulated during NK cell serial killing.
Mutational and Selective Processes Involved in Evolution during Bacterial Range Expansions
Authors: Lars Bosshard, Stephan Peischl, Martin Ackermann, Laurent Excoffier
Journal: Molecular Biology and Evolution (2019)

Abstract Bacterial populations have been shown to accumulate deleterious mutations during spatial expansions that overall decrease their fitness and ability to grow. However, it is unclear if and how they can respond to selection in face of this mutation load. We examine here if artificial selection can counteract the negative effects of range expansions. We examined the molecular evolution of 20 mutator lines selected for fast expansions (SEL) and compared them to 20 other mutator lines freely expanding without artificial selection (CONTROL). We find that the colony size of all 20 SEL lines have increased relative to the ancestral lines, unlike CONTROL lines, showing that enough beneficial mutations are produced during spatial expansions to counteract the negative effect of expansion load. Importantly, SEL and CONTROL lines have similar numbers of mutations indicating that they evolved for the same number of generations and that increased fitness is not due to a purging of deleterious mutations. We find that loss of function mutations better explain the increased colony size of SEL lines than nonsynonymous mutations or a combination of the two. Interestingly, most loss of function mutations are found in simple sequence repeats (SSRs) located in genes involved in gene regulation and gene expression. We postulate that such potentially reversible mutations could play a major role in the rapid adaptation of bacteria to changing environmental conditions by shutting down expensive genes and adjusting gene expression.
Phase 3 Study of L-Glutamine in Sickle Cell Disease: Analyses of Time to First and Second Crisis and Average Cumulative Recurrent Events
Authors: Yutaka Niihara, Rafael Razon, Suvankar Majumdar, Brian Claggett, Onyinye C. Onyekwere, Alan Ikeda, Tammuella Singleton, Andrew Kohei Wood, Rajani Singh, Lan Tran, Charles William Stark
Journal: Blood (2017)