tbuckley/cabot-search huggingface dataset:
Abstract 1455: Vitamin D receptor (VDR) gene polymorphisms among Sudanese females with breast cancer attending Radio and Isotope Center of Khartoum
Authors: Sara O. Yousif, Amar M. Ismail, Abdelrahim O. Mohamed, Abdelrahim O. Mohamed
Journal: Cancer Research (2017)

Abstract Background: Vitamin D Receptor (VDR) gene polymorphisms has been reported to be associated with different cancers, including breast cancer. geographical and environmental factors have an impact on vitamin D (VD) metabolism. This study aims to evaluate VDR-gene polymorphisms (Fok1, Bsm1, Taq1, Apa1) and its association with breast cancer risk among Sudanese females. Materials and Methods: this is a case control study done in the Radio and Isotope Center in Khartoum, Sudan. Hundred thirty seven patients and 69 healthy controls were enrolled after informed consent. Blood genomic DNA was extracted using quinidine chloroform method, and single nucleotide polymorphisms (SNPs) Fok1 (T/C) [rs2228570], Bsm1 (G/A) [rs1544410], Taq1 (C/T) [rs731236] and Apa1 (C/A) [(rs7975232] in VDR-gene were detected by PCR and restriction fragment length polymorphism (PCR-RFLP) analysis. Results: VDR-SNPs rs731236 correlated significantly with low risk of breast cancer (OR=0.5, p= 0.002). There was no significant association observed with rs1544410 and rs7975232. Although our study did not show an overall statistically significant association of VDR-SNPs rs2228570 with the risk of breast cancer, we found a 1.3 fold increased risk of breast cancer (OR= 1.3) among females with FF genotype when compared with ff genotype, suggesting that females homozygous for F allele, might be at more risk than females carrying homozygous f allele. Conclusions: These results suggested that, VDR-SNPs rs2228570 may be related to higher risk of breast cancer and VDR-SNPs rs731236 associated with lower risk of breast cancer in Sudanese females. Key words: Breast Cancer, VDR, Polymorphisms, SNPs Citation Format: Sara O. Yousif, Amar M. Ismail, Abdelrahim O. Mohamed, Abdelrahim O. Mohamed. Vitamin D receptor (VDR) gene polymorphisms among Sudanese females with breast cancer attending Radio and Isotope Center of Khartoum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1455. doi:10.1158/1538-7445.AM2017-1455
Intrahepatic cholangiocarcinoma arising from HBV infection may be a highly selected population for liver transplantation
Authors: Jinyang Gu, Seogsong Jeong, Qiang Xia
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. TO THE EDITOR: In a recent study in Hepatology, Sapisochin et al.1 introduced prognostic outcomes of liver transplantation (LT) for cirrhotic liver with incidental and misdiagnosed intrahepatic cholangiocarcinoma (iCCA) and concluded that patients with very early iCCA (single tumor ≤2 cm) with cirrhosis might be suitable candidates for LT. In Western countries, a majority of iCCAs develop on the basis of cirrhotic liver, such as primary sclerosing cholangitis, which requires routine serological and imaging examinations, thus providing an opportunity for very early iCCA to be detected. In Eastern countries, a newly identified major risk factor of iCCA is viral hepatitis infection, making early diagnosis of iCCA difficult and rarely transplanted in the Model for End‐Stage Liver Disease (MELD) era. A few recent works have revealed that hepatitis B virus (HBV)‐associated iCCA is a malignancy with distinctive characteristics between hepatocellular carcinoma and iCCA with younger age, a predominance of male patients, frequent elevation of alpha‐fetoprotein, and infrequent lymph node metastasis.2 In addition, survival outcomes of patients with HBV‐associated iCCA have been found to be significantly better than those without HBV infection after hepatic resection.3 Most importantly, the representative hallmark of iCCA, lymph node metastasis, which significantly worsens prognosis and critically contributes to the tumor recurrence after surgical resection, has been found to be significantly more infrequent in HBV‐associated iCCA.4 Therefore, apart from the number and the size of iCCA, HBV infection should also be considered when establishing inclusion criteria of LT for iCCA. In addition, as suggested by Gupta and Gupta,5 the role of antiviral therapy on the outcomes of iCCA upon LT also needs to be evaluated. Because patients with hilar cholangiocarcinoma who have received neoadjuvant therapies have been awarded with a MELD exception score by the United Network for Organ Sharing, the assessment on safety and efficacy of neoadjuvant radiochemotherapy for highly selected iCCA followed by LT should be implemented.
Hilar cholangiocarcinoma diagnosed by endoscopic ultrasound-guided hepaticogastrostomy and cholangioscopy
Authors: Theodore James, Ian Grimm, Todd Baron
Journal: Endoscopy (2017)

A 77-year-old woman, with a history of Whipple resection 20 years previously for a lesion in the porta hepatis that was later determined to be benign, was found to have elevated bilirubin and alkaline phosphatase on routine laboratory testing, prompting a computed tomography (CT) scan of the abdomen ([Fig. 1]). This showed intrahepatic ductal dilatation and pancreatic duct prominence. The patient was referred for gastroenterological investigation with concern for malignancy versus autoimmune cholangiopathy.
Abstract 3116: Dysregulated cholesterol synthesis is a therapeutic vulnerability in glioblastoma
Authors: Diane M. Kambach, Alan S. Halim, A. Gesine Cauer, Qian Sun, Carlos A. Tristan, Orieta Celiku, Aparna H. Kesarwala, Uma Shankavaram, Eric Batchelor, Jayne M. Stommel
Journal: Cancer Research (2017)

Abstract A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in normal astrocytes but have lost this regulation in glioma cells. Here we report that at high cell density, normal astrocytes turn off cholesterol synthesis but glioma cells keep this pathway on. Correspondingly, cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely-plated glioma cells increase oxygen consumption to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP, but without a compensating increase in aerobic glycolysis. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma. Citation Format: Diane M. Kambach, Alan S. Halim, A. Gesine Cauer, Qian Sun, Carlos A. Tristan, Orieta Celiku, Aparna H. Kesarwala, Uma Shankavaram, Eric Batchelor, Jayne M. Stommel. Dysregulated cholesterol synthesis is a therapeutic vulnerability in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3116. doi:10.1158/1538-7445.AM2017-3116
Abstract 270: Rnd3/RhoE Haploinsufficient Mice are Hypersensitive to Pressure Overload and Develop Apoptotic Cardiomyopathy with Heart Failure
Authors: Xiaojing Yue, Xiangsheng Yang, Xi Lin, Tingli Yang, Xin Yi, Yuan Dai, Jiang Chang
Journal: Circulation Research (2014)

Rationale: Rho family guanosine triphosphatase (GTPase) 3 (Rnd3, also called RhoE), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. Objective: To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism. Methods and Results: we generated Rnd3 +/- haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3 +/- mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd3 +/- haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by Fasudil treatment partially improved Rnd3 +/- mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3 +/-/ROCK1-/- ). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. Conclusion: Downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.
Abstract 825: Cetixumab enhanced apoptosis effects of radiation on human prostate cancer cell line PC-3
Authors: Chia-lun Chang, Szu-Yuan Wu
Journal: Cancer Research (2017)

Abstract Prostate cancer is a leading cause of cancer death in men in developed countries. Radiotherapy is the main treatment to prostate cancer. Dose escalation of irradiation with image guide rasdiotherapy and intensity modulated radiotherapy were used with more and more evidences in prostate cancer patients and bring in longer PSA-free survival time. Although the evolution of radiation techniques bring better outcomes, but modern modalities were not avaliable in non-western world. Radiation enhancement is still an improtant issus in prostate cancer in non-western world, especially in androgen independnt prostate cancer. The epidermal growth factor receptor (EGFR) network has rich targets for prostate cancer killing. The chimeric monoclonal antibody Cetuximab (IMC-A12, Erbitux®) binds to EGFR and prevents its intracellular signaling. Currently, it is approved for treatment of wild-type KRAS colon and head and neck cancer. The effect and mechanisms of Erbitux and radiotherapy are still not clear. In this study, we evaluated the effects of combining the EGFR inhibition and radiation on PC-3 prostate cancer cells. PC-3 cells were treated with various doses(1,2.5,5 and 10 ug/ml) of anti-EGFR antibody (CETUXIMAB) and irradiation(5, 7.5 Gy). The results revealed that 5 and 10 ug/ml of CETUXIMAB significnatly reduced the colony formation. The cell cycle analysis revealed that CETUXIMAB significnatly enhanced the radiation induced G2/M phase arrest and subG1 peak increasing. The Hoechst staining and DNA laddering analysis revealed radiation and CETUXIMAB combined use will induced more apoptotic bodies or DNA fragmentation than radiation alone use. By using a apaptosis protein array, we found that several apaptosis related protein (Catalase, cIAP-1, Clusterin, Fas, HIF-1α, HSP27, HSP60, HSP70, SMAC and Survivin) were significantly downregulated in radiation and CETUXIMAB combined group. Taken together, our results demonstrated that Erbitux enhanced apoptosis effects of radiation on PC-3. Citation Format: Chia-lun Chang, Szu-Yuan Wu. Cetixumab enhanced apoptosis effects of radiation on human prostate cancer cell line PC-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 825. doi:10.1158/1538-7445.AM2017-825
131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment
Authors: Matthias D'Huyvetter, Jens De Vos, Catarina Xavier, Marek Pruszynski, Yann G.J. Sterckx, Sam Massa, Geert Raes, Vicky Caveliers, Michael R. Zalutsky, Tony Lahoutte, Nick Devoogdt
Journal: Clinical Cancer Research (2017)

Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a 131I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with 131I using [131I]SGMIB and evaluated in vitro Biodistribution was evaluated in two HER2+ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [131I]SGMIB-2Rs15d was investigated in two HER2+ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [127I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.Results: [131I]SGMIB-2Rs15d bound specifically to HER2+ cells (Kd = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo [131I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [127I]SGMIB-2Rs15d.Conclusions: These findings demonstrate the theranostic potential of [131I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [131I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2+ breast cancer patients. Clin Cancer Res; 23(21); 6616-28. ©2017 AACR.
Abstract 141: CD44 positive and sorafenib resistant hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128
Authors: Mohamed Badawi, Jihye Kim, Dhruvitkumar Sutaria, Tasneem Motiwala, Ryan Reyes, Nissar Wani, Samson Jacob, Mitch Phelps, Thomas Schmittgen
Journal: Cancer Research (2017)

Abstract The PI3K/AKT/mTOR pathway is activated in about 50% of patients with hepatocellular carcinoma (HCC). Allosteric mTOR inhibitors, also known as rapalogs, fail to show any significant clinical utility. In an effort to identify new pathways and compounds to treat advanced HCC, we considered the ATP-competitive mTOR inhibitor INK128. ATP-competitive mTOR inhibitors attenuate both mTORC1 and mTORC2. We evaluated INK128 in sorafenib sensitive and insensitive HCC cell lines, CD44low and CD44high HCC and those cell lines with acquired sorafenib resistance. CD44 was significantly increased in Huh7 cells made resistant to sorafenib. Forced expression of CD44 enhanced cellular proliferation and migration, and rendered the cells more sensitive to the anti-proliferative effects of INK128. INK128 suppressed CD44 expression by blocking phosphorylation of eukaryotic translation initiation factor 4EBP1 in HCC cells while allosteric mTOR inhibitors do not. Moreover, INK128 exhibited potent anti-proliferative and anti-migration effects on the mesenchymal-like HCC cells, CD44high and sorafenib resistant HCC cells compared to the allosteric mTOR inhibitor everolimus. Combination studies of INK128 and sorafenib showed an additive to synergistic anti-proliferative effect in CD44high HCC cells. Our findings suggest that ATP-competitive mTOR inhibitors are effective in treating advanced HCC patients who express CD44, and are insensitive or resistant to sorafenib. It also highlights the potential use of CD44 as a biomarker of response in these patients. Citation Format: Mohamed Badawi, Jihye Kim, Dhruvitkumar Sutaria, Tasneem Motiwala, Ryan Reyes, Nissar Wani, Samson Jacob, Mitch Phelps, Thomas Schmittgen. CD44 positive and sorafenib resistant hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 141. doi:10.1158/1538-7445.AM2017-141
CLASH's life history foundations [commentary on Van Lange et al., 2017]
Authors: W.E. Frankenhuis, J. Fenneman, J.L. van Gelder, I. Godoy
Journal: Behavioral and Brain Sciences (2017)

We recommend extending CLASH by incorporating two evolutionary accounts of the shift toward fast life histories under harsh, unpredictable conditions. These accounts, if integrated with CLASH, make different predictions about the distributions of aggression and violence within and between societies. We discuss these predictions and propose ways of testing them.
Abstract 5306: p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status
Authors: Tarinee Lubpairee, Elena Prigge, Magnus von Knebel Doeberitz, Miriam Reuschenbach, Lewei Zhang, Miriam P. Rosin
Journal: Cancer Research (2017)

Abstract Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated with protection from cancer, including cell cycle control and senescence. Elevated expression of this gene is strongly correlated with biological activity of HPV infection and cancer development in uterine cervix and tonsil. Although HPV DNA has been found in a small portion of oral cavity cancers and dysplasia, the relevance of its presence to cancer development at this site is unclear, as is the significance of an expression change in p16INK4a as a predictor of HPV status, tissue behavior and outcome. Methods: Formalin-fixed, paraffin-embedded biopsies from 164 patients with mild, moderate and severe oral dysplasia in the “Oral Cancer Prediction Longitudinal study” (OCPL), British Columbia, Canada, were analyzed for HPV DNA using a semi-quantitative viral load Luminex technology. Expression of p16INK4a was assessed and categorized into 3 staining patterns (diffuse, focal, and negative). Results: HPV DNA was found in 13 (8%) lesions, 7 had HPV-16 infection and 1 HPV-18. Of the 164 samples, diffuse p16INK4a expression was present in 18%, focal in 56% and no p16 staining in 23% of samples. There was no significant correlation between HPV DNA-positivity and p16INK4a staining. Different p16 staining patterns showed significantly different progression rates (P &amp;lt; 0.0001): progression occurred in 1/92 (1.1%) focally stained, 1/29 (3.5%) diffusely stained and 10/43 (23.3%) with no staining. Conclusion: HPV DNA-positivity occurs in a small proportion of oral dysplasia but is poorly associated with p16INK4a expression. Future assessment of these samples for HR-HPV oncogene transcripts will provide information on its biological activity. The low likelihood of progression of p16INK4a focally stained lesions suggests a value of this marker in identification of low-risk cases. Acknowledgements: Supported by Else Kröner-Fresenius-Stiftung Foundation, Germany Citation Format: Tarinee Lubpairee, Elena Prigge, Magnus von Knebel Doeberitz, Miriam Reuschenbach, Lewei Zhang, Miriam P. Rosin. p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5306. doi:10.1158/1538-7445.AM2017-5306
Abstract 1577: GRK3 is a direct target of ADT-induced CREB1 activation and it promotes neuroendocrine differentiation of prostate cancer cells
Authors: Dayong Zheng, Mohit Hulsurkar, Meixiang Sang, Songlin Zhang, Jianming Xu, Martin Gleave, Michael Ittmann, Wenliang Li
Journal: Cancer Research (2017)

Abstract Treatment-related neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer that is believed to arise through neuroendocrine differentiation (NED) from prostate adenocarcinoma (PAC) upon castration resistance to androgen deprivation treatment (ADT). t-NEPC is highly metastatic with poor prognosis. With the recent introduction of potent ADT drugs in clinic, the incidence of t-NEPC is expected to increase dramatically. No effective therapeutic is available for t-NEPC and its molecular mechanisms remain poorly understood. We reported that GRK3 (G protein-coupled receptor kinase 3) promotes prostate cancer progression. We further demonstrated that the ADT activates CREB1 (cAMP response element binding protein 1), which directly targets and induces GRK3. GRK3 expression is higher in t-NEPC than in PAC cells and mouse models, and it positively correlates with the expression and activity of CREB1 in human prostate cancers. Notably, overexpression of GRK3 in PAC cells increased the expression of NE markers. Conversely, silencing GRK3 blocked CREB1-induced NED in PAC cells, reversed NE phenotypes and inhibited proliferation of t-NEPC cells in culture and in xenograft. Currently, we are investigating the mechanisms underlying NEPC progression promoted by the CREB1/GRK3 axis. Taken together, these results indicate that GRK3 is a new critical activator of NE phenotypes and mediator of CREB1 activation in promoting NED of prostate cancer cells. Citation Format: Dayong Zheng, Mohit Hulsurkar, Meixiang Sang, Songlin Zhang, Jianming Xu, Martin Gleave, Michael Ittmann, Wenliang Li. GRK3 is a direct target of ADT-induced CREB1 activation and it promotes neuroendocrine differentiation of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1577. doi:10.1158/1538-7445.AM2017-1577