tbuckley/cabot-search huggingface dataset:
Abstract 327: Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy
Authors: Liz J. Hernandez Borrero, Shengliang Zhang, David Dicker, Wafik El-Deiry
Journal: Cancer Research (2016)

Abstract Tumor suppressor p53 is a master regulator of genotoxic and cellular stress signals, controlling cell fate by transcriptionally activating genes involved in DNA repair, cell cycle arrest, and apoptosis. p53 is mutated in over half of human cancers and this is associated with tumor development and chemotherapy resistance. TP53 gene mutations can result in the abolishment of p53 contact with DNA and disruption of p53 structural conformation. These mutations not only prevent p53 to exert its normal tumor suppressive functions but can result in gain-of-function activity, acquiring oncogenic characteristics. Therefore, altering the stability of mutant p53 protein is an attractive therapeutic strategy in cancer cells. We investigated small molecules that modulate mutant p53 stability and restore the p53-signaling pathway. We identified a small molecule, CB002, as a candidate for restoration of the p53 pathway in mutant p53-bearing cancer cells. Three colorectal cancer cell lines: SW480, DLD-1, HCT116-R175H and the RXF393 renal cancer cell line, were treated with different concentrations of CB002 at various time points. Cell lines exposed to CB002 showed an increase in apoptotic and cell death markers, such as NOXA/DR5 induction, cleaved caspases and PARP, as early as 16 hrs. CB002 decreased mutant p53 stability in structural conformation-mutant bearing cells (HCT116 R175H and RXF393). Our data suggests that CB002 stimulates an increase of p53 target genes and promotes expression of pro-apoptotic proteins. R175H p53 mutant protein expression was largely rescued by the co-treatment with MG132, a proteasomal inhibitor, implicating a role for the ubiquitin proteasome system. Furthermore, we observed significant autophagy induction upon CB002 treatment, as indicated by LC3 conversion and p62 levels. Autophagy inhibition decreased levels of cell death markers and increased the stability of the R175H-mutant p53, suggesting that autophagy might be required for CB002-induced cell death and mutant p53 turnover. Therefore, we hypothesize that CB002 is capable of degrading mutant p53 and restoring the p53 pathway through p53 family members in colorectal cancer cells. Currently we are investigating p53 degradation mechanism by CB002, the role of p53 family members in the restoration of the pathway and autophagy on mutant p53 stability. Hence, our results provide an insight on effective p53 pathway activation through the use of small molecules. Citation Format: Liz J. Hernandez Borrero, Shengliang Zhang, David Dicker, Wafik El-Deiry. Anti-tumor effect and destabilization of R175H-mutant p53 by CB002, a p53-pathway restoring small molecule that stimulates autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 327.
Abstract 1994: Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells
Authors: Kevin Brasseur, Pascal Adam, Laurence Tardif, François Fabi, Sophie Parent, Éric Asselin
Journal: Cancer Research (2016)

Abstract Prostate Apoptosis Response-4 (Par-4) is a tumor suppressor protein whose expression level in cancer is frequently decreased; however, it is rarely mutated nor suppressed. Par-4 is not only regulated at the expression level, but also post-translationally. Most recently, we reported the cisplatin-induced caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kd cleaved-Par-4 (cl-Par-4) fragment. In the present study, we investigated the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines. Briefly, we used cancer cell lines in which we produced stable clones expressing the cleaved form of PAR-4 (cl.PAR-4) using lentiviral particles. Using these models, we studied the regulation of cl.PAR-4 at the protein level using Western blots. Intriguingly, cl-Par-4 protein was weakly expressed in all stable clones despite constitutive transgene expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. We assessed the subcellular localization of cl-Par-4 in baseline and cisplatin-treated conditions using cytoplasmic/nuclear fractionation. Results showed that cl-Par-4 is localized in both the cytoplasm and nucleus compartments, but cisplatin treatment did not alter its localization. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure may in fact protect cl-Par-4 from proteasome-dependent degradation. To confirm proteasome involvement in this process, potential ubiquitination sites were predicted using bioinformatic tools. Interestingly, we showed that PI3K and MAPK pathways are also implicated in this post-translational regulation, as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors (Wortmannin and NVP-BEZ235) and a decrease of cl-Par-4 using MAPK inhibitors (U0126 and PD98059). Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4. Indeed, we have showed, using data from a published study, that the use of Bortezomib (a potent proteasome inhibitor) significantly increased Par-4 expression in MCF7 cancer cells. These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynecological cancer cells. Citation Format: Kevin Brasseur, Pascal Adam, Laurence Tardif, François Fabi, Sophie Parent, Éric Asselin. Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1994.
Abstract LB-236: Self-renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers
Authors: Pasquale Sansone, Ceccarelli Claudio, Marjan Berishaj, Qing Chang, Rajasekhar Vinagolu, Fabiana Perna, Robert Bowman, Michele Vidone, Laura Daly, Jennifer Nnoli, Donatella Santini, Taffurelli Mario, Natalie Shih, Michael Feldman, Jun James Mao, Christopher Colameco, Jinbo Chen, Angela DeMichele, Nicola Fabbri, John Healey, Monica Cricca, Giuseppe Gasparre, David Lyden, Massimiliano Bonafe, Jacqueline F. Bromberg
Journal: Cancer Research (2016)

Abstract The mechanisms of metastatic progression from hormonal therapy (HT)-induced tumour dormancy to hormonal therapy resistance is largely unknown in luminal breast cancer. Analysis of clinical specimens revealed the enrichment of CD133hi/ERlo cancer cells in primary tumours following neo-adjuvant endocrine therapy and in HT refractory metastatic disease. We developed spontaneous experimental models of metastatic luminal breast cancer and determined that endocrine therapy can promote the generation of HT- resistant, self-renewing CD133hi/ERlo/IL6hicells. Dual pharmacological inhibition of IL6R-IL6 (tocilizumab) and ER (HT) abrogated the establishment of CD133hi/ERlo/IL6hi cancer stem cells (CSCs), restoring endocrine sensitivity to hormone-refractory metastatic disease, in both experimental and patient-derived endocrine-resistant bone metastasis. Hormonal therapy, initially abrogated oxidative phosphorylation (OXPHOS) generating dormant (self-renewal deficient-CD133hi/ERlo/OXPHOSlo) cancer cells, These cells exited metabolic dormancy via an IL6 driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. Importantly, the inhibition of IL6R/IL6-Notch pathways switched the self-renewal of CD133hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy. Citation Format: Pasquale Sansone, Ceccarelli Claudio, Marjan Berishaj, Qing Chang, Rajasekhar Vinagolu, Fabiana Perna, Robert Bowman, Michele Vidone, Laura Daly, Jennifer Nnoli, Donatella Santini, Taffurelli Mario, Natalie Shih, Michael Feldman, Jun James Mao, Christopher Colameco, Jinbo Chen, Angela DeMichele, Nicola Fabbri, John Healey, Monica Cricca, Giuseppe Gasparre, David Lyden, Massimiliano Bonafe, Jacqueline F. Bromberg. Self-renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-236.
Abstract 1594: Contribution of Stromal Lymphocytes to Lung Cancer Metastasis: Role in Epithelial Mesenchymal Transition
Authors: Ylia Salazar, Magdalena Huber, Anja Schmall, Werner Seeger, SoniSavai Pullamsetti, Rajkumar Savai, Magdalena Huber, Anja Schmall, Werner Seeger, SoniSavai Pullamsetti.
Journal: Cancer Research (2016)

Abstract The tumor microenvironment and its immune components play a critical role in cancer development, progression, and control. In this study we aim to investigate the role of tumor infiltrating lymphocyte subpopulations in lung cancer progression. Conditioned media (CM) from co-cultures of human lymphocytes with adenocarcinoma cells (A549) induced the loss of the epithelial markers (E-Cadherin and ZO2 and an increase of mesenchymal markers (vimentin, N-cadherin on mRNA and protein level. In addition, the cells demonstrated a spindled shape-like morphological changes and an increased migratory property. In order to explore the molecular mechanism that led to lymphocyte-induced EMT and migration, we performed a cytokine array from the co-culture CM and found elevated levels of IL-8, IL-16, CCL2 and G-CSF. Furthermore, we observed that lymphocyte-induced EMT was mediated via a TGFβ-independent pathway that involves phosphorylation of ERK1/2. Notably, this EMT phenotype induction by lymphocytes was independent of the pre-activation of lymphocytes with PMA. Furthermore, in order to identify the specific CD4+ T cell subpopulations (Th0, Th1, Th9 and Th17) responsible for the EMT effect, we generated specific subpopulations from mouse spleen T cells. Interestingly, we observed that Th9 and Th17 subpopulation CM led to EMT and increased migratory phenotype in mouse lung cancer cell lines. Additionally, we identified the T lymphocyte secretory cytokine, IL9, as responsible for the Th9 induced EMT and migratory phenotype of lung cancer cells. This study reveals that specific T lymphocyte subpopulations, i.e. Th9 and Th17 induce EMT in lung cancer cells, suggesting T cell regulated mechanisms of metastasis. Citation Format: Ylia Salazar, Magdalena Huber, Anja Schmall, Werner Seeger, SoniSavai Pullamsetti, Rajkumar Savai, Magdalena Huber, Anja Schmall, Werner Seeger, SoniSavai Pullamsetti. Contribution of Stromal Lymphocytes to Lung Cancer Metastasis: Role in Epithelial Mesenchymal Transition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1594.
Cortisol in the Evaluation of Adrenal Insufficiency
Authors: Fady Hannah-Shmouni, Andrew Demidowich, Constantine A. Stratakis
Journal: JAMA (2016)

A 32-year-old woman with hypothyroidism presented for evaluation of chronic fatigue and weight loss of 9 kg. She had normal vital signs, darkening of her palmar creases, and buccal mucosa. Her test results showed low cortisol and elevated adrenocorticotropin hormone levels. What would you do next?
Abstract 2354: Cancer vaccine development for hepatocellular carcinoma - HEPAVAC
Authors: Sarah Kutscher, Roberto Accolla, Yuk T. Ma, Regina Heidenreich, Francesco Izzo, Alfred Koenigsrainer, Markus Loeffler, Phillip Mueller, Andrea Mayer, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Danila Valmori, Toni Weinschenk, Harpreet Singh-Jasuja, Luigi Buonaguro
Journal: Cancer Research (2016)

Abstract The HEPAVAC Consortium aims to develop a highly innovative, novel cancer vaccine approach for hepatocellular carcinoma (HCC). The international project consortium consists of 9 European Partners from academia and the biotech industry with complementary and substantial expertise in developing immunotherapeutic strategies to treat cancer. The project has started in September 2013 and is supported by the European Commission's 7th Framework Program (www.hepavac.eu). HCC/normal adjacent tissue matched samples have been collected for HLA immunopeptidome analysis. 17 HCC samples from HLA-A*02+ patients and 15 samples from HLA-A*24+ patients have been analysed by mass spectrometry (LC-MS/MS). RNA-expression profiles have been established for 12 HCC samples. HLA-presentation/expression of peptides and mRNA on primary HCC samples are compared to &amp;gt;140 normal tissue samples from relevant organs (including heart, brain, lung, kidney, liver, nerve, skin etc.) from Immatics’ database. A total of 9051 HLA-A*02-restricted different tumor-associated peptides (TUMAPs) have been identified from HLA-A*02+ samples, while a total of 3286 different HLA-A*24-restricted TUMAPs have been identified from HLA-A*24+ samples. Of these, 33 HLA-A*02+ TUMAPS and 33 HLA-A*24+ TUMAPs have been validated, including peptide synthesis, immunogenicity testing and pharmaceutical evaluation. Most promising TUMAP candidates show selective expression only in HCC samples and no expression in normal tissues. In parallel, more than 6600 HLA-DR TUMAPs have been identified in Hep3B cells transfected with CIITA as well as an average of 1500 HLA-DR TUMAPs have been identified in HCC samples. A total of 16 newly identified HCC-specific epitopes have been selected for the HEPAVAC vaccine cocktail and are currently synthesized according to GMP standard. Of these, 7 are restricted to HLA- class I A*02; 5 HLA-A*24 and 4 HLA class II. In parallel, preclinical studies assessing the formulation and combination of the immunological RNA-based adjuvant (RNAdjuvant®) with peptide cocktails are underway. A multi Center phase I/II clinical trial in early HCC patients is predicted to start in July 2016. Citation Format: Sarah Kutscher, Roberto Accolla, Yuk T. Ma, Regina Heidenreich, Francesco Izzo, Alfred Koenigsrainer, Markus Loeffler, Phillip Mueller, Andrea Mayer, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Danila Valmori, Toni Weinschenk, Harpreet Singh-Jasuja, Luigi Buonaguro. Cancer vaccine development for hepatocellular carcinoma - HEPAVAC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2354.
A single sodium channel mutation causing both long QT- and Brugada syndrome
Authors: CR Alshinawi, MW Veldkamp, MP Van Den Berg, AV Postma, Martin B. Rook, J.W. Viersma, IM van Langen, G. Tan Sindhunata, Margaretha Bink Boelkens, van der Annemarie Hout, Mmam Mannens, Aam Wilde
Journal: Circulation (1999)
Abstract 4292: Mitochodrial D-loop polymorphisms are associated with colorectal adenoma risk
Authors: Bharat Thyagarajan, Weihua Guan, Veronika Fedirko, Helene Barcelo, Myron D. Gross, Michael Goodman, Roberd M. Bostick
Journal: Cancer Research (2016)

Abstract Somatic mutational events in the mitochondria have been detected in adenomatous polyps. However, the contribution of germline variation in the mitochondrial DNA towards risk of colorectal adenomas, well recognized precursor lesions to colorectal cancer, has not been evaluated previously. Hence, we evaluated associations of mitochondrial polymorphisms in the D-loop and non-D loop regions with incident colorectal adenoma in three pooled colonoscopy-based case-control studies (n = 327 colorectal adenoma cases and 420 controls) that used identical methods for case ascertainment and risk factor determination. We sequenced a 1,124 bp fragment to comprehensively identify all genetic variation in the mitochondrial D-loop region, and used the Sequenom platform to genotype 64 previously described tagSNPs in the non-D loop region. We used multivariate unconditional logistic regression to analyze the association between the mitochondrial polymorphisms and colorectal adenoma risk after adjustment for potential confounders. We identified 320 germline mutations in the D-loop region; 30 (9%) had a minor allele frequency (MAF) ≥ 5%. Most of the mutations clustered in the hypervariable regions HV1 (n = 124; 39%) and HV2 (n = 111; 35%) of the D-loop region. Among the nine common polymorphisms (MAF ≥ 5%) in the HV1 region, four polymorphisms (mt16069, mt16278, mt16294, and mt16296) were statistically significantly directly associated with colorectal adenoma risk (odds ratios [OR]: 1.76 - 2.66; p-values: 0.001 - 0.04). In addition, the polyC tract in the HV1 region was inversely associated with colorectal adenoma risk (OR: 0.90; p = 0.03). None of the other polymorphisms in the mitochondrial D-loop region tract was associated with colorectal adenoma risk. After correction for multiple comparisons, none of the mitochondrial tagSNPs in the non-D loop region was associated with colorectal adenoma risk. These findings suggest that polymorphisms in the HV1 region of the mitochondrial D-loop may be associated with colorectal adenoma risk and support further investigation in future studies. Citation Format: Bharat Thyagarajan, Weihua Guan, Veronika Fedirko, Helene Barcelo, Myron D. Gross, Michael Goodman, Roberd M. Bostick. Mitochodrial D-loop polymorphisms are associated with colorectal adenoma risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4292.
LincRNA-p21 Impacts Prognosis in Resected Non–Small Cell Lung Cancer Patients through Angiogenesis Regulation
Authors: Joan J. Castellano, Alfons Navarro, Nuria Viñolas, Ramon M. Marrades, Jorge Moises, Anna Cordeiro, Adela Saco, Carmen Muñoz, Dolors Fuster, Laureano Molins, Josep Ramirez, Mariano Monzo
Journal: Journal of Thoracic Oncology (2016)
Addition of PLA2 to CRP enhances sepsis diagnosis
Authors: Tom S.J. Elliott, Anna L. Casey, Tarja J. Karpanen, Miruna D. David, Tony Whitehouse, Peter A. Lambert, Ann B. Vernallis, Tony Worthington, Gita Parekh, Christopher R. Dunston, Josh Kirby, Paul Davis
Journal: Journal of Infection (2016)
Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment
Authors: G. Sapisochin, M. Facciuto, L. Rubbia‐Brandt, J. Marti, N. Mehta, F.Y. Yao, E. Vibert, D. Cherqui, D.R. Grant, R. Hernandez‐Alejandro, C.H. Dale, A. Cucchetti, A. Pinna, S. Hwang, S.G. Lee, V.G. Agopian, R.W. Busuttil, S. Rizvi, J.K. Heimbach, M. Montenovo, J. Reyes, M. Cesaretti, O. Soubrane, T. Reichman, J. Seal, P.T.W. Kim, G. Klintmalm, C. Sposito, V. Mazzaferro, P. Dutkowski, P.A. Clavien, C. Toso, P. Majno, N. Kneteman, C. Saunders, J. Bruix
Journal: Hepatology (2016)

The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor &gt;2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 [2.5‐4.4] versus 1.6 [1.5‐1.8]). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (H epatology 2016;64:1178‐1188)