tbuckley/cabot-search huggingface dataset:
Abstract 794: A genetic polymorphism of ALDH2 and breast cancer risk: an analysis of 6,624 cases and 5,750 controls from the Breast Cancer Association Consortium
Authors: Tomotaka Ugai, Roger L. Milne, Hidemi Ito, Keitaro Matsuo
Journal: Cancer Research (2016)

Abstract Background. Numerous epidemiological studies consistently indicate that consumption of alcoholic beverages is an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, it has been hypothesized that ethanol is mutagenic via its first metabolite, acetaldehyde. An impact of acetaldehyde on the carcinogenesis of several types of cancer has been shown in experimental models and in epidemiological studies in East Asian countries where a functional aldehyde dehydrogenase 2 (ALDH2) polymorphism Glu504Lys (rs671) is prevalent. However, its association with breast cancer risk has not been fully elucidated. We conducted an association analysis of original data from Asian studies participating in the Breast Cancer Association Consortium (BCAC). Patients and Methods. Nine studies were used for this analysis, including 6,624 cases and 5,750 controls. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with the ALDH2 polymorphism was estimated using logistic regression models. We estimated unadjusted ORs and adjusted ORs for potential confounders. Results. In the unadjusted (crude) analysis, no significant association between ALDH2 polymorphism and breast cancer was observed, with ORs relative to Glu/Glu, of 1.02 (95% CI = 0.95-1.11; P = 0.51) for Glu/Lys, 1.13 (0.96-1.32; 0.14) for Lys/Lys and 1.04 (0.97-1.12; 0.29) for carriers of any Lys allele. In addition, after adjustment for all potential confounding factors, this lack of significant association was consistently observed, with ORs relative to Glu/Glu, of 0.95 (95% CI = 0.86-1.04; P = 0.25) for Glu/Lys, 0.99 (0.82-1.20; 0.93) for Lys/Lys and 0.95 (0.87-1.04; 0.29) for carriers of any Lys allele. These findings were consistent across ER, PR and HER2 status. Conclusions. No significant association between ALDH2 polymorphism and breast cancer was observed in this study. Considering the established impact of ALDH2 504Lys on the carcinogenesis of several types of alcohol-induced cancer, our findings suggest that acetaldehyde is less influential to the breast carcinogenesis induced by alcohol, as is the case for upper-aerodigestive tract cancers. Citation Format: Tomotaka Ugai, Roger L. Milne, Hidemi Ito, Keitaro Matsuo. A genetic polymorphism of ALDH2 and breast cancer risk: an analysis of 6,624 cases and 5,750 controls from the Breast Cancer Association Consortium. [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 794.
Safety of Baxter’s Longer Acting rFVIII (BAX 855) After Repeated Application in Rats and Cynomolgus Monkeys
Authors: Barbara Dietrich, Margit Spatzenegger, Reinhard Stidl, Martin Wolfsegger, Hartmut J. Ehrlich, Friedrich Scheiflinger, Hans Peter Schwarz, Eva-Maria Muchitsch
Journal: Blood (2011)
Primary Neuroendocrine Carcinoma of the Kidney on FDG PET/CT
Authors: Ximin Shi, Fang Li, Yaping Luo, Li Huo
Journal: Clinical Nuclear Medicine (2016)

A 28-year-old woman presented gradually worsening intermittent right groin pain for 10 months. FDG PET/CT was performed to evaluate the suspected renal malignancy. The images demonstrated a large hypermetabolic tumor occupying the entire right kidney. Pathological examination demonstrated a primary neuroendocrine carcinoma of the kidney.
Copy number alterations of <i>P53</i>, <i>RB1,</i> and <i>MDM2</i> as prognostic markers in intermediate-risk prostate cancer.
Authors: Osman Mahamud, Melvin Chua, Emilie Lalonde, Jonathan So, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul Boutros, Robert G. Bristow
Journal: Journal of Clinical Oncology (2016)

117 Background: We interrogated copy number alternations (CNA) of p53, Rb1 and MDM2 as prognostic determinants of biochemical failure in localized intermediate-risk prostate cancer. Methods: Using Affymetrix Oncoscan array technology, we characterized copy number alterations (CNA) for 284 D’Amico-classified intermediate-risk prostate cancers. Of the 284 patients, 143 underwent image-guided radiotherapy (IGRT), while 141 underwent radical prostatectomy (RadP). Biochemical-relapse free survival (bRFS) was assessed as a clinical end-point, with biochemical failure defined using the Phoenix and AUA criteria for IGRT and RadP patients, respectively. Results: We observed allelic losses ofp53 and Rb1 in 23.9% (n = 68) and 31.0% (n = 88) and allelic gains of MDM2 in 3.17% (n = 9) in our cohort, respectively. 7.7% (n = 22), 1.1% (n = 3) and 0.4% (n = 1) of all cases exhibited concurrent losses of p53 and Rb1, p53 loss and MDM2 gain, and concurrent p53/Rb1 loss and MDM2 gain, respectively. Patients with allelic losses of p53, Rb1 and allelic gain of MDM2 loci exhibited increased percent genome aberration (PGA) (Mean 9.2 vs. 6.1 p &lt; 0.001; 10.1 vs. 5.4 p &lt; 0.001; 18.1 vs. 6.5 p &lt; 0.001 respectively). Rb1 loss and MDM2 gain were not significant predictors of bRFS, independent of treatment modality. Allelic loss of p53 was predictive of poor bRFS in the RadP cohort (HR = 1.86, 95% CI 1.10-3.16, p = 0.022), but not for IGRT patients (HR = 1.16, 95% CI 0.63-2.12, p = 0.629). Additionally, patients in the RadP cohort with concurrent losses of p53 and Rb1 also had a higher likelihood of poorer bRFS (HR = 2.32, 95% CI 1.1-4.93, p = 0.029). On multivariate analysis, incorporating PGA and pre-treatment PSA, concurrent p53/Rb1 losses, but not single p53 loss, was prognostic for bRFS in patients who underwent RadP (p53/Rb1 losses, HR = 2.16, 95% CI 1.0-4.65, Wald's p = 0.05; p53loss, HR = 1.62, 95% CI 0.94-2.79, Wald's p = 0.08). Conclusions: In a cohort of men with intermediate-risk prostate cancers, we identified an unfavourable subgroup of patients harbouring concurrent copy number losses of p53 and Rb1 that was associated with an adverse prognosis of biochemical failure following radical prostatectomy.
Evaluation of emerging technologies for coronary revascularization. Participants in the National Heart, Lung, and Blood Institute Conference on the Evaluation of Emerging Coronary Revascularization Technologies.
Authors: Gordon Johnson, Kenneth Kent, Spencer King, Timothy Sanborn, John Simpson, Eric Topol
Journal: Circulation (1992)

Despite significant advances in coronary angioplasty, the problems of restenosis, chronic total occlusion, diffuse disease, and abrupt closure after the procedure remain to be solved. New devices that address these problems continue to evolve. Although a controlled clinical trial is the ultimate test of any device, rapid device design changes and resource limitations require evaluating which of the new devices justify a full clinical trial. A registry mechanism for this initial evaluation is proposed and detailed. Payment for procedures using new devices is a problem for industry, insurers, hospitals, and physicians. It is proposed that reimbursement be based on the service performed rather than the device used to perform it. Costs beyond the clinical costs should be borne by the sponsor of the device. Financial conflict of interest is a recognized problem in new device evaluation. It is not always practical to insist on exclusion from the evaluation process of individuals with a financial stake in the outcome, but disclosure of the presence of such a financial interest is recommended in the reporting of results.
Plasmocytosis and Immunoparesis but Not Neutrophil to Lymphocyte Ratio Can Predict Time to Treatment in Smoldering Myeloma
Authors: Alessandra Romano, Marzia L Consoli, Marina Parisi, Maide Cavalli, Nunziatina L Parrinello, Concetta Conticello, Francesco Di Raimondo
Journal: Blood (2015)
Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with <i>CYP4F22</i> mutations
Authors: R. Gruber, G. Rainer, A. Weiss, A. Udvardi, H. Thiele, K.M. Eckl, R. Schupart, P. Nürnberg, J. Zschocke, M. Schmuth, B. Volc-Platzer, H.C. Hennies
Journal: British Journal of Dermatology (2016)

Autosomal recessive congenital ichthyosis (ARCI) caused by mutations in CYP4F22 is very rare. CyP4F22, a protein of the cytochrome‐P450 family 4, encodes an epidermal ω‐hydroxylase decisive in the formation of acylceramides, which is hypothesized to be crucial for skin‐barrier function. We report a girl with consanguineous parents presenting as collodion baby with contractures of the great joints and palmoplantar hyperlinearity. In the course of the disease she developed fine scaling of the skin with erythroderma, the latter disappearing until the age of 6 months. Her sister showed a generalized fine‐scaling phenotype, and, interestingly, was born without a collodion membrane. The analysis of all known candidate genes for ARCI in parallel with a next‐generation sequencing approach using a newly designed dermatogenetics gene panel revealed a previously unknown homozygous splice‐site mutation c.549+5G>C in CYP4F22 in both girls, confirming the diagnosis of ARCI. Ultrastructural analysis by transmission electron microscopy in both patients showed epidermal hyperplasia, orthohyperkeratosis with persistence of corneodesmosomes into the outer stratum corneum layers, fragmented and disorganized lamellar lipid bilayers, which could be ascribed to inhomogeneous lamellar body secretion, as well as lamellar body and lipid entombment in the corneocytes. These findings correlated with increased transepidermal water loss on the functional level. For the first time, we report a collodion baby phenotype and epidermal barrier impairment in CyP4F22‐deficient epidermis at both the ultrastructural and functional level, and corroborate the importance of CyP4F22 for epidermal maturation and barrier function.
Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction
Authors: Rachele Pandolfi, Bianca Barreira, Enrique Moreno, Victor Lara-Acedo, Daniel Morales-Cano, Andrea Martínez-Ramas, Beatriz de Olaiz Navarro, Raquel Herrero, José Ángel Lorente, Ángel Cogolludo, Francisco Pérez-Vizcaíno, Laura Moreno
Journal: Thorax (2016)

Pulmonary hypertension (PH) is frequently observed in patients with acute respiratory distress syndrome (ARDS) and it is associated with an increased risk of mortality. Both acid sphingomyelinase (aSMase) activity and interleukin 6 (IL-6) levels are increased in patients with sepsis and correlate with worst outcomes, but their role in pulmonary vascular dysfunction pathogenesis has not yet been elucidated. Therefore, the aim of this study was to determine the potential contribution of aSMase and IL-6 in the pulmonary vascular dysfunction induced by lipopolysaccharide (LPS).Rat or human pulmonary arteries (PAs) or their cultured smooth muscle cells (SMCs) were exposed to LPS, SMase or IL-6 in the absence or presence of a range of pharmacological inhibitors. The effects of aSMase inhibition in vivo with D609 on pulmonary arterial pressure and inflammation were assessed following intratracheal administration of LPS.LPS increased ceramide and IL-6 production in rat pulmonary artery smooth muscle cells (PASMCs) and inhibited pulmonary vasoconstriction induced by phenylephrine or hypoxia (HPV), induced endothelial dysfunction and potentiated the contractile responses to serotonin. Exogenous SMase and IL-6 mimicked the effects of LPS on endothelial dysfunction, HPV failure and hyperresponsiveness to serotonin in PA; whereas blockade of aSMase or IL-6 prevented LPS-induced effects. Finally, administration of the aSMase inhibitor D609 limited the development of endotoxin-induced PH and ventilation-perfusion mismatch. The protective effects of D609 were validated in isolated human PAs.Our data indicate that aSMase and IL-6 are not simply biomarkers of poor outcomes but pathogenic mediators of pulmonary vascular dysfunction in ARDS secondary to Gram-negative infections.
GENO-02INTEGRATED ANALYSIS OF MOLECULAR SUBTYPES IN GLIOBLASTOMA MULTIFORME
Authors: Durairaj Renu, Pritha Aggarwal, Sunil Cherukuri, Pramila Tata, Vadiraja Bhat, Carolina Livi, Michael Rosenberg, Mona Al-Gizawiy, Wade Mueller, Jennifer Connelly, Kathleen Schmainda, Shama Mirza
Journal: Neuro-Oncology (2015)

BACKGROUND: The Cancer Genome Atlas (TCGA) project previously identified genetic changes in the DNA sequence and copy number, DNA methylation, and gene expression of glioblastoma multiforme (GBM) tumors, leading to an enthused effort to compile and characterize changes in the genome, transcriptome, and proteome of human GBM tumors, so that aberrantly functioning molecular pathways and tumor subtypes could be identified. METHODS: Agilent GeneSpring and Mass Profiler Professional (MPP) software was used to perform integrated multi-omics analysis of mRNA expression, miRNA expression, protein expression, and copy number aberration associated with GBM. Additionally, analysis was performed on an independent discovery proteomics study of GBM and control (brain fragments from epilepsy surgery) patients measured using a label-free proteomics approach. RESULTS: Correlation analysis performed between mRNA and miRNA datasets from TCGA identified potential candidate miRNAs regulating the known Proneural signature genes OLIG2, NKX2-2, and SOX11. It also highlighted the molecular events leading to suppression of p53 in Proneural tumor signaling. Sample-sample correlation and PCA analysis on patient specimens resulted in clear separation between control and tumor samples. In addition, the tumor samples were segregated into two to three subgroups, suggesting that different TCGA subtypes may be present. Indeed, combined analysis of mRNA expression data from TCGA study and proteomics data from the label-free study identified a core subset of 54 GBM subtype signatures, clearly differentiating the known subtypes in the larger TCGA cohort. CONCLUSION: Our observation suggests that GBM tumor heterogeneity may be best characterized by both mRNA and protein abundance of the signature genes, opening a possibility for follow-up studies with potential diagnostic and clinical significance.
Abstract 596: Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC)
Authors: Natasha Bodyak, Alex Yurkovetskiy, Dmitry R. Gumerov, Dongmei Xiao, Joshua D. Thomas D. Thomas, Laura L. Poling, LiuLiang Qin, Mao Yin, Michael J. DeVit, Peter U. Park, Winnie Lee, Bianka Prinz, Donald A. Bergstrom, Timothy B. Lowinger
Journal: Cancer Research (2016)

Abstract XMT-1522 is an anti-HER2 ADC that incorporates HT-19, a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery. Several parameters such as cell binding, internalization rate, cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) downstream signaling, affinity maturation, NHP cross-reactivity, normal human tissue cross-reactivity and in vivo efficacy were used to screen a wide range of antibodies to select a lead candidate optimized for use in ADC applications. In addition HT-19 was selected to be non-competitive for HER2 binding with existing therapies - trastuzumab or pertuzumab, to allow for potential combinability. In vivo efficacy as an ADC did not directly correlate with typical parameters used in antibody screening cascade such as in vitro cytotoxicity, internalization or binding affinity. The lead antibody underwent affinity maturation, and despite increases in affinity, affinity maturation significantly decreased the in vivo efficacy of the ADC in vivo xenograft models. This phenomenon was observed in all the antibody hits. HT-19 showed antibody-dependent cell-mediated cytotoxicity (ADCC) activity. When administered as a single agent in NCI-N87 gastric cancer xenograft model it had biological activity at 20 mg/kg as well as at 3 mg/kg. Consistent with the hypothesis that a non-competitive ADC is combinable with current anti-HER2 regimens, the combination of XMT-1522 with trastuzumab and/or pertuzumab showed more rapid internalization, more complete HER2 degradation, and significantly great anti-tumor activity in the NCI-N87 gastric cancer xenograft model relative to XMT-1522 alone or the combination of pertuzumab + trastuzumab. Citation Format: Natasha Bodyak, Alex Yurkovetskiy, Dmitry R. Gumerov, Dongmei Xiao, Joshua D. Thomas D. Thomas, Laura L. Poling, LiuLiang Qin, Mao Yin, Michael J. DeVit, Peter U. Park, Winnie Lee, Bianka Prinz, Donald A. Bergstrom, Timothy B. Lowinger. Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC). [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 596.
Isoniazid metabolism and hepatotoxicity
Authors: Pengcheng Wang, Komal Pradhan, Xiao-bo Zhong, Xiaochao Ma
Journal: Acta Pharmaceutica Sinica B (2016)

Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.
Abstract 3877: A new frontier for molecular profiling of neoplastic bone tissue
Authors: Claudius Mueller, Lance A. Liotta, Antonella Chiechi, Piero Picci, Marco Alberghini, Lorenzo Memeo, Vincenzo Canzonieri, Virginia Espina
Journal: Cancer Research (2016)

Abstract Background: Tissue is alive and reacting to ex vivo stress during “cold ischemia time”. Tumor cells react to the absence of vascular perfusion, hypoxia, acidosis, and accumulation of cellular waste, which can critically mask cancer related signaling network data. Standard formalin fixation of calcified tissue requires decalcification with formic/nitric acid solution, which greatly interferes with downstream molecular analysis. We developed a non-formalin fixative (TheraLin) for preserving biomarker molecules and tissue histomorphology in one step, which greatly facilitates the analysis of phosphoprotein signaling pathways in calcified tumor samples. Methods: Fifty specimens of neoplastic bone were collected at the Istituto Ortopedico Rizzoli (Bologna, Italy). Matched 0.5 cm samples were fixed in TheraLin preservative; or fixed in 4% buffered formalin and decalcified with formic/nitric acid solution. Specimens were processed into paraffin blocks and 5 μm tissue sections cut onto glass slides. Enriched tumor cell populations were procured using Laser Capture Microdissection. Reverse Phase Protein Microarrays were constructed with the microdissected tumor cells and probed with &amp;gt;40 antibodies to unmodified or phosphorylated proteins. Immunohistochemistry (&amp;gt;200 stains in total) was performed on routine clinical protein targets and a subset of phosphorylated proteins. Results: TheraLin fixation greatly facilitated molecular profiling of bony tissues by eliminating the need for decalcification (18.5 hour average reduction in processing time) while maintaining or improving histomorphology (&amp;gt;85% of cases) and immunohistology (&amp;gt;75% of cases). In addition, we were able to demonstrate full compatibility with laser capture microdissection, reverse phase protein microarrays and downstream analysis of cell signal protein activation. Protein extractability from microdissected material was significantly increased (&amp;gt;2.5 fold, p&amp;lt;0.01) compared to formalin fixed, decalcified bone tissue. Conclusion: TheraLin obviates the need for decalcification of bone tissue while simultaneously preserving histomophology and immunohistochemistry. TheraLin enables reliable quantification of phosphorylated signal transduction proteins, the substrates of kinase drug targets, and greatly facilitates tumor cell enrichment compared to standard formalin fixation and decalcification. Citation Format: Claudius Mueller, Lance A. Liotta, Antonella Chiechi, Piero Picci, Marco Alberghini, Lorenzo Memeo, Vincenzo Canzonieri, Virginia Espina. A new frontier for molecular profiling of neoplastic bone tissue. [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 3877.
Abstract 4890: Preclinical analysis of combination therapy using radiation and cellular immunotherapy
Authors: Satoshi Wada
Journal: Cancer Research (2016)

Abstract Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colonystimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting. Citation Format: Satoshi Wada. Preclinical analysis of combination therapy using radiation and cellular immunotherapy. [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 4890.