tbuckley/cabot-search huggingface dataset:
The Epidemiologic Approach
Authors: Sidney Pell
Journal: Environmental Health Perspectives (1978)

Epidemiological studies rarely provide unequivocal data on the effects of toxic substances on human health. Unlike experimental studies, pertinent variables frequently cannot be controlled and some are often unknown. Nevertheless, these limitations can be dealt with by various facets of an epidemiological investigation. These include, the choice of a study design, selection of controls or comparison populations, evaluation of available data, statistical analysis, and the drawing of appropriate inferences from the data. Among the special problems that might be encountered in studies of the effects of cardiotoxic substances are, difficulties in establishing diagnoses, errors in death certificates, observer errors in electrocardiographic interpretations, and taking into account the effects of various risk factors known to be implicated in the etiology of cardiovascular diseases. In spite of various methodological problems and certain inherent limitations of epidemiological studies, they can, when properly conducted, make significant contributions to knowledge of disease etiology and provide the means of reducing the risk of a disease, even when its etiology is not completely known.
151 REDUCED DOSE AND DURATION OF SORAFENIB TREATMENT ARE ASSOCIATED TO TUMOR PROGRESSION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA
Authors: F.R. Ponziani, B.E. Annichiarico, M. Siciliano, C. Barone, M. Basso, V. Cesario, M. Campanale, G. Caracciolo, M. Garcovich, M. Zocco, G. Gigante, E. Rinninella, G. Sarno, T.A. Di Rienzo, F. D'Aversa, G. Gasbarrini, A. Gasbarrini
Journal: Journal of Hepatology (2012)
ETIOLOGY, TIMING AND IMPACT OF DUAL ANTIPLATELET THERAPY DISCONTINUATION AFTER DRUG-ELUTING STENT IMPLANTATION: INSIGHTS FROM THE ADAPT-DES STUDY
Authors: Daniel Musikantow, Ajay Kirtane, Claire Litherland, Bernhard Witzenbichler, Giora Weisz, Michael Rinaldi, David Metzger, Timothy Henry, David Cox, Thomas Stuckey, Akiko Maehara, Philippe Genereux, Roxana Mehran, Gregg Stone
Journal: Journal of the American College of Cardiology (2016)
Abstract 1748: Cyclin D1 harboring T286I mutation promotes oncogenic activation in endometrial cancer.
Authors: Yuji Ikeda, Katsutoshi Oda, Takahiro Koso, Aki Miyasaka, Tomoko Kashiyama, Osamu Hiraike-Wada, Daichi Maeda, Kei Kawana, Shunsuke Nakagawa, Osamu Tetsu, Yoshihiro Kikuchi, Tomoyuki Fujii, Tetsu Yano, Shiro Kozuma
Journal: Cancer Research (2013)

Abstract Introduction. Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr-286 by GSK3beta triggers nuclear export and its cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however,mutations of CCND1 (encoding cyclin D1) have been only reported in endometrial cancer and esophageal cancer. We previously reported T286I mutations of CCND1 in 2 endometrial carcinomas (2.3%). The objective of this study was to identify the functions of T286I mutant of cyclin D1 in endometrial cancer. Materials and methods. T286I mutant cyclin D1 (CD1-T286I) plasmid was generated using wild-type cyclin D1 (CD1-WT) plasmid via site-directed mutagenesis technique. pcDNA3 empty plasmid was used as a control (CD1-Ct). Using these plasmids, the functions of mutant CD1-T286I were analyzed by luciferase assays, immunofluorescence, western blotting and colony formation assays in HEK293T (kidney) and HEC-50B (endometrial cancer) cells, both of which do not possess CCND1 mutations. Statistical analysis was performed by student-T test and p&amp;lt;0.05 was considered statistically significant. Result. Immunofluorescence and western blotting showed predominant accumulation of exogenous CD1-T286I in nucleus, whereas expression of exogenous CD1-WT and endogenous cyclin D1 were observed diffusely in cytoplasm and nucleus. Luciferase assay revealed that pRB1 expression was partially decreased by introduction of CD1-WT and that the pRB1 expression was further decreased by introduction of CD1-T286I (p=0.002). In colony formation assays, introduction of CD1-T286I significantly increased the colony number, compared with CD1-WT (p=0.007) and CD1-Ct. Conclusion. Stabilization and accumulation of mutant cyclin D1 (T286I) in the nucleus might overcome regulation by pRb and induce cell proliferation in certain endometrial cancers. Phosphorylation-dependent nuclear export of cyclin D1 at Thr286 might be critical for prevention of aberrant cell proliferation in human cells. Citation Format: Yuji Ikeda, Katsutoshi Oda, Takahiro Koso, Aki Miyasaka, Tomoko Kashiyama, Osamu Hiraike-Wada, Daichi Maeda, Kei Kawana, Shunsuke Nakagawa, Osamu Tetsu, Yoshihiro Kikuchi, Tomoyuki Fujii, Tetsu Yano, Shiro Kozuma. Cyclin D1 harboring T286I mutation promotes oncogenic activation in endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1748. doi:10.1158/1538-7445.AM2013-1748
A novel endoscopic weight loss therapy using gastric aspiration: results after 6 months
Authors: Henrik Forssell, Erik Norén
Journal: Endoscopy (2014)

<b>Background and study aims:</b> Obesity is a major public health problem with few effective treatment options. A novel device for treating obesity, the AspireAssist aspiration therapy system, was evaluated. <b>Patients and methods:</b> After 4 weeks taking a very-low-calorie diet, 25 obese men and women (BMI 39.8 ± 0.9 kg/m<sup>2</sup>) had the AspireAssist gastrostomy tube placed during a gastroscopy. A low-profile valve was installed 14 days later and aspiration of gastric contents was performed approximately 20 minutes after meals three times per day. Cognitive behavioral therapy was also started. <b>Results:</b> At month 6, mean weight lost was 16.5 ± 7.8 kg in the 22 subjects who completed 26 weeks of therapy (<i>P</i> = 0.001). The mean percentage excess weight lost was 40.8 ± 19.8 % (<i>P</i> = 0.001). Two subjects were hospitalized for complications: one subject for pain after gastrostomy tube placement, which was treated with analgesics, and another because of an aseptic intra-abdominal fluid collection 1 day after gastrostomy tube placement. No clinically significant changes in serum potassium or other electrolytes occurred. <b>Conclusion:</b> In this study, substantial weight loss was achieved with few complications using the AspireAssist system, suggesting its potential as an attractive therapeutic device for obese patients. Trial Register ISRCTN 49958132.
Biliary papillomatosis in the common bile duct
Authors: R. Kassir, G. Barabino, S. Bageacu, G. Ferrari, K. Abboud, O. Dumas, M. Peoc'h, J. Porcheron
Journal: Endoscopy (2013)

A 62-year-old woman was admitted to our hospital with abdominal pain. Clinical examination revealed definite tenderness in the right hypochondrium only. Laboratory assessment on admission was normal. An abdominal ultrasound was performed, which showed an irregular hyperechoic pseudomass of the gallbladder.
A7.01 Abrogation of collagen-induced arthritis by a second generation peptidyl arginine deiminase inhibitor is associated with a shift from TH1/TH17 to TH2-mediated immune responses
Authors: J Kawalkowska, AM Quirke, F Ghari, V Subramanian, R Li, PR Thompson, RO Williams, R Fischer, NB La Thangue, PJ Venables
Journal: Annals of the Rheumatic Diseases (2016)

<h3></h3> Citrullination is catalysed by peptidylarginine deiminases (PADs) and may play a role in joint inflammation by generating proteins recognised by autoantibodies and/or by targeting histones and thereby modulating gene transcription. The PAD inhibitor Cl-amidine was shown to have a modest anti-inflammatory effect in collagen-induced arthritis (CIA), when given prophylactically at high doses. While much of this benefit was thought to be due to PAD4 inhibition, recent studies have highlighted the pro-inflammatory effects of PAD2. The objective of this study was to assess the therapeutic potential BB-Cl-amidine, which is 10 fold more active than Cl-amidine against PAD2. We chose CIA as a reproducible model of immune-mediated arthritis and used a clinically-relevant therapeutic protocol, in which mice were treated after disease onset. CIA was induced in DBA/1 mice by immunisation with bovine type II collagen. After disease onset, mice were treated daily with vehicle or BB-Cl-amidine (10 mg/kg, n = 12). On day 10, mice were culled, and paws, blood and lymph nodes collected for further analysis. In serum, cytokines were measured using a multiplex platform and anti-citrullinated peptide antibodies (ACPA) by ELISA. The phenotypes of T cells were determined by FACS. Citrullinated proteins were identified by mass spectrometry. Treatment of arthritic mice with BB-Cl-amidine, resulted in a significant reduction in clinical scores and paw swelling. Histological changes in joints were almost completely normalised by BB-Cl-amidine. Unexpectedly, while pro-inflammatory cytokine (TNF-α, IL-1β, IL-6) levels in serum remained unaffected by BB-Cl-amidine, IL-4, IL-5 and IL-10 levels were significantly elevated. In line with this, IL-4-expressing Th2 cells were increased in the lymph nodes of BB-Cl-amidine treated mice. Further analysis revealed a decrease in Th1 and Th17 numbers with BB-Cl-amidine. In addition BB-Cl-amidine reduced histone H3.2 citrullination, with little affect on the ACPA response which suggests that BB-CL-amidine may inhibit gene expression in disease via an epigenetic mechanism. In conclusion, BB-Cl-amidine is therapeutic in CIA due to immunomodulation rather than immunosuppression and supports anti-inflammatory Th2-type, while inhibiting pro-inflammatory Th1/Th17-type responses. We propose that these effects are mediated by transcriptional regulation and that targeting PADs is a realistic strategy for the treatment of chronic inflammatory diseases.
Abstract 4371: Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor.
Authors: Sinisa Dovat, Chunhua Song, Kimberly J. Payne
Journal: Cancer Research (2013)

Abstract An increase in the expression and activity of pro-oncogenic Casein Kinase II (CK2) is associated with the development of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in humans. The mechanism by which CK2 promotes leukemogenesis is unknown. Previously, we demonstrated that CK2 kinase phosphorylates the Ikaros tumor suppressor in vivo and that phosphorylation of Ikaros at specific amino acids interferes with the normal function of the Ikaros protein. We hypothesized that CK2 exerts its pro-oncogenic effect by reducing the tumor suppressor activity of Ikaros and that inhibition of CK2 could enhance Ikaros tumor suppressor activity in leukemia. Here we show that Ikaros binds to the promoter regions and represses transcription of several genes that promote cell cycle progression in leukemia. Inhibition of CK2 results in: 1) enhanced Ikaros DNA-binding affinity to its target genes as indicated by quantitative chromatin immunoprecipitation (qChIP) assay); 2) increased Ikaros-mediated transcriptional repression of Ikaros target genes as demonstrated by luciferase reporter assay; 3) impaired proliferation of leukemia cells and 4) increased sensitivity of leukemia cells to Doxorubicin. The use of specific CK2 inhibitors in vivo in a human-mouse leukemia xenograft model produced a strong anti-leukemia effect. Functional analysis of leukemia cells from xenografts demonstrated that CK2 inhibition results in strong binding of Ikaros at the promoters of its target genes and reduced transcription of these genes as indicated by quantitative real-time PCR (qRT-PCR). Our results provide evidence that CK2 inhibitors have a potent anti-leukemia effect in vitro and in vivo, and suggest the mechanism through which CK2 inhibitors exert their therapeutic effect. The presented data demonstrate that one of the mechanisms of action for CK2 inhibitors involves increasing Ikaros activity as a transcriptional repressor in leukemia cells, resulting in enhanced tumor suppressor activity. These results provide a rationale for the use of CK2 inhibitors as a novel therapeutic modality for leukemia. Supported by National Institutes of Health R01 HL095120, a St. Baldrick's Foundation Career Development grant, and the Four Diamonds Fund Endowment (to S.D.). Citation Format: Sinisa Dovat, Chunhua Song, Kimberly J. Payne. Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2013-4371
Abstract 3312: Molecular profiling of melanoma primary tumors
Authors: Richard Essner
Journal: Cancer Research (2010)

Abstract Objectives: A number of pathologic features have been identified from primary melanoma that are useful for determining patient prognosis including tumor thickness, ulceration, mitotic rate and Clark level; and the tumor status of the sentinel nodes (SN). Because none of these factors is useful for evaluating the outcome of individual patients we used a cDNA microarray to determine the relevance of molecular profiling of the primaries to determine the presence of lymph node metastases. Methods: We obtained intact melanoma primaries and SN from 12 patients and microdissected both for molecular analysis. RNA was extracted and purified by RNeasy (Qiagen, Valencia, CA). GEArray Q series-Human Tumor Metastasis Gene Array Kits (Superarray, Bethesda, MD) were used to evaluate gene expression from biotinylated cDNA and images were acquired on the Molecular Dynamics storm 860 imaging station (Amersham Pharmacia Biotech, United Kingdom, Ltd). The signal intensity which corresponds to the quantity of cDNA bound to the array was analyzed by the ScanAlyze V2.50 image analysis software (Covance, Berkeley, CA). Results: RNA was evaluated from 12 primary melanoma and matching SN, 7 with metastases. Four genes: caveolin (CAV1), Lim kinase (LIMK), matrix metalloproteinase 15 (MMP15) and vascular endothelial growth factor (VEGF) demonstrated consistent up-regulation in primary melanoma associated with SN metastases identified by H &amp; E and the presence of these genes expressed in SN. Human melanoma cell lines and tumor-negative SN served as controls. Receiver operator curves (ROC) for genes: CAV1, LIMK, MMP15 and VEGF were constructed and the area under the curves (AUC) were determined as: 0.956+0.056, 0.978+0.039, 0.822+0.114 and 0.91+0.08, respectively. The combined concordance of LIMK and VEGF to predict metastases was 0.94 Conclusions: Gene expression profiling of primary melanoma can be used for predicting the presence of SN metastases. Up-regulation of LIMK and VEGF from the primary tumors may be an important first step to understand the early mechanism for patients developing lymph node metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3312.
Abstract 2138: Functional characterization of the 19q12 amplicon in grade 3 breast cancers
Authors: Rachael C. Natrajan, Daniel Wetterskog, Maryou BK Lambros, Geyer Felipe, Alan Mackay, Radost Vatcheva, Jose Palacios, Jorge Reis-Filho
Journal: Cancer Research (2010)

Abstract Grade III (GIII) invasive ductal carcinomas of no special type (IDC-NST) comprise up to 60% of all invasive breast cancers and have an aggressive clinical behavior. We have previously identified 19q12 amplification in a subgroup of estrogen receptor (ER)-negative HER2 amplified (4%) and basal-like (16%) subtypes of breast cancer. This amplicon comprises 9 genes, including cyclin E1 (CCNE1), which has been proposed as its driver due to a strong association with gene over-expression. The aims of this study were to identify functionally the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harboring this amplification. We analyzed a series of 48 micro-dissected GIII IDC-NSTs using high-resolution microarray CGH and mRNA expression arrays and identified 19q12 amplification in 7.6% of ER negative GIII tumors. Of the 9 genes mapping to the smallest region of amplification, UQCRFS1, POP4, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified (P&amp;lt;0.05). Breast cancer cell lines with (MDAMB157 and HCC1569) and without (Hs578T, MCF7, MDAMB231 and ZR75.1) 19q12 amplification were screened with an RNAi library targeting the 9 genes mapping to the smallest region of amplification on 19q12. Individual short interfering RNA (siRNA) SMARTpools targeting these genes were plated in 96-well plates and cell viability was assessed after 9 days using CellTiter-Glo Luminescent Cell viability assay. Silencing of POP4, PLEKHF1, ZNF536 and ZNF537 selectively inhibited cell viability in 19q12-amplified cells compared to control cells. CCNE1 silencing was neither selectively lethal to cells harboring 19q12 amplification, nor lethal in all cells with this amplification. Our results demonstrate that expression of POP4, PLEKHF1, ZNF536 and ZNF537 is required for the survival of cancer cells displaying their amplification and suggest that the 19q12 amplicon may harbor more than one ‘driver’. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2138.
Successful management of traumatic pancreatic transection using ERCP-guided pancreatic stenting
Authors: João Santos-Antunes, Pedro Pereira, Eduardo Rodrigues-Pinto, Armando Ribeiro, Carlos Mariz, Guilherme Macedo
Journal: Endoscopy (2015)

An 11-year-old boy was admitted to the emergency department with severe abdominal pain and vomiting after falling off his bicycle. A round hematoma was noted in the left hypochondrium consistent with bicycle handlebar trauma. Blood analysis showed mild leucocytosis and marked elevation of lipase (2507 U/L) and amylase (1331 U/L). Abdominal ultrasound excluded spleen injury, and thoracic X-ray was unremarkable.
SP0123 Pulmonary Vascular Remodeling in Systemic Sclerosis - New Targets for Therapy on the Horizon
Authors: M. Humbert
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Pulmonary arterial hypertension (PAH) and pulmonary fibrosis are major causes of morbidity and death in systemic sclerosis. Recent progresses have been achieved in the treatment of PAH with the development of therapies targeting dysfunctional endothelial cells (prostacyclin derivatives, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors). These approaches have led to the approval of several agents worldwide, an outstanding result for a rare and devastating condition. However PAH remains a devastating disease in the modern management era and PAH drugs are less efficacious in the setting of systemic sclerosis. There is thus a need for novel therapies targeting new pathways. Pulmonary vascular remodeling and growth factors including Platelet-Derived Growth Factor (PDGF) are believed to play a significant role in PAH. Pioneer authors have attempted to treat experimental and human pulmonary hypertension with nonselective inhibitors of the PDGF receptor tyrosine kinase such as imatinib, which also inhibits <i>abl</i> and <i>kit</i> (thus improving outcomes in chronic myelogenous leukemia and gastrointestinal stromal tumours). This novel approach was efficacious in animal models, and interesting results were reported in rare case reports of either compassionate off label use of the drug or treatment of PAH patients with comorbid chronic myelogenous leukemia. Enthusiasm was tapered by the publication of the phase II and phase III studies showing that imatinib is poorly tolerated in some patients and that it improves cardiac output and walk distance at the expense of increased morbidity. Are we witnessing the twilight of kinase inhibitors in the treatment of PAH? Only time will tell. There is little doubt, however, that overall risks conferred with most, if not all, kinase inhibitors (imatinib, nilotinib, sorafenib, sunitinib, etc…) that have recently been proposed as treatments for PAH outweigh any potential benefits. Yet there is a signal of a potential hemodynamic effect from this therapeutic class that should be further evaluated. In addition, a better description of the pathobiology of pulmonary vascular remodeling in PAH ought to help with the designing of new drugs exclusively blocking PAH-specific pathways. A better understanding of the pathways involved in the efficacy and safety aspects of imatinib will be paramount in order to design more targeted and better tolerated agents in the field of personalized PAH medicine. Until then, healthcare professionals should be discouraged to offer compassionate imatinib therapy to PAH patients. <h3>Disclosure of Interest</h3> M. Humbert Consultant for: Actelion, Aires, Bayer, BMS, GSK, Novartis, and Pfizer
Abstract P2-09-12: Phosphoproteomic Pathway Profiling of Breast Cancers for Biomarker and Target Discovery for Personalized Therapy
Authors: C Kay, P Mullen, SP Langdon, DJ Harrison, D. Faratian
Journal: Cancer Research (2010)

Abstract Introduction: The control and activation of signaling pathways has been shown to influence response to targeted therapy (PTEN and PI3K for trastuzumab, KRAS and MAPK for cetuximab). Single tissue biomarkers (eg HER2-receptor status) are often poor surrogates for the activation state of downstream pathways such as MAPK and PI3K. We have used phosphoproteomic profiling in order to reclassify breast tumors for therapeutic response prediction. Methods: Eleven cell lines were profiled using phosphoproteome arrays (250 targets) and reclassified using unsupervised clustering. Sensitivity to therapy predicted by pathway activation status was correlated with sensitivity to therapies in vitro measured by the AlamarBlue cell viability assay. Target specificity was assayed using in-cell western blotting. Phosphoprotein clusters were validated in 107 breast tumors by reverse phase protein arrays (RPPA), and the expression of targets validated in independent cohorts of cancers by quantitative immunofluorescence (AQUA) on tissue microarrays. Results: Phosphoproteomic profiling revealed 3 main clusters of breast tumors with overlap with existing molecular phenotypes (luminal, basal, and mixed) and different profiles of pathway activation (Cluster A: anti-apoptotic, Cluster B: growth factor-dependent, Cluster C: cell cycle-dependent). Good to excellent correlations between pathway activation and in vitro sensitivity to targeted therapies were shown for several pathways and individual molecules within pathways, including components of NFkB, STAT, and cell cycle. These biomarkers were shown to be present in clinical cohorts by RPPA and AQUA, and related to molecular phenotype. Conclusions: Phosphoproteomic profiling can be used to reclassify tumors in order to make a priori predictions about therapeutic targeting. These clusters exist in real clinical specimens and are therefore also promising biomarkers for targeted therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-12.
Scintigraphic Images of Massive Tumoral Calcinosis
Authors: Yiyan Liu
Journal: Clinical Nuclear Medicine (2016)

Tumoral calcinosis is a rare family disorder characterized by massive periarticular calcification deposits of the soft tissue. Although radiographic findings of tumoral calcinosis are recognized, there were very scant publications of scintigraphic imaging of the disease. We present here the images of FDG PET/CT and bone scintigraphy in a patient with idiopathic tumoral calcinosis, which are unique in the locations of the lesions and distribution of abnormal uptake.