tbuckley/cabot-search huggingface dataset:
Life Expectancy and Cause-Specific Mortality in Type 2 Diabetes: A Population-Based Cohort Study Quantifying Relationships in Ethnic Subgroups
Authors: Alison K. Wright, Evangelos Kontopantelis, Richard Emsley, Iain Buchan, Naveed Sattar, Martin K. Rutter, Darren M. Ashcroft
Journal: Diabetes Care (2016)

This study 1) investigated life expectancy and cause-specific mortality rates associated with type 2 diabetes and 2) quantified these relationships in ethnic subgroups.This was a cohort study using Clinical Practice Research Datalink data from 383 general practices in England with linked hospitalization and mortality records. A total of 187,968 patients with incident type 2 diabetes from 1998 to 2015 were matched to 908,016 control subjects. Abridged life tables estimated years of life lost, and a competing risk survival model quantified cause-specific hazard ratios (HRs).A total of 40,286 deaths occurred in patients with type 2 diabetes. At age 40, white men with diabetes lost 5 years of life and white women lost 6 years compared with those without diabetes. A loss of between 1 and 2 years was observed for South Asians and blacks with diabetes. At age older than 65 years, South Asians with diabetes had up to 1.1 years' longer life expectancy than South Asians without diabetes. Compared with whites with diabetes, South Asians with diabetes had lower adjusted risks for mortality from cardiovascular (HR 0.82; 95% CI 0.75, 0.89), cancer (HR 0.43; 95% CI 0.36, 0.51), and respiratory diseases (HR 0.60; 95% CI 0.48, 0.76). A similar pattern was observed in blacks with diabetes compared with whites with diabetes.Type 2 diabetes was associated with more years of life lost among whites than among South Asians or blacks, with older South Asians experiencing longer life expectancy compared with South Asians without diabetes. The findings support optimized cardiovascular disease risk factor management, especially in whites with type 2 diabetes.
Abstract 2881: Systemic Chromosome Instability (CIN) resulted in transcriptomic changes in metabolic and proliferation regulators in colonic mucosal tissue of Sgo1-/+ mice
Authors: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Arun Reddy, Stan Lightfoot, Altaf Mohammed, Wei Dai, Hiroshi Y. Yamada
Journal: Cancer Research (2015)

Abstract (a) Colon cancer is the second most lethal cancer and is predicted to claim 50,310 lives in 2014. Chromosome Instability (CIN) is observed in 80-90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. We developed animal models focusing on mitotic error-induced CIN, Shugoshin-1 (Sgo1) haploinsufficient (-/+) mice, to investigate the impact of CIN on colon cancer development. Sgo1-/+ mice showed altered profiles in colonic lesions and cancer development. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1-/+ mice to investigate underlying molecular events in the altered carcinogenesis profiles. (b) We treated control and Sgo1-/+ mice with colonic carcinogen azoxymethane (AOM), and tracked colon cancer development 12, 24, and 36 weeks after AOM treatments. We performed Next Generation Sequencing (NGS)-based transcriptome analysis at 24 weeks. (c) There were 349 hits with 2-fold expression difference threshold, P&amp;lt;0.05 (217 upregulated genes, 132 downregulated genes). In normal-looking colonic mucosal tissue from Sgo1 mice, we observed notable transcriptomic changes in the lipid metabolism, Notch signaling, insulin signaling, and peroxisome proliferator-activated receptor (PPAR) pathways. The profile had partial overlap with the colon tumor transcriptome, consistent with high prevalence of CIN in colon cancer. By applying secondary selection criteria, we also identified cell surface markers that may be used to selectively target colonic CIN cells with antibody-based or vaccine approaches. (d) Systemic Chromosome Instability resulted in transcriptomic changes in metabolic and proliferation regulators in the colon. We propose that the CIN effect may be countered through manipulation of these pathways. Citation Format: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Arun Reddy, Stan Lightfoot, Altaf Mohammed, Wei Dai, Hiroshi Y. Yamada. Systemic Chromosome Instability (CIN) resulted in transcriptomic changes in metabolic and proliferation regulators in colonic mucosal tissue of Sgo1-/+ mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2881. doi:10.1158/1538-7445.AM2015-2881
Abstract 5197: Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikisin gastric cancer
Authors: Jiangfang Li, Jie Huang, Bingya Liu, Zhenggang Zhu
Journal: Cancer Research (2015)

Abstract Claudin-1 (CLDN1) is overexpressed in gastric cancer and correlated with tumor invasion, metastasis and poor outcome. Here, we both down and up regulated CLDN1 expression in gastric cancer cells to elucidate its role in gastric carcinogenesis and tumor progression. As results, we found that deficiency of CLDN1 inhibited cells migration, invasion, and colony formation in vitro and tumorigenicity, metastasis in vivo. Furthermore, CLDN1 expression promoted cell aggregation and increased anoikis resistance. Down or up regulated CLDN1 were accompanied with variations of membrane β-catenin expression and activities of Akt and Src signals. When β-catenin was up-regulated in CLDN1-KD cell, cell aggregation and anoikis resistance were restored, and Akt and Src signal pathways were re-activated. Taken together, these findings suggested that CLDN1 may function as an oncogene in gastric cancer and its malignant potential may attribute to the regulation of cell anoikis through mediating membrane β-catenin regulated cell-cell adhesion and survival signals of Akt and Src. Note: This abstract was not presented at the meeting. Citation Format: Jiangfang Li, Jie Huang, Bingya Liu, Zhenggang Zhu. Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikisin gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5197. doi:10.1158/1538-7445.AM2015-5197
Phase II study of sunitinib as second-line treatment in advanced biliary tract carcinoma: Multicenter, multinational study.
Authors: J. Yi, S. Thongprasert, D. Doval, J. Lee, M. N. Cho, S. H. Park, J. O. Park, Y. S. Park, W. K. Kang, H. Y. Lim
Journal: Journal of Clinical Oncology (2011)

e14653 Background: Biliary tract carcinoma (BTC) is rare in the West, but not uncommon in Asia and is highly fatal malignancy. While gemcitabine-based regimen is considered as reasonable option for first-line treatment, most patients progress eventually. VEGF expression is related with poor outcome in patients with BTC. Therefore, we conducted phase II study to evaluate the efficacy and safety of sunitinib as second-line treatment in previously treated unresectable, metastatic BTC. Methods:This was a prospective, single-arm, multicenter, multinational study. Patients with unresectable, metastatic BTC who progressed after first-line cytotoxic chemotherapy were eligible. Sunitinib was administered at 37.5 mg once daily continuously with 4-week cycle until progression, unacceptable toxicity or consent withdrawal. The primary end point was the time to progression (TTP) and the secondary end points were response rate (RR), overall survival (OS) and safety profile. Results:Between May 2009 and October 2010, a total of 56 patients were enrolled from three countries. The median age was 55 years (range 38-75) and male to female ratio was 37:19 (66.1% : 33.9%). Forty one (73.2%) had intra or extrahepatic duct cancer and 15 (26.8%) had gall bladder cancer. Median TTP was 1.7 months. (95% CI 1.0-2.4) The objective response rate was 8.9% (95% CI 3.0-19.6: 5 PR, 18 SD, 28 PD) and disease control rate was 50.0%. (95% CI 36.3-63.7) The median overall survival was 4.8 months. (95% CI 3.8-4.8) grade 3–4 toxicities were observed in 42.1% of the patients with neutropenia being the most frequent. (17.9%). Conclusions: This phase II study demonstrated that sunitinib monotherapy was a feasible treatment for metastatic BTC patients who have failed to previous chemotherapy.
Sirolimus-Containing Graft-Versus-Host Disease Prophylaxis and High- Resolution HLA Typing Improves the Outcome of Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Ronald J. Maggiore, Dennis L. Cooper, Francine M. Foss, Warren D. Shlomchik, Stuart E. Seropian
Journal: Blood (2008)
Abstract 5453: Different mechanism of Oxaliplatin resistance in human colorectal cancer cell lines
Authors: Tomoki Yamano, Shuji Kubo, Aya Yano, Naohiro Tomita
Journal: Cancer Research (2015)

Abstract Purpose: The mechanism of Oxaliplatin (OHP) resistance is partly understood and no molecular marker for prediction of the sensitivity is available in clinic. We analyzed OHP resistant clones to establish the molecular marker for OHP sensitivity in colorectal cancer. Experimental design: We established several OHP-resistant clones from human colon cancer cell lines, DLD1 and HCT116. Then we assayed IC50 of OHP- resistant clones against OHP, 5-FU, and CPT-11. We measured gene expression profiling by microarray analysis and gene mutations by exome sequencing. Based on these results, we selected candidate genes associated with OHP sensitivity, which had gene mutations with significant change of gene expression. To validate the results, we assessed the gene expression of candidate genes in colorectal cancer patients. Results: All OHP-resistant clones derived from HCT116 were also resistant against 5-FU and CPT-11, although all OHP-resistant clones derived from DLD1 were still sensitive against 5-FU and CPT-11. Microarray analysis and exon sequencing indicated gene mutations in SMAD7 and IRF9 with amplified gene expression were candidate molecular markers for multidrug resistance in OHP-resistant clones derived from HCT116, although the gene expression in tumors of these genes were lower than normal mucosa in most of colorectal cancer patients. Conclusions: The mechanisms of OHP resistance were different between OHP-resistant clones derived from DLD1 and those from HCT116, but the same among the clones if the parental cells were same. SMAD7 and IRF9 were candidate molecular markers to predict multidrug resistance. Citation Format: Tomoki Yamano, Shuji Kubo, Aya Yano, Naohiro Tomita. Different mechanism of Oxaliplatin resistance in human colorectal cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5453. doi:10.1158/1538-7445.AM2015-5453
Survival prediction for terminally ill patients with cancer: Revision of palliative prognostic score with incorporation of delirium.
Authors: E. Scarpi, M. Maltoni, O. Nanni, R. Miceli, L. Mariani, A. Caraceni, D. Amadori
Journal: Journal of Clinical Oncology (2011)

e19552 Background: The validated Palliative Prognostic (PaP) score predicts survival in terminally-ill cancer patients and is calculated on the basis of dyspnea, anorexia, Karnofsky Performance Status, clinical prediction of survival, total white blood count and lymphocyte rate. The impact of delirium is known but was not incorporated in the original PaP score. Our aim was to incorporate information on delirium into this score. Methods: The study was based on a retrospective series of 361 terminally-ill cancer patients. The main endpoint was overall survival. We used the ‘validation by calibration’ approach proposed by van Houwelingen et al. and later adapted by Miceli et al. to obtain a score revision with inclusion of a new variable. A new model is fitted including the original score and the new variable as covariates; the model parameter estimates are then used to calculate the partial score for the new variable and the revised cutoffs to define the prognostic categories. Results: The prognostic contribution of delirium was confirmed as statistically significant (p<0.001) and the variable was incorporated into the PaP score (D-PaP score) accordingly. With such a revision, 30 day survival in the three risk groups (A>70%, B 30-70%, C<30%) was 83% (95% Confidence Interval CI 77-90), 50% (95% CI 42-58) and 9% (95% CI 3-15) vs 87% (95% CI 80-93), 51% (95% CI 44-59) and 16% (95% CI 8-24) obtained using the original PaP score. PaP and D-PaP score classifications were in accordance in 292 patients (80.9%). Seventeen (4.7%) patients were switched to a group with a less favorable prognosis and 52 (14.4%) were switched to a more favorable prognostic group. The frequency of patients with delirium, 14 (10.1%) and 37 (25.9%) in groups A and B, sharply increased to 48 (60.8%) in group C. The overall prognostic performance of the revised score was better than that obtained with the original one. Conclusions: The model validation and revision was carried out by modifying the cut-off values used for prognostic grouping without affecting the partial scores of the original PaP score. The revision improved the performance of the original PaP score whilst maintaining its key feature of simplicity.
Heading for new shores! Overcoming pitfalls in BCI design
Authors: Ricardo Chavarriaga, Melanie Fried-Oken, Sonja Kleih, Fabien Lotte, Reinhold Scherer
Journal: Brain-Computer Interfaces (2016)

Research in brain-computer interfaces has achieved impressive progress towards implementing assistive technologies for restoration or substitution of lost motor capabilities, as well as supporting technologies for able-bodied subjects. Notwithstanding this progress, effective translation of these interfaces from proof-of-concept prototypes into reliable applications remains elusive. As a matter of fact, most of the current BCI systems cannot be used independently for long periods of time by their intended end-users. Multiple factors that inhibit the achievement of this goal have already been identified. However, it is not clear how they affect the overall BCI performance or how they should be tackled. This is worsened by publication bias, where only positive results are disseminated, preventing the research community from learning from its errors. This paper is the result of a workshop held at the 6th International BCI meeting in Asilomar. We summarize here the discussion on concrete research avenues and guidelines that may help overcome common pitfalls and make BCIs a useful alternative communication device.
Looking Beyond Statins
Authors: Neil J. Stone
Journal: Circulation (2016)

It is always wise to look ahead, but difficult to look further than you can see."-Winston Churchill t he noteworthy article by Ray et al 1 in this issue of Circulation provides a tantalizing glimpse into the future.It points to the potential of 2 nonstatins-alirocumab, a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, and ezetemibe-to reduce atherogenic lipoproteins with proportional reductions in major adverse cardiovascular events beyond that achieved with statins alone.The authors make an important observation: a continuous relationship exists between average on-treatment low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events.Moreover, they found no observed effect attenuation at low achieved levels of LDL-C <50 mg/dL.But their analysis is not conclusive.As the authors note, there are significant limitations due to a low number of events, the short trial duration (≤2 years), and, importantly, the post hoc nature of the analysis.On the other hand, if results from prospective outcome trials are in accord with these preliminary data, it will be appropriate to update current cholesterol guidelines.
Abstract 301: RealTVac, a novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination
Authors: Piotr Jachimczak, Andreas Mitsch, Achim Aigner
Journal: Cancer Research (2015)

Abstract Novel anti-cancer immune therapeutic strategies, like various new antibody formats and/or tumor vaccines, show promising results in patients. However, due to the “immune-escape phenomenon” driven by tumor-secreted Transforming Growth Factor-beta (TGF-beta), the host immune system of cancer bearing patients frequently fails to control tumor re-growth. The RealTVac® approach aims at avoiding this “immune-escape phenomenon” by intratumoral inhibition of active TGF-beta isotypes while simultanously and synergistically inducing an efficient immune response by a highly potent combination of immune stimulating factors. The synergistic effects of the proposed combination of a TGF-beta inhibitor with immunostimulating cytokines upon human immune cell activation are demonstrated in in-vitro experiments. Both, immune cell proliferation and tumor cell cytotoxicity were significantly enhanced. Initial experiments in a syngenic B16 melanoma xenograft model in immunocompetent mice indicate that the RealTVac® therapy of established subcutaneous B16 tumor xenografts reduced local tumor growth compared to untreated controls. To summarize, the goal of the local application of RealTVac® is to allow the host immune system to scan in real-time all Tumor Associated Antigens (TAAs) being currently expressed by those tumor cells that are exposed to sufficient TGF-beta inhibition. The repetitive administration of the RealTVac® approach is furthermore expected to provide a continuous update of the immune response, reflecting the changing pattern of TAAs related to the dynamic intratumoral heterogeneity in malignant tumors. Citation Format: Piotr Jachimczak, Andreas Mitsch, Achim Aigner. RealTVac, a novel strategy to treat advanced, late-stage tumors with real-time tumor vaccination. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2015-301
Abstract 2201: EGFR regulates the expression and activity of ARID3B through phosphoinositide 3-kinase
Authors: William M. Hallas, Karen Cowden Dahl
Journal: Cancer Research (2015)

Abstract ARID3B is a transcription factor that is upregulated in ovarian cancer and its expression correlates with relapse following chemotherapy. However, the mechanism that leads to ARID3B's elevated expression in ovarian cancer has not been elucidated. EGFR is commonly overexpressed in ovarian cancer, as is phosphoinositide 3-kinase (PI3K), lending us to believe that this pathway may be regulating ARID3B. We demonstrated that epidermal growth factor receptor (EGFR) signaling induces expression of ARID3B through the ETS family transcription factor PEA3. However, the exact mechanism that controls EGFR induction of ARID3B has not been elucidated, and the impact of EGFR on ARID3B activity is unknown. To find the optimal time point for EGF induction of ARID3B mRNA, ovarian cancer cells were serum-starved and then treated with EGF for different amounts of time. We then examined the expression of ARID3B mRNA induced by this treatment in each case. We found that ARID3B was most strongly induced between 2 and 4 hours after treatment with EGF. We then performed dose curve experiments for the PI3K inhibitors, wortmannin and LY294002. We performed qRT-PCR to examine ARID3B mRNA expression under the different concentrations of inhibitors. Western blots for the presence of phosphorylated Akt under each concentration demonstrated the effectiveness of the inhibitors. Next, ovarian cancer cells were serum-starved and then treated with EGF or EGF in combination with PI3K inhibitors. Both immunoprecipitation and chromatin immunoprecipitation (ChIP) were performed on these samples. Western blot for phospho-serine was conducted on immunoprecipitated samples to test for serine phosphorylation of ARID3B in response to growth factor signaling. We found that ARID3B is serine phosphorylated. Next, we performed ChIP to assess the binding of ARID3B to select target genes. We found on the genes we tested, EGF treatment decreased DNA promoter binding. Binding was greatest in the serum-starved samples and the samples treated with the PI3K inhibitors. Very little binding was seen in the EGF treated cells. These results were consistent for a number of ARID3B target genes. In future studies, we will determine which serine residues are phosphorylated by doing a mass spectrometric analysis. Then, site directed mutagenesis will be conducted to test the requirement of serine phosphorylation to target gene regulation. By understanding how ARID3B functions as a transcription factor, we will gain critical insight into ovarian cancer relapse and progression. Citation Format: William M. Hallas, Karen Cowden Dahl. EGFR regulates the expression and activity of ARID3B through phosphoinositide 3-kinase. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2201. doi:10.1158/1538-7445.AM2015-2201
MPTH-29CONNECTING MUTANT GENOTYPES TO ABERRANT TRANSCRIPTIONAL SIGNATURES ACROSS SERIAL SECTIONS OF A HUMAN TUMOR
Authors: Samuel Shelton, Brett Johnson, Tali Mazor, Matthew Potts, Michael McDermott, Eric Huang, Daniel Lim, Russell Pieper, Mitchel Berger, Joanna Phillips, Joseph Costello, Michael Oldham
Journal: Neuro-Oncology (2015)

Identifying the transcriptional consequences of mutations that cause tumors may reveal new targets for the development of cancer therapies. However, this task is complicated by the variability that characterizes tumors from different individuals, which arise from unique genetic backgrounds, consist of various cell types in different proportions, and often exhibit clonal heterogeneity. Here we present a novel strategy to connect mutant genotypes to aberrant transcriptional signatures within individual human tumors. This strategy deconstructs a tumor by extracting RNA from serial sections and comparing genome-wide gene coexpression relationships to control samples analyzed in a similar fashion. In parallel, quantitative genomic analysis of the same serial sections enables identification and mapping of clonal populations within the tumor. We apply this strategy to a single grade II human astrocytoma and identify tumor-specific transcriptional signatures. Genomic analysis reveals clonal heterogeneity, including a dominant clone marked by mutations in IDH1 and TP53. Expression patterns of the two largest tumor-specific transcriptional signatures are almost perfectly associated with the spatial distribution of the dominant clone and consist of genes that are activated or repressed within malignant cells and their microenvironment. Our experimental strategy offers an unbiased and personalized method for identifying aberrant transcriptional signatures that are associated with specific mutant genotypes in any solid tumor while preserving the complex cellular milieu of the tumor microenvironment. More generally, this strategy can reveal shared and distinct patterns of transcriptional organization between any pair of tissue samples, thereby facilitating novel comparisons of diverse biological systems in health and disease.
HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.
Authors: Steven M. Devine, Robert J Soiffer, Marcelo C. Pasquini, Shelly Carter, Parameswaran N Hari, Stephanie DeVore, Anthony Stein, Hillard M. Lazarus, Charles Linker, Edward A. Stadtmauer, Carolyn A. Keever-Taylor, Richard J O'Reilly
Journal: Blood (2009)