Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Return to endnote 79 referrer Footnote 80 Association of total cholesterol/high-density lipo-protein cholesterol ratio with proximal coronary atherosclerosis detected by multislice computed tomography. Prev Cardiol. 2009;12(1):19-26. Return to endnote 80 referrer Footnote 81. Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Cohort). Cardiol. 2008;101(4):497-501. DOI: 10. 1016/j. amjcard. 2007. 09. 109. Return to endnote 81 referrer Footnote 82 The 2003 Canadian recommendations for dyslipidemia management. CMAJ. 2005;172(8): 1027-31. Return to endnote 82 referrer Footnote 83 Society/ Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations. Cardiol. 2009;25(10): 567-79. Return to endnote 83 referrer Footnote 84 The 2003 Canadian recommendations for dyslipidemia management: revisions are needed. CMAJ. 2005;172(8):1027-31. Return to endnote 84 referrer Footnote 85 Describing and analysing primary health care system support for chronic illness care in Indigenous communities in Australia's - use of the Model. . 2008;8:112. DOI: 10. 1186/1472-6963-8-112. Return to endnote 85 referrer Footnote 86 Towards a national primary health care strategy: a discussion paper from the Australian government. Canberra (AU): Australian Government, Department of Health and Ageing; 2008. Return to endnote 86 referrer Footnote 87 Association. Position paper on access to oral health care for Canadians. Ottawa (ON): Association; 2010 May. Return to endnote 87 referrer Footnote 88 Agency of Canada. Organized breast cancer screening programs in Canada: report on program performance in 2005 and 2006. Ottawa (ON): Agency of Canada; 2011. Cat. : HP32-1/2006E-PDF Return to endnote 88 referrer Footnote 89 A review of screening mammography participation and utilization in Canada. Inj Can. 2011;31(4):152-6.

Output: pass


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: (A) Saos2 cells were transiently cotransfected with pEGFP-N and expression constructs coding for wildtype 53, wildtype HIPK2 or the kinase defective HIPK2 mutant K221A as indicated. After 24 h cells were lysed and analysed by Western blotting with the indicated antibodies. (B) GFP fluorescence was measured by quantitative fluorometry to show equal transfection efficiencies. Background fluorescence was set to 1 (lane 0). Fluorescence fold is increased above background (lanes 1 to 4). Bars, SD. Full size image HIPK2 overexpression does not change Mdm2 mRNA expressionNext we asked the question whether HIPK2 downregulates Mdm2 by decreasing Mdm2 transcription. We transiently transfected Saos2 cells either with vector alone or with expression plasmids coding for p53 or HIPK2. In addition, the plasmid coding for p53 was transiently transfected in the presence of either wildtype HIPK2 or the kinase defective HIPK2 K221A mutant (Fig. 4). Relative Mdm2 mRNA levels were detected by quantitative TaqMan RT-PCR with sequence specific primers for human Mdm2 (GenBank accession AF201370). As expected, p53 led to an approximately 4 fold increase of Mdm2 mRNA levels [16, 17]. In contrast, overexpression of HIPK2 did not lead to a change of Mdm2 mRNA compared to vector transfected controls (Fig. 4). Overexpression of p53 together with either wildtype HIPK2 or the kinase defective HIPK2 mutant K221A showed no significant decrease in p53-induced Mdm2 mRNA levels. Similar data were obtained with HeLa cells (data not shown). Therefore, HIPK2 does not downregulate Mdm2 at the transcriptional level. It seems that HIPK2 destabilizes Mdm2 by modifying the Mdm2 protein. Figure 4Quantitative mRNA Expression levels of Mdm2. Saos2 cells were transiently transfected with the indicated expression constructs. Mdm2 mRNA expression levels were determined by TaqMan RT-PCR as described in Materials and Methods. As internal reference, mRNA expression of GAPDH mRNA was used.

Output: pass


Input: Claim: Gene therapy is being researched to treat diseases like cystic fibrosis and sickle cell anemia. [SEP] Text: Data synthesis If the trials are found to be clinically homogenous, meta‐analysis will be conducted. For comparable trials, we will summarize their findings using a fixed‐effect model. We shall consider the appropriateness and value of a meta‐analysis if there is significant clinical heterogeneity among the included trials. Subgroup analysis and investigation of heterogeneity In the event of significant heterogeneity, we plan to explore the possible causes by undertaking the following subgroup analyses: gene therapy technique; age; sex; and type of SCD. Sensitivity analysis We plan to perform a sensitivity analysis based on the generation of the allocation sequence within the trials (including and excluding quasi‐randomised trials). Summary of findings and assessment of the certainty of the evidence In a post hoc change, we aim, in future updates when trials are included, to present summary of findings tables for each comparison included. We aim to report on all seven outcomes as pre‐defined in 'Types of outcome measures'. We will determine the quality of the evidence using the GRADE approach; and downgrade evidence in the presence of a high risk of bias in at least one trial, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We will downgrade evidence by one level if we consider the limitation to be serious and by two levels if very serious. of studies We did not identify any trials that were eligible for inclusion in this review. Results of the search We did identify 26 studies by searching trial registries, however, none of these required further investigation. Included studies We did not identify any trials that were eligible for inclusion in this review. Excluded studies We did not identify any trials that were eligible for inclusion in this section of the review. Risk of bias in included studies No trials were eligible for inclusion in the review. trials were eligible for inclusion in the review. trials were eligible for inclusion in the review. Incomplete outcome data No trials were eligible for inclusion in the review. Selective reporting No trials were eligible for inclusion in the review. Other potential sources of bias No trials were eligible for inclusion in the review. Effects of interventions No trials were eligible for inclusion in the review. therapy aims to replace a defective gene with a normal one. Though no trials were found that are eligible for inclusion in this review, the fact that gene therapy is an evolving field assures us that trials will be available in the future.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: (CA): Google; 2010 [cited 2012 Aug 3]. Available from: support. google. com/trends/bin/answer. py? hl=en&answer=96693 Return to footnote15 referrer Footnote 16 [Internet]. Boston (MA): iProspect; 2006 Apr[cited 2011 Jul 20]. Available from: district4. extension. ifas. ufl. edu/Tech/TechPubs/WhitePaper_2006_ SearchEngineUserBehavior. pdf Return to footnote16 referrer Footnote 17 Is the data normalized? [Internet]. (CA): Google; [cited 2011 Jun 8]. Available from: www. google. com/support/insights/bin/bin/answer. py? answer=87284&&hl=en Return to footnote17 referrer Footnote 18. Auld lang Syne: success predictors, change processes, and self-reported outcomes of New Year's resolvers and nonresolvers. J Clin Psychol. 2002;58(4):397–405. Return to footnote18 referrer Footnote 19 LA Fitness times email marketing campaign to perfection [Internet]. Brighton (UK): Pure360; [cited 2011 Aug 3]. Available from: www. pure360. com/customer-success/case-studies Return to footnote19 referrer Footnote 20 Calendar of health promotion days - 2010 [Internet]. Ottawa (ON): Health Canada; [cited 2011 Aug 3]. Available from: www. hc-sc. gc. ca/ahc-asc/calend/index-eng. php#may Return to footnote20 referrer Footnote 21 May 2010: portal: current events [Internet]. (CA): Wikipedia; [cited 2011 Aug 3]. Available from: en. wikipedia. org/wiki/May_2010 Return to footnote21 referrer Footnote 22 Loser (U. S. TV series) [Internet]. (CA): Wikipedia; [cited 2011 Aug 3]. Available from: Return to footnote22 referrer Footnote 23 Ybarra ML, Suman M. Help seeking behavior and the Internet: a national survey. Med Inform. 2006 Jan;75(1):29-41. Return to footnote23 referrer Footnote 24. An investigation of smoking cessation video content on YouTube. Misuse 2011;46(7): 893-7.

Output: pass


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Relative Mdm2 mRNA expression is shown and Mdm2 mRNA expression of vector transfected cells was set to 1. Bars, SD. Full size image HIPK2 induces Elk1- but not NFκB-mediated transcriptionTo test the expected influence of HIPK2 on other transcription factors we used a chimeric protein consisting of the GAL4 DNA binding domain fused to the activation domain of the transcription factor Elk1. The transcription activator Elk1 becomes phosphorylated and activated by the MAP (mitogen-activated protein) kinase. Direct or indirect phosphorylation of this transactivator by HIPK2 would activate transcription of the luciferase gene from a reporter plasmid with the GAL4-binding element. Cotransfection of the trans-activator plasmid pFA-Elk1, the luciferase reporter plasmid pFR-Luc and the positive control MEK1 encoding plasmid pFC-MEK1 resulted in an 115 fold increase in luciferase activity in 293 cells compared to pFA2-Elk1 and pFR-Luc transfected control cells (data not shown). In comparison, cotransfection of pFA2-Elk1 and the wildtype HIPK2 expression construct gave only a 6 fold increase (Fig. 5A). This increase was reduced to 3 fold when the kinase defective HIPK2 mutant K221A was used. However, using the carboxy-terminal deletion AC with an intact kinase domain, the increase of luciferase activity was about 17 fold. A possible direct effect of HIPK2 on the luciferase construct has been tested by cotransfection of wildtype HIPK2 and pFR-Luc into 293 cells. In this control, the luciferase activity was similar to the pFR-Luc and pFA2-Elk1 transfected control cells (data not shown). These results suggest that HIPK2 may weakly activate the transactivator Elk1-GAL4 and that the kinase function of HIPK2 is necessary for this activation. The carboxy-terminus of HIPK2 may contain inhibitory sequences for Elk1-phosphorylation. The conclusion is, that HIPK2 seems to activate components of the MAP kinase pathway. The exact role remains to be elucidated.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: C, Programmed cell death ligand-1 expression was strongly expressed in IPCs generated from commercially obtained ADSCs. D, PDL-1 expression was also strongly expressed in IPCs generated from ADSCs isolated from the adipose tissue of the type 1 diabetes mellitus patient. E, Immunostained placenta is shown as a positive control stained with PDL-1. have focused on MSCs, especially ADSCs as a feasible cell source for β-cell replacement thrapy. 24,25 Adipose-derived stem cells are easy to procure, less invasive procedure compared with other MSCs, less ethical problems (often under local anesthesia) compared with ES cells and are reported that their multipotency is superior to other MSCs. 26 Indeed, we succeeded in the establishment of effective IPC generation in vitro and demonstrated their in vivo functions. 8–10 These IPCs are monoclonal (insulin positive, glucagon negative, and pancreatic peptide negative). 7 Moreover, these generated IPCs had a DNA quantity of 88. 4% and same level of cell viability by ATP assay compared with original ADSCs. 9 If the stable generation of own effective IPCs can be realized by an easy, safe and low cost procedure, IPCs autotransplantation would be extremely beneficial for T1DM patients. However, there are some major issues to be resolved before clinical application. 8–10 The first issue is whether functional IPCs can be generated from a T1DM patient’s own fat tissue. The present study demonstrated not only that functional IPCs could be generated from ADSCs freshly isolated from human adipose tissue but also that these IPCs, including those obtained from the T1DM patient, were capable of secreting enough insulin to normalize the blood glucose concentrations of diabetic nude mice. Freshly isolated ADSCs from the T1DM patient and commercially provided ADSCs had similar cell surface marker expression, reflecting both stromal and stem cell characteristics. Moreover, the generated IPCs demonstrated the ability to secrete insulin autonomously in vitro, even when derived from T1DM patient adipose tissue. Indeed, these IPCs performed similarly to those derived from nondiabetic patients. However, the insulin responsiveness was significantly lower when the IPCs were derived from visceral fat tissue. The number of T1DM patients was small.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: To be consistent, we classified 2007 to 2010 respondents as and Métis only if they had also reported being born in one of these four countries. Footnote 20 We used mutually exclusive ethnocultural categories despite that respondents could report multiple Aboriginal identities. For example, any respondent who replied that they were only or and Inuit was classified as First Nations. Any respondent who replied that they were Métis only or Métis and any other Aboriginal identity was classified as Métis. Due to small sample sizes, we did not generate Inuit-specific estimates in this report. Our definitions of and Métis are further illustrated in Table 1. TABLE 1 Definitions of (off-reserve), Métis and non-Aboriginal identity based on responses Aboriginal identityTable 1 - Footnote a Subgroup identityTable 1 - Footnote b aRespondents were asked: ''Are you an Aboriginal person, that is, Indian, Métis or Inuit? '' bRespondents were asked: ''Are you Indian (First Nations)? …Métis? …Inuit (Inuk)? '' and were permitted to provide multiple affirmative responses. Dark grey boxes are used because single and multiple identity responses are mutually exclusive. (off-reserve) étis Yes Métis Nations Métis Yes Métis Métis Inuit Non-Born in any country outside of analysis The CCHS has a multi-stage, complex sampling design. Sampling weights assigned by are used to account for selection probability, nonresponse and non-coverage. For this report, weights were also adjusted to take into account the amalgamation of several survey cycles. Footnote 14 We used bootstrapping techniques to calculate the coefficient of variation (CV) and 95% confidence intervals (CIs). In accordance with regulation, estimates with a CV ranging from 16. 6% to 33. 3% are flagged to be interpreted with caution. Those with a CV greater than 33. 3% are suppressed because of extreme sampling variability. Estimates were age-standardized to the age structure of the identity population in the 2006 Census using the age groups 20 to 24, 25 to 44, 45 to 64, and 65 years and over. For those indicators whose cut-off points for age did not line up with those provided by the census, age-standardization was to the nearest age group (e. g.

Output: pass


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Figure 5Activation of Elk 1-mediated transcription but no activation of NFκB by HIPK2 overexpression. (A) 293 cells were cotransfected with a GAL4-luciferase reporter construct, an Elk1-GAL4 transactivator expression construct and the indicated HIPK2 constructs or vector. (B) 293 cells were cotransfected with an NFκB-luciferase reporter construct and the indicated HIPK2 constructs or vector. Results represent the mean of three independent experiments. Bars, SD. Full size image In a similar assay, which we have used to study HIPK2-mediated activation of p53 specific promoter elements, we looked for a role of HIPK2 in activation of NFκB-mediated transcription. 293 cells were cotransfected with a luciferase reporter plasmid containing five tandem NFκB binding sites and different HIPK2 expression constructs (Fig. 5B). Only wildtype HIPK2 activated NFκB-mediated transcription slightly but not significantly. No effect was seen with the HIPK2 mutants (Fig. 5B). NFκB-mediated luciferase activation was 100 fold with a MEK kinase positive control plasmid (data not shown). The luciferase values of vector and pNF-κB-luc transfected cells were set as 1. Taken together, we conclude that HIPK2 does not activate NFκB. DiscussionHIPK2 enhances p53 activity and p53 expression or stabilityHIPK2 acts as a co-repressor for homeodomain containing transcription factors. We show here that HIPK2 has additional functions, namely the activation of transcription mediated by p53 specific promoter elements. Thereby, overexpression of HIPK2 leads to an increase of the p53 protein level. Neither the transcriptional activation nor the enhancement of p53 protein amounts is detected with overexpressed HIPK2 mutants. The p53 responsive enhancer element becomes activated by HIPK2 in cell lines with p53 but not in a cell line devoid of p53 (Fig. 1). We conclude, that the activation of the enhancer element is indeed mediated by p53 and not by another transcription factor of the p53 family.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: PDX1-engineered embryonic stem cell-derived insulin producing cells regulate hyperglycemia in diabetic mice Download PDF Download eeOpen access Published: 18 October 2012 PDX1-engineered embryonic stem cell-derived insulin producing cells regulate hyperglycemia in diabetic mice Raikwar1 & Nicholas Zavazava1 3. Transplantation of the IPCs under the kidney capsule led to sustained long-term correction of hyperglycemia in diabetic mice. Although these newly generated IPCs effectively rescued hyperglycemic mice, an unexpected result was teratoma formation in 1 out of 12 mice. We attribute the development of the teratoma to the presence of either non-differentiated or partially differentiated stem cells. ConclusionsOur data show the potential of Pdx1-engineered ES cells to enhance pancreatic lineage commitment and to robustly drive the differentiation of ES cells into glucose responsive IPCs. However, there is an unmet need for eliminating the partially differentiated stem cells. BackgroundType 1 diabetes is an autoimmune disease that can be surgically corrected by the transplantation of either the whole pancreas or that of pancreatic islets [1–4]. However, chronic shortage of organ donors, lifelong immunosuppressive therapy and chronic graft rejection currently limit the therapeutic potential of both options. Ultimately, chronic graft rejection leads to insulin dependence and the development of serious diabetic complications [5–10]. With the incidence of diabetes increasing at an alarming rate worldwide, there is an urgent and compelling need to develop novel treatment approaches. In this regard, embryonic stem (ES) cells and the recently developed induced pluripotent stem (iPS) cells potentially offer a novel alternative for the development of stem cell-based therapies [11–13]. However, the generation of functional insulin producing cells (IPCs) from ES or iPS cells has been rather inefficient; thus there is a need to improve on the protocols for the differentiation process. Published work by others appeared to suggest that it is feasible to directly differentiate ES cells into IPCs [14]. Unfortunately, this work has remained irreproducible in many laboratories around the world. During embryonic development, a wide variety of transcription factors, including Pdx1, Ngn3, 4, Gata6, Ptf1a and Pax4 are involved in pancreatic β cell development and function.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: To monitor trends and identify targets for intervention, analyses such as this should be repeated over time. The increased prevalence of chronic disease risk factors among and Métis reported here supports provincial recommendations that culturally appropriate and specific actions be taken to address these factors to reduce the burden of cancer in particular and chronic disease more generally in this and future generations. Footnote 41 2006. Return to footnote4 referrer Footnote 5 Survey, 2011: Aboriginal peoples in Canada: People, Métis and Inuit [Internet]. Ottawa (ON): Statistics Canada; 2013 [Statistics Canada, Catalogue No. : 99-011-X2011001]. Return to footnote5 referrer Footnote 6 Gionet L, Roshanafshar S. Select health indicators of people living off-reserve, Métis and Inuit. Health at a Glance. 2013 Jan [Statistics Canada, Catalogue No. : 82-624-X]. Return to footnote6 referrer Footnote 7 Institute (NCI). Tobacco facts [Internet]. Bethesda (MD): Institute; 2013 [cited 2013 Jul 13]. Return to footnote7 referrer Footnote 8 Institute (NCI). Obesity and cancer risk [Internet]. Bethesda (MD): of Health; 2012 [updated 2012 Jan 3; cited 2013 Jul 13]. Return to footnote8 referrer Footnote 9 Institute (NCI). Physical activity and cancer [Internet]. Bethesda (MD): Institute; 2009 [updated 2009 Jul 22; cited 2013 Jul 13]. Return to footnote9 referrer Footnote 10 UK. Diet and cancer: the evidence [Internet]. London (UK): UK; 2009 Sep 25 [cited 2013 Jul 13]. Return to footnote10 referrer Footnote 11 Institute (NCI). Alcohol and cancer risk [Internet]. Bethesda (MD): Institute; 2013 [updated 2013 Jun 24; cited 2013 Jul 13]. Return to footnote11 referrer Footnote 12 Lynch BM. Sedentary behavior and cancer: a systematic review of the literature and proposed biological mechanisms. Biomarkers Prev. 2010;19(11): 2691-709. Return to footnote12 referrer Footnote 13 Statistics Canada. Other reference periods – – [Internet]. Ottawa (ON): Statistics Canada; [cited 2013 Nov 3]. Return to footnote13 referrer Footnote 14 Thomas S, Wannell B. Combining cycles of the Health Survey. Health Rep.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: The kinase defective mutant of HIPK2, K221A, leads to a decrease of p53 protein amounts (Fig 2A). However, this decrease does not correspond with a further decrease on p53-mediated transcription compared to HIPK2 mutants AC and AN (Fig. 1A and 1B). HIPK2 is not sufficient for phosphorylation of crucial serine residues of p53The nuclear phosphoprotein p53 is regulated and stabilized by different modifications [3, 18], e. g. serine 15 phosphorylation has been detected as prerequisite for phosphorylation of tyrosine residue 18 [19]. HIPK2 could not activate or stabilize p53 either directly or indirectly by phosphorylation. DNA damaging agents such as doxorubicin induce increased p53 phosphorylation by as yet undefined mechanisms. In the presence of wildtype HIPK2 and doxorubicin, serine residue 15 and 20 of p53 become phosphorylated, which could be either due to transfected or endogenous HIPK2 of HeLa cells. In the presence of doxorubicin alone or together with mutants of HIPK2 serines 15 and 20 could be phosphorylated by endogenous HIPK2 (Fig. 2C). Thus, we conclude that HIPK2 is not sufficient for serine 15 and 20 phosphorylation, for which doxorubicin may be required. HIPK2 is also not sufficient for phosphorylation of residue 392, but doxorubicin requirement is excluded. Additional phosphorylation sites have not been tested since the absolute requirement of phosphorylation for DNA-damage induced stabilization of p53 remains controversial [20]. Other proteins, which regulate p53, like e. g. Mdm2, could be the targets for phosphorylation by HIPK2. Doxorubicin treatment and HIPK2 overexpression show an additive effect on p53 protein expression or stability (Fig. 2B). The relative amounts of the increase of the p53 protein levels and the increase in doxorubicin induced phosphorylation of serine residue 15 are comparable and give rise to the assumption that the total amount of p53 protein present becomes phosphorylated under doxorubicin treatment.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: Pdx1 is the master regulator of pancreatic development [15–18] during embryogenesis, β cell differentiation [16, 19–21] and is essential for the maintenance of β-cell function in the adults [15, 16, 22, 23]. Mutations in the Pdx1 coding sequence in humans and mice lead to failure of the pancreatic organ to develop [25]. Here, we hypothesized that pancreatic lineage commitment of ES cells by pancreatic β cell-specific transcription factor Pdx1 enhances the generation of IPCs, thereby providing an unlimited source of cells for the treatment of diabetes. The rationale underlying this approach is that expression of pancreatic β cell-specific transcription factor Pdx1 will maximize the pancreatic lineage commitment and differentiation of ES and iPS cells into IPCs [15, 17, 26–31]. To facilitate greater efficiency of the generation of IPCs from ES cells, we have generated a double transgenic ES cell line R1Pdx1AcGFP/RIP-Luc to stably express an in-frame Pdx1AcGFP fusion protein [32]. Here, we describe the generation of IPCs in vitro using ES cells ectopically expressing Pdx1. For the real-time non-invasive in vivo bioluminescence imaging (BLI), we engineered a rat insulin promoter (RIP) driven luciferase reporter to monitor the fate and function of the IPCs post transplantation. Further, we show that transplantation of ES cell-derived IPCs efficiently corrects hyperglycemia in diabetic mice. However, the lack of cell surface markers specific for IPCs raises the potential for teratoma formation by residual non-differentiated ES cells. These studies justify the need to develop novel strategies for ES cell differentiation and purification of IPCs prior to transplantation. Materials and methodsCell linesWe have recently described the generation and characterization of the double transgenic mouse ES cell line R1Pdx1AcGFP/RIP-Luc stably expressing an in-frame Pdx1AcGFP fusion protein and RIP driven luciferase reporter in detail elsewhere [32]. The R1Pdx1AcGFP/RIP-Luc mouse ES cell line was maintained in DMEM containing 1,000 IU/ml leukemia inhibitory factor (1107, Inc.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: · Number 2-3 · July 2014 and Injuries in feedback to editors Modelling preventive effectiveness to estimate the equity tipping point: at what coverage can individual preventive interventions reduce socioeconomic disparities in diabetes risk? Download this 0. 2 Mb - 9 pages) Submit a manuscript the This 10. 24095/hpcdp. 34. 2/3. 04 This 1. 76%. Assuming complete coverage across all income groups, the difference was reduced to 0. 90% (144 000 cases prevented) with lifestyle interventions and 1. 24% (88 100 cases prevented) with pharmacotherapy. The equity tipping point was estimated to be a coverage difference of 30% for preventive interventions (100% and 70% coverage among the highest and lowest income earners, respectively). Conclusion: Disparities in diabetes risk could be measurably reduced if existing interventions were equally adopted across SEP. However, disparities in coverage could lead to increased inequity in risk. Simple modelling approaches can be used to examine the community effectiveness of individual preventive interventions and their potential to reduce (or increase) disparities. The equity tipping point can be used as a critical threshold for disparities analyses. Keywords: inequalities, public health, health impact assessment, diabetes role of individual preventive therapy in reducing health disparities is the subject of current debate. One the one hand, health disparities may be reduced when relative treatment effects are constant across the spectrum of underlying risk. Footnote 1, Footnote 2, Footnote 3 If this assumption held true, the absolute community effectiveness from health interventions would be greater for disadvantaged groups compared to others because disadvantaged groups tend to have a higher baseline risk. Greater gains in absolute benefit for those in the lowest socioeconomic position (SEP) compared to those in higher SEP would therefore lead to a decrease in disparities between them. Footnote 1 On the other hand, constant intervention efficacy should not be assumed and intervention coverage is often inequitable. Intervention coverage, defined as the proportion of the target population that is adherent to the intervention, encompasses the range of factors that affect the uptake of interventions, such as accuracy in identifying the target population, level of participation in the intervention and consumers' adherence. Footnote 4 Groups at a lower socioeconomic level tend to experience greater barriers in access to care, for example through income effects, or they may be less adherent to preventive therapies, for example, education effects. Footnote 5 Together, differences in efficacy and coverage undermine efforts to reduce disparities or else they can, perversely, increase disparities.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Since p53 has a high turnover rate [4], the increase of p53 protein levels seems to be due to stabilization of p53 rather than induction of enhancement of transcription of p53. An increase of p53 mRNA stability or translation efficiency could play additional roles. HIPK2 downregulates Mdm2 proteinHIPK2 may exert all its effects on p53 via Mdm2, since it leads to a decrease of the p53-induced Mdm2 protein level (Fig. 3). HIPK2 has no influence on Mdm2 transcription (Fig. 4). Therefore, HIPK2 regulates Mdm2 stability at the protein level. The most likely mechanism is serine/threonine phosphorylation of Mdm2 either directly or indirectly by HIPK2. At present, we did not get convincing data showing a direct serine/threonine phosphorylation of Mdm2 by HIPK2. Mdm2 shuttles between the nucleus and the cytoplasm and this nucleo-cytoplasmic shuttling of Mdm2 is essential for its ability to promote p53 degradation by the cytoplasmic proteasome [21]. Mdm2 seems to have a role in exporting p53 from the nucleus [22, 23]. HIPK2 did not directly interact with either p53 or Mdm2 in yeast and 293T cells (data not shown). Whether HIPK2 can influence the shuttling of Mdm2 remains to be clarified. Effect of HIPK2 on target genes of p53We have addressed the issue to check expression of described downstream targets of p53 at the protein level in HeLa cells. The best characterized target gene that becomes transactivated by p53 is the cyclin/Cdk inhibitor p21 (Waf1/Cip1) [3]. But we did not detect a significant increase of expression of p21 (Waf1/Cip1) mediated by overexpression of HIPK2 or treatment with doxorubicin in Western blotting analysis. As a positive control 2 μg of the wildtype p53 expression construct pFC-p53 was transiently transfected and transient overexpression of wildtype p53 led to a weak increase of p21 (Waf1/Cip1) expression (data not shown).

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: In all cases, *P < 0. 05 was considered significant. ResultsES cell-derived IPCs secrete insulinThe results from multiple earlier studies have indicated low insulin secretion by ES cell-derived IPCs [27, 35–39]. Since Pdx1 is a major transcription factor for the development of the pancreas as well as pancreatic β cells, we reasoned that generating a stable Pdx1-expressing ES cell line R1Pdx1AcGFP/RIP-Luc and directing its differentiation towards IPCs could increase the yield of IPCs. To investigate which approach was more effective at generating IPCs, four different differentiation protocols as described in the methods section and depicted in Figure 1a were studied. The progressive differentiation of the R1Pdx1AcGFP/RIP-Luc ES cell line into IPCs was monitored by immunostaining for various pancreatic markers (Figure 1b). As expected the differentiation process led to the expression of insulin producing cell clusters. Our immunostaining results using the differentiation protocol D indicate that the cells express Foxa2, Sox17, Ngn3 and NeuroD markers during the early steps of differentiation (Figure 1b). In addition to C-peptide and insulin expressing cells, we found that a significant cell population expressed glucagon. The newly generated IPCs were organized into small islet-like clusters (Figure 1b). Based on immunostaining results, we estimated that approximately 25 to 30% of the cells were expressing insulin. To further confirm that the cells had differentiated into pancreatic lineage, the expression of various pancreatic genes was studied. We used real-time quantitative RT-PCR analysis on RNA isolated from the cells at the completion of various stages to monitor the in vitro differentiation of ES cells into IPCs (Figure 1c). The RT-PCR results from a representative differentiation using protocol D indicate a progressive up-regulation of pancreatic β-cell-specific genes commensurate with the differentiation status of the ES cells. A significant up-regulation of Foxa2, Pax4, insulin 1, insulin 2, PC2/3 and glucagon gene expression in the IPCs was observed. The insulin production by ES cell-derived IPCs was determined by an ultrasensitive ELISA. results indicate that the ES cell-derived IPCs robustly secrete insulin (Figure 2a).

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Footnote 6 In this study, we show how a simple modelling approach can be used to estimate the potential effectiveness of prevention interventions at reducing disparities (see Formula 1). We demonstrate this using diabetes prevention in Canada. 1 Community effectiveness = target population X baseline risk X intervention efficacy X intervention coverageFootnote * Community effectiveness: the benefit, or absolute risk reduction, of preventive interventions in the real-world community setting. Target population: the proportion of the population, or each sociodemographic strata, that is eligible for the preventive intervention. Baseline risk: the risk or probability of developing a disease prior to intervention implementation. Intervention efficacy: the relative benefit of an intervention as determined from intervention trials or other studies, i. e. ideal or controlled settings. Intervention coverage: the proportion of the target population that is adherent to the intervention. Footnote 1 Derived from the ''evidence equity loop. '' Return to footnote1 referrer The potential for interventions to reduce inequalities can be estimated when we calculate and compare community effectiveness for each socioeconomic stratum. Disease disparities will narrow if community effectiveness is larger for low socioeconomic groups compared to their higher SEP counterparts. A common challenge when estimating community effectiveness for individual socioeconomic strata is the lack of information that is specific to the different strata, including variation in the target population size, baseline risk, intervention efficacy and coverage. For such situations, we introduce the concept of the ''equity tipping point,'' defined as the point at which the disparity between highest and lowest socioeconomic strata becomes larger as a result of differences in intervention efficacy, coverage or target population. The objective when calculating the equity tipping point is to gauge whether potential differences realistically exist. In the example of diabetes prevention, we sought to identify the point at which intervention coverage gaps resulted in a widened disparity in diabetes risk. To show this better, we did not vary intervention efficacy or target population criteria. We examined 2 types of diabetes prevention interventions that have well-established efficacy: lifestyle interventions and pharmacotherapy. Footnote 7 Lifestyle interventions reduce obesity through diet and exercise programs. Pharmacotherapy uses medications such as metformin to reduce weight and insulin resistance so as to reduce new cases of diabetes among those at risk. While these therapies appear to be efficacious across socioeconomic groups,Footnote 7, Footnote 8 achieving high coverage for diabetes in particular and chronic diseases in general is a challengeFootnote 9, Footnote 10 and the level of coverage likely varies across socioeconomic groups.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Western blotting does not seem to be sensitive enough to detect a significant difference in p21 expression between vector and wildtype HIPK2 transfected cells. In the same experimental setting an increase of expression of the pro-apoptotic Bcl2 family member Bax, whose gene has been described as a p53 target [3], was not detectable (data not shown). Therefore, induction of p53 target genes seems to be cell type specific. The recently described p53-dependent pro-apoptotic Bcl-2 family member Noxa [24] is a further candidate that could be regulated via HIPK2. In this respect, a further difficulty is that HIPK2 downregulates the p53-induced Mdm2 protein level. This may also be the case for other p53-induced proteins. Other functions of HIPK2HIPK2 is also termed PKM (for Mx-interacting protein kinase) since it has been cloned in a yeast two-hybrid screen as an interaction partner for the interferon type I-induced protein MxA, that displays antiviral activity against a variety of RNA viruses [10]. The nuclear distribution of murine Mx1 is similar to HIPK2/PKM, but a direct interaction of the Mx protein with HIPK2/PKM and phosphorylation of Mx by HIPK2/PKM could not be demonstrated so far [10]. HIPK2/PKM phosphorylates several phosphoproteins expressed in E. coli. This reaction is inhibited by a kinase defective mutant K221W of HIPK2/PKM. Thereby it was also shown that HIPK2/PKM is a true serine/threonine kinase, rather then a dual specificity protein kinase which is able to phosphorylate both, serine/threonine and tyrosine residues [10]. HIPK2 interacts with the death factor receptor CD95 in the yeast two-hybrid system [25]. When overexpressed in mammalian cells it associates with TRADD [26]. TRADD has been described to bind to the tumor necrosis factor type I and thereby executing essential functions in signaling [27, 28]. Whether HIPK2 plays an important role in death receptor mediated apoptosis is not clear at present.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: Finally, to rule out the possibility of endogenous pancreatic β cell regeneration, we performed hematoxylin-eosin staining of the pancreas on Day 150 from the STZ treated mice that were transplanted with IPCs. Our histopathology data (Figure 3c) demonstrates that the normal pancreas has extremely large pancreatic islets. However, the pancreas from the mice transplanted with IPCs revealed near complete loss of pancreatic islets and no evidence of endogenous pancreatic β-cell regeneration. Taken together, our data suggest that ES cell-derived IPCs were indeed responsible for the long-term survival and correction of the diabetic phenotype post-transplantation in the diabetic mice. Figure 3R1Pdx1cell-derived IPCs correct hyperglycemia in diabetic mice. (a) The therapeutic efficacy of R1Pdx1AcGFP/RIP-Luc ES cell-derived IPCs was evaluated following transplantation under the kidney capsule of syngeneic 129/SvJ mice (n = 12) rendered diabetic by streptozotocin (STZ) treatment. The blood glucose levels continued to decline beyond Day 15 post-transplantation and stabilized thereafter. Normal nondiabetic mice (n = 5) and STZ-treated 129/SvJ mice (n = 5) were used as appropriate controls for comparing the blood glucose levels. As early as Day 15 and throughout the duration of the study, the blood glucose levels of mice transplanted with IPCs were significantly lower compared to the STZ-treated mice. The data were analyzed by one-way ANOVA and are presented as mean ± SD, ***P < 0. 0001, using Tukey’s pairwise multiple comparison for Day 15. (b) The kidney bearing the transplanted IPCs was evaluated for insulin expression by immunostaining using an anti-insulin antibody. The results indicate the localized presence of ES cell-derived insulin expressing cells. (c) Control mouse pancreas and the pancreas from IPCs transplanted mice 150 days post transplantation were examined by hematoxylin-eosin staining. Unlike control pancreas from non-diabetic mouse, the IPCs transplanted streptozotocin-treated diabetic mouse pancreas did not show any evidence of pancreatic beta cell regeneration.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: 33 Cases preventedTable 3 - Footnote d, n 27 100 30 500 10 800 90 100 159 000 Pharmacological intervention Absolute risk reduction,Table 3 - Footnote c % 2. 05 1. 68 1. 36 1. 23 1. 43 1. 90 0. 82 Cases preventedTable 3 - Footnote d, n 16 600 18 700 6610 55 200 97 000 Figure 2 shows how the complete coverage of health interventions affects diabetes risk disparities across different levels of income and education. As expected, the disparity widens when the intervention coverage drops in the lowest SEP groups, but is maintained at 100% for the highest SEP groups. The equity tipping point is reached at 70% coverage for lowest income earners and 60% for lowest education groups. Below these coverage levels, there is progressive widening of diabetes risk between SEP groups. 2 Estimating the impact of intervention coverage on the disparity in diabetes risk and identifying the equity tipping point for lifestyle and pharmacological interventions 2 [2, Text Equivalent] and Injuries in Canada - Number 2-3, July 2014 2 Estimating the impact of intervention coverage on the disparity in diabetes risk and identifying the equity tipping point for lifestyle and pharmacological interventions Figure 2 shows how the complete coverage of health interventions affects diabetes risk disparities across different levels of income and education. As expected, the disparity widens when the intervention coverage drops in the lowest SEP groups, but is maintained at 100% for the highest SEP groups. The equity tipping point is reached at 70% coverage for lowest income earners and 60% for lowest education groups. Below these coverage levels, there is progressive widening of diabetes risk between SEP groups. Note: These scenarios assume 100% coverage in the highest socioeconomic group and varying coverage among the lowest socioeconomic group. study presents a straightforward modelling approach to estimate the potential reduction in socioeconomic disparities in disease risk using individual preventive interventions. In the considerable debate about whether individual interventions can or should have a role for reducing health disparities, the discussion is typically buttressed with either theoretical arguments or examples from specific studies or populations. Footnote 13, Footnote 14 In practice, most preventive interventions—whether they are individual-based or community-wide—have the potential to narrow or widen health disparities depending on the extent of disparities in baseline risk, intervention efficacy and intervention coverage. The ability to analytically examine the settings in which preventive interventions will likely narrow or widen health disparities is helpful for practical health planning and for more general discussions about disease prevention.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Recently, it has been described that HIPK3, a member of the HIPK family, binds to CD95 and thereby inhibits c-Jun N-terminal kinase activation [29]. An additional function of HIPK2 may be the activation of the mitogen-activated protein kinase pathways since we detected a weak activation of Elk1 mediated transcription. The carboxy-terminal deletion of HIPK2 ΔC augments the activation of Elk1-mediated transcription in comparison to wildtype HIPK2. The carboxy-terminal deletion of HIPK2 ΔC is equally distributed in the nucleus. In contrast, wildtype HIPK2 and the kinase defective K221A mutant localize to nuclear speckles [25]. This suggests that the equal nuclear distribution of the HIPK2 mutant ΔC is responsible for the increase in Elk1 mediated transcription. It has been shown that DNA damage in addition to stabilization of p53 leads to an activation of a MAP kinase homolog, the c-Jun N-terminal kinase or stress activated protein kinase [30]. ConclusionsHIPK2 is a nuclear kinase that activates transcription mediated by tumor suppressor p53 responsive promoter elements upon overexpression. Furthermore, it plays a role in the induction of expression or stability of p53 protein. Overexpression of HIPK2 does not lead to a change of Mdm2 mRNA levels, but it leads to a downregulation of p53-induced Mdm2 protein. Most likely, this HIPK2-induced decrease of Mdm2 is responsible for the stabilization of p53. The involvement of HIPK2 kinase activity remains to be identified. Materials and methodsCell lines and cell cultureHeLa cells were maintained in RPMI 1640 containing 10% heat-inactivated fetal bovine serum, L-glutamine, and penicillin/streptomycin (all from Technologies, Karlsruhe, Germany). The stock solution of doxorubicin (Amersham-Pharmacia, Freiburg, Germany) was 2 mg/ml in H20.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: Our ES cells were engineered using rat insulin promoter (RIP) driven luciferase reporter. Following differentiation of the ES cells, the transcriptional activation of the RIP leads to a selective robust expression of luciferase in the IPCs. In one of the IPC transplanted mouse, the BLI signal showed a progressive increase, especially beyond Day 40 post-transplantation with maximum BLI signal intensity at Day 50 post-transplantation. (b) The mouse transplanted with ES cell-derived IPCs was sacrificed and the internal organs were examined. The kidney bearing the transplanted IPCs revealed the presence of teratoma formation covering the dorsal and ventral sides of the kidney. (c) Histopathology following hematoxylin-eosin staining revealed the presence of epidermal, mucous secreting, ciliated epithelial as well as the neuronal tissues. However, there was no evidence of any metastatic lesions in any other organs. (d) Immunostaining using anti-GFP and anti-C-peptide antibodies revealed the presence of both AcGFP and insulin-positive transplanted cells. Full size imageHistopathological examination of the teratoma revealed the presence of epidermoid, mucous secreting, ciliated epithelial as well as neuronal cells (Figure 4c). Finally, to confirm the presence of IPCs in the kidney bearing teratoma, immunostaining was performed. Insulin staining cells were detectable (Figure 4d) in the kidney containing IPCs but not in control kidneys from the contra-lateral side, suggesting that the transplanted cells were producing insulin under the renal capsule. Taken together, our results highlight the potential of ES cells to generate IPCs that can be used therapeutically. However, the differentiation process is not yet optimal since one of the IPC-transplanted mouse developed a teratoma. DiscussionES and iPS cells could potentially overcome the chronic shortage of cadaveric organs if we are able to establish efficient differentiation protocols. Derivation of specific cell types and tissues from ES and iPS cells could end the need for donated cadaveric tissue. However, the current protocols for the in vitro differentiation of ES and iPS cells into IPCs are still very inefficient, time consuming and very expensive.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: RoseFootnote 15 rightly indicated that an understanding of absolute measures of risk is a cornerstone of population health planning. However, the limitations of Rose's approach for evaluation of equity issues have been much debated. Footnote 6, Footnote 13, Footnote 16 Tugwell et al. Footnote 4 outlined a framework for considering equity issues when evaluating health policies. The modelling approach used here is similar to the ''effectiveness equity loop'' described by Tugwell et al. ,Footnote 4 except that our calculations were specific to preventive interventions and used a multivariate risk tool to estimate baseline risk. As a measure the equity tipping point is also analogous to threshold or sensitivity analyses in economic studies where there is uncertainty or variation in costing of components and estimates of effectiveness. Footnote 17, Footnote 18 We varied only one component of community effectiveness—coverage—to examine its effect on the equity tipping point. We chose this variable because of concerns that coverage varies considerably across socioeconomic groups and because lower coverage of diabetes preventive therapies has been observed in low-income communities. Footnote 19 Intervention uptake is influenced by a complex array of individual, provider and health system factors—attitudes, language and cultural barriers, trust in the health care system, quality of the communication relationship and continuity of careFootnote 9, Footnote 10, Footnote 20, Footnote 21, Footnote 22—all of which can have varied effects on intervention coverage. As expected, we found that when intervention coverage decreased among those in the lowest SEP group, so did the ARR. We further demonstrated the potential for poor coverage to exacerbate baseline disparity in diabetes risk when the intervention coverage surpasses the equity tipping point. At this threshold, the difference in intervention coverage voided any equity benefit of the health intervention and led to an increased disparity in diabetes risk. In an attempt to explain this predicted effect, others have theorized that health interventions may increase disparities if advantaged groups are more likely than their poorer, less educated and unemployed counterparts to have the financial and knowledge resources to capitalize on available opportunities to improve health. Footnote 13, Footnote 23 However, Anderson et al.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Human osteosarcoma Saos2 cells and human embryonic kidney 293 cells were cultured in Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal bovine serum, L-glutamine, and penicillin/streptomycin (all from Technologies, Karlsruhe, Germany). Plasmids, construction of expression plasmids, mutagenesis and transient transfectionThe full length human HIPK2 cDNA [25] was subcloned into the EcoR1 and XhoI sites of pcDNA3. 1-zeo(+) (Invitrogen, Groningen, The Netherlands). The DNA fragments for the deletion constructs were generated by PCR using polymerase (Biolabs, Frankfurt, Germany) and primers with appropriate restriction sites and epitope tags. Details about the used primers can be obtained upon request. The carboxy-terminal HIPK2 deletion AC contains amino acids until position 527, the amino-terminal deletion AN from amino acid position 559. The PCR fragments were subcloned in pBSIIsk(-) (Stratagene, Offenbach, Germany), sequenced using an automated sequencer (Applied Biosystem, Langen, Germany) and inserted into pcDNA3 (Invitrogen, Groningen, The Netherlands). The point mutant HIPK2 K221A was generated using the QuickChangeTM kit (Stratagene, Offenbach, Germany) according to the manufacturer's instructions. The plasmid pEGFP-Nl coding for a green fluorescent protein was obtained from Clontech (Heidelberg, Germany). The plasmid coding for wildtype p53 was a kind gift from M. Oren (Institute of Science, Israel). HeLa and Saos2 cells were transiently transfected by using the () according to the protocol of the manufacturer. Transient transfections of 293 cells were performed by the calcium phosphate method. Prior to transfection approximately 5 × 105 cells were plated onto a 60 mm dishes to a confluency of 20%. Cells were harvested at 20–30 h following transfection and lysed in 500 μl of lysis buffer (20 mpH 7. 4, 150 mM NaCl, 5 mM EDTA, 10 % glycerol, 0.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: Our results are not entirely surprising because in an earlier study, inducible biphasic expression of Pdx1 led to the differentiation of mouse ES cells into both insulin and glucagon expressing cells [26]. It is possible that sustained Pdx1 expression in our ES cells leads to the development of a bihormonal progenitor cell population during differentiation, which in turn gives rise to both insulin- and glucagon-expressing cells. These findings suggest that ectopic Pdx1 expression alone may not be sufficient to allow for the complete maturation of the IPCs in vitro. We, however, anticipate that these cells eventually mature in vivo post-transplantation and become mono-hormonal. In a recent study, adenoviral-mediated coexpression of Pdx1 and MafA with either Ngn3 or NeuroD has been shown to improve the generation of IPCs [56]. However, the critical transplantation experiments to demonstrate the therapeutic efficacy of the ES cell-derived IPCs were not performed. The insulin secretion, as well as glucose responsiveness, of the R1Pdx1AcGFP/RIP-Luc ES cell-derived IPCs was confirmed by an ultrasensitive ELISA. data suggest that constitutive Pdx1 expression in our R1Pdx1AcGFP/RIP-Luc ES cell-derived IPCs leads to a robust glucose responsive insulin secretion as compared to the biphasic Pdx1 expression or combined inducible Pdx1 and Ngn3 expression as reported earlier [26, 57]. It is possible that constitutive Pdx1 expression maintains the insulin processing and secretion mechanism in ES cell-derived IPCs in a dynamic state, thereby facilitating glucose responsive insulin secretion. Moreover, in these earlier studies, the much needed transplantation experiments to evaluate the therapeutic efficacy of ES cell-derived IPCs to correct hyperglycemia in diabetic mice were not performed. The therapeutic efficacy of the IPCs derived using our new differentiation protocol was tested in streptozotocin-treated 129/SvJ syngeneic diabetic mice by transplanting the cells under the kidney capsule. The 129/SvJ mice administered STZ for five consecutive days become progressively diabetic, do not recover from severe hyperglycemia and die between Days 10 and 15 due to failure of endogenous β-cell regeneration as reported earlier [32].

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: 85) Compared with the adjusted estimates from the original data, the imputed ORs for facial injury risk tended to be further from 1. 00. The odds of facial injury increased significantly if the helmet tilted back (OR = 4. 81, 95% CI: 2. 74–8. 46), shifted to the side (OR = 1. 83, 95% CI: 1. 04–3. 19) or came off (OR = 3. 31, 95% CI: 1. 24–8. 85). Data quality and reliability For helmet fit, overall observed agreement was 87. 5% and expected agreement was 81. 0% (Table 4). Weighted kappa was calculated since the responses were ordered, and kappa was 0. 34 (95% CI: 0. 16–0. 64), which represents fair agreement. Endnote 14 For head and face injury cases (n = 24), observed agreement was 91. 7% and expected agreement was 79. 8%, resulting in a kappa of 0. 59 (95% CI: 0. 28–1. 00), representing moderate agreement. For controls, kappa was 0. 22 (95% CI: 0. 00–0. 44). TABLE 4 Agreement and kappa for helmet fit and position by cases and controls for cyclists injured in Calgary and Edmonton, agreement, % Expected agreement, % k 95% CI Abbreviations: CI, confidence interval; k, kappa. Cases (n = 24) Helmet fit 91. 7 79. 8 0. 59 (0. 28–1. 00) Helmet position 62. 5 49. 3 0. 26 (0. 00–0. 54) Controls (n = 53) Helmet fit 85. 5 81. 6 0. 22 (0. 00–0. 44) Helmet position 90. 6 85. 6 0. 35 (0. 19–0. 71) Overall (n = 77) Helmet fit 87. 5 81. 0 0. 34 (0. 16–0. 64) Helmet position 81. 8 72. 0 0. 35 (0. 20–0. 74) An un-weighted kappa score was calculated for helmet position. For head and face injury cases, observed agreement was 62. 5%, expected agreement was 49. 3% and kappa was 0. 26 (95% CI: 0. 00–0. 54) or fair agreement.

Output: pass


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: 5% Triton X-100, 20 μl/ml protease inhibitor cocktail (Sigma, Taufkirchen, Germany). Elk1 activation assay293 cells have been transiently cotransfected with 1 μg pFR-Luc (Stratagene, Offenbach, Germany) and 50 ng pFA2-Elk1 (PathDetect in vivo signal transduction pathway trans-reporting systems, Stratagene, Offenbach, Germany) with or without 1 μg of the indicated plasmids coding for HIPK2. 50 ng of pFC-MEK1 (Stratagene, Offenbach, Germany) served as positive control. After 24 h cells were starved for 8 h. Then lysophosphatidic acid (Sigma, Taufkirchen, Germany) was added to a final concentration of 10 μM for 30 min. Cells lysis and measurement of luciferase activity were done according to the instructions for the luciferase assay system (Promega, Mannheim, Germany). p53 and NFκB activation assay293 or HeLa cells have been transiently cotransfected with 1 μg pNF-κB-Luc (PathDetect in vivo signal transduction pathway cis-reporting systems, Stratagene, Offenbach, Germany) with or without 1 μg of the indicated plasmids coding for HIPK2. 50 ng of pFC-MEKK (Stratagene, Offenbach, Germany) served as positive control for activation of NFκB-mediated transcription. For measuring activation of p53, 1 μg pf p53-Luc (PathDetect in vivo signal transduction pathway cis-reporting systems, Stratagene, Offenbach, Germany) has been used for cotransfection instead of pNF-κB-Luc. The positive control for activation of p53-mediated transcription was 50 ng pFC-p53 (Stratagen, Offenbach, Germany), which contains the p53 cDNA under the control of a cytomegalovirus promoter. Cells were collected after 24 h. Cell lysis and measurement of luciferase activity were done according to the instructions for the luciferase assay system (Promega, Mannheim, Germany). Western blottingHeLa or Saos2 cells were transiently transfected with either the vector pcDNA3.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: : Our results show that UCMSCs can differentiate into islet-like cells in vitro under certain conditions, which can function as IPCs both in vivo and in vitro. Key Words: Human umbilical cord mesenchymal stem cells; 90% pancreatectomy; Diabetic mellitus Core tip: It is well known that islet transplantation can decrease the morbidity related to diabetes mellitus (DM) after total pancreatectomy (TP); however, islet shortage limits its application. To solve the islet shortage problem, we tried to induce mesenchymal stem cells isolated from human Wharton’s jelly to differentiate into insulin-producing cells (IPCs) in this study. To imitate the pathophysiological status of diabetic patients after TP, we used Sprague-Dawley rats after 90% pancreatectomy as a model of type 1 DM. We for the first time tested the possible curative effects of transplanting IPCs differentiated from umbilical cord mesenchymal stem cells into the model rats. Citation:. Transplantation of insulin-producing cells to treat diabetic rats after 90% pancreatectomy. Gastroenterol 2015; 21(21): 6582-6590 URL: DOI: adenocarcinoma is a highly malignant and invasive disease. It has the worst prognosis of all gastrointestinal malignancies[1]. Pancreatic resection plays an essential role in the treatment of pancreatic adenocarcinoma and is the only treatment with the potential to achieve long-term survival[2]. The most common operation for pancreatic neoplasia is pancreaticoduodenectomy. heel of this operation is the pancreatic anastomosis, with an incidence of pancreatic leak ranging from 2%-29%[3]. The prognosis remains poor even in patients undergoing radical resection, and there is a median overall survival period of about 20 mo due to the high rate of relapse[4]. Theoretically, elimination of high risk pancreatic anastomosis by performing total pancreatectomy (TP) could reduce perioperative morbidity. Thus, TP has attracted more attention. TP for pancreatic adenocarcinoma was first reported in 1943 and the patient died in the perioperative period because of a bile duct leak[5].

Output: pass


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Exposure to complex chlorinated organic compounds, some of which are probable carcinogens, may occur through contact with slimicides (e. g. , pentachlorophenol), pesticide-treated wood, or compounds formed during the bleaching process. Welders are exposed to hexavalent chromium in stainless steel welding. Perhaps most importantly from a cancer risk perspective, in the past workers (especially maintenance workers) were commonly exposed to asbestos. Table 1Occupational exposures in the pulp and paper industry Production area/job Potential exposures Raw wood preparation (i. e. , debarking, chipping) Wood volatiles, wood dust, spores, fungi, microbes Production of cooking liquor Sulphate: ammonia, hydrogen sulphide, sulphur dioxide, mercaptan, chromate and other contaminants Sulphite: sulphur, sulphur dioxide, calcium carbonate, zinc, sulphuric acid, lead fumes, asbestos, sulphurous acid Pulp production, cooking Sulphate: lime, magnesium, wood volatilesSulphite: pigments, dyes, wood volatilesGround wood: wood volatiles, aniline Pulp bleaching, bleach plant Chlorine compounds, ozone, hydrogen peroxide, boron compounds, caustic acids Wet pulp, paper additives Talc, clays, titanium dioxide, urea and melamine formaldehyde, pigments, dyes Paper rolling, sizing, dying, drying, glazing, coating Urea and melamine formaldehyde, paper dust, coating and pigment dusts plant exposures, asbestos, welding fumes Unknown jobs, power, utility General plant exposures, asbestos Unexposed jobs No significant exposures Important challenges in occupational cancer studies Workers represent a well-defined group of people for epidemiological assessment. The occupational health status of pulp and paper mill workers has been studied for a variety of endpoints, including cancer, pulmonary function, skin diseases, and hearing impairment. For some endpoints, such as cancer and respiratory effects, findings have varied considerably across studies. Exposure assessment has been a significant issue in past studies. Lacking measurement of exposure to specific chemicals, most cohort studies have divided workers into at least three exposure categories: those who work in a paper mill, a sulphate (kraft) pulp mill, or a sulphite pulp mill. For simplicity, workers usually are categorized according to the last job they held, and exposure is defined as duration of employment.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: 1-zeo+ (Invitrogen, Groningen, The Netherlands), the p53 (pFC-p53, Stratagene, Offenbach, Germany) or the HIPK2 expression construct. Cells were harvested 20–30 h following transfection and lysed in 100 μl of lysis buffer (20 mpH 7. 4, 150 mM NaCl, 5 mM EDTA, 10% glycerol, 0. 5% Triton X-100, 20 μl/ml protease inhibitor cocktail (Sigma, Taufkirchen, Germany)). The protein concentration was determined by the BCA-Pierce-kit according to the protocol of the manufacturer. analysis, 20–30 μg of protein was separated on 10–20% gradient gels (Bio-) and blotted onto nitrocellulose membranes (Amersham-Pharmacia, Freiburg, Germany) according to standard protocols. The monoclonal anti-p53 antibody DO-7 and the monoclonal anti-p21 (Waf1/Cip1) antibody SX118 were purchased from Phar(Hamburg, Germany), the polyclonal anti-Bax antibody Ab-1 (150-165) from Calbiochem (Schwalbach, Germany), the polyclonal phospho-p53 (Ser 15) (Ab-3), phospho-p53 (Ser 392) (Ab-4) and the monoclonal Mdm2 (Ab-1) antibodies from OncogeneTM (Schwalbach, Germany) research products, the polyclonal phospho-p53 (Ser 20) from New(Frankfurt, Germany), the monoclonal anti-Flag antibody M2 from Stratagene (Offenbach, Germany) and the monoclonal anti-β-actin antibody AC-15 from Sigma (Taufkirchen, Germany). An anti-mouse secondary IgG1 antibody coupled to horseraddish peroxidase (Biotechnology, Heidelberg. Germany) was used at a dilution 1:5000. Antibody reactive bands were detected by using the enhanced chemiluminescence Western detection system (Amersham-Pharmacia, Freiburg, Germany).

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: The result showed that differentiated cells secreted C-peptide in a low glucose concentration (5. 5 mmol/L) medium and secreted approximately twice as much in a high glucose concentration (25 mmol/L) medium (Figure 2G). Thus, these differentiated MSCs could respond to changes in glucose concentration by altering their C-peptide production and, presumably, insulin production. Genetic analysis of the differentiated cellsTo determine whether the UCMSCs had been induced to differentiate into pancreatic endocrine cells, gene expression profiles for pancreatic β-cell differentiation markers and hormones were assayed by RT-PCR and real-time RT-PCR. As illustrated in Figure 3, the inductive cells expressed genes of pancreatic β-cell markers PDX1, Pax4, Glut2, Ngn3 and insulin. However, the expression of PDX1, Ngn3, and insulin in differentiated IPCs was significantly greater than that in undifferentiated MSCs (Figure 3). Open in 3 Reverse transcription-polymerase chain reaction and real-time reverse transcription-polymerase chain reaction analysis of the expression of pancreatic β-cell development-related genes and insulin production-related genes. A: RT-PCR of the undifferentiated UCMSCs and those during the phases of differentiation (weeks 3 and 4). At the end of differentiation (week 4), the gene expression of IPCs was similar to that of human islets; B: Real-time RT-PCR analysis of UCMSCs. After three-step induction, the UCMSCs expressed high levels of the specific regulation genes for neogenesis and development of pancreatic β-cells, including PDX1, Ngn3 and of hallmark genes for mature islet cells, including insulin. Compared to those of human islets, the differentiated cells (week 4) expressed more Ngn3 and Pax4 and insulin (P < 0. 05, n = 3). Each gene was tested in triplicate. RT-PCR: Reverse transcription-polymerase chain reaction; UCMSCs: Umbilical cord mesenchymal stem cells. Blood glucose and body weight of rats after surgeryThe blood glucose concentrations and body weight of Px rats and sham rats over the 8 wk of study are shown in Figure 4A and B.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: 198670d Jappinen et al. 198762d Henneberger et al. 198960b Band et al. 199753e Henneberger et Lax 199861c Matanoski et al. 199868e Langseth et Andersen 200065d Band et al. 200154d Years of follow-up 18 25 42 25 22 40 42 Type of risk estimate SMR* (n) SIR** (n) SMR (n) SMR (n) SMR (n) (n) SIR (n) All cancers 79* -88 105 -33 120 -36 114* -351 108 -123 82** 117* (464) Oral cavity/ pharynx 103 -7 105 91 -11 Esophagus 147 -11 86 126 -7 Stomach 149 -11 129 -6 72 -1 73 -19 78 94 -17 Colon 48 -5 102 -3 83 -21 71** 130 -23 98 -34 Rectum 121 -16 77 124 -27 Liver 199 -8 116 277* -8 Pancreas 32 -2 305 -5 156* -29 185 -11 74 177* -21 Larynx 202 -3 55 133 -12 Lung 81 -26 90 -9 113 -11 132 -121 95 -35 79** 150** -46 132* -112 Pleura 240 -2 Skin melanoma 172 -5 160 -10 139 -10 Prostate 111 -9 104 -3 67* -19 108 111 -78 Bladder 270 -3 72 -7 110 87 -23 Kidney 148 -4 289 -2 143 -11 143 106 -12 Brain 172* -16 34** 153 -10 Non-Hodgkin's lymphoma 133 -4 69 -6 89 91 -12 Hodgkin's disease 159 -4 40 Multiple myeloma 171 -8 103 -5 Leukemia 67 -3 90 -1 51 -6 60 124 -14 Testis 86 SMR: Standardized mortality ratio SIR: Standardized incidence ratio * Significant at 90% level of significance ** Signficant at 95% level of significance a Cause-specific number of deaths not available; total deaths: 1,539 Langseth and Andersen also found a statistically significant increase in lung cancer incidence among sulphite workers. 64 However, the authors suggest that most of the excess can, in fact, be attributed to smoking.

Output: contrast


Input: Claim: Urban living always leads to increased stress levels. [SEP] Text: Fluorometric protein quantification was done by excitation at 485 nm and emission measurement at 510 nm of cellular extracts in a fluorometer (Victor, Wallac, Freiburg, Germany). For reprobing, membranes were treated with stripping buffer (62. 5 mM Tris-HCl pH 6. 7, 2% SDS, 100 mM β-mercaptoethanol) at 50°C for 30 min. Quantitative TaqMan RT--PCR (real time PCR) was carried out by Toplab GmbH (München, Germany) by using an 7700. Sequence specific internal Primers were labelled with FAM/TAMRA. Endogenous reference mRNA was human GAPDH mRNA. AbbreviationsHIPK2: homeodomain-interacting protein kinase 2 MAP: mitogen-activated protein Mdm2: murine double minute clone 2. 1399. CAS PubMed 53. Oncogene. 1999, 18: 7706-7717. 10. 1038/sj. onc. 1202952239. 10. 1002/(SICI)1097-4652(199911)181:2<231::AID-JCP5>3. 0. CO;2-L331. 6034. 10. 1074/jbc. 274. 51. 360312. Nature. 1997, 387: 299-303. 10. 1038/387299a029. 10. 1016/S0378-1119(99)00487-4310. 10. 1038/350426755879. 10. 1074/jbc. 273. 40. 258757377. 10. 1074/jbc. 275. 10. 73731. Proc. Natl. Acad. Sci. USA. 1999, 96: 12350-12355. 10. 1073/pnas. 96. 22. 1235053. Nat. Genet. 1992, 1: 45-49. 1542. 53. J. Virol. 1993, 67: 3111-3117. 1650. CAS PubMed 468. 1132. 7655. 10. 1038/sj. onc. 12030159283. 10. 1074/jbc. 275. 13. 92781758. 53. Proc.

Output: pass


Input: Claim: Genetic engineering is used in producing insulin for diabetic patients. [SEP] Text: It indicated the ability of islet generated to synthesize, store and release insulin in response to glucose challenge. In our in vitro studies, RT-PCR and real time RT-PCR were used to examine the expression of β-cell development-related genes before and after induction of differentiation. After 3 wk of differentiation, the IPCs expressed the genes of pancreatic β-cell marker s PDX1, Pax4, Glut2, Ngn3 and insulin. Real-time RT-PCR showed that the expression of PDX1, Ngn3, and insulin was significantly greater in differentiated IPCs than in undifferentiated MSCs. According to a previous study[14], we created the experimental diabetic rat models by removing 90% of the pancreas. We then transplanted the differentiated cells into diabetic rats in order to examine the function of IPCs. The portal vein[22], renal subcapsularspace[23], and tail lateral vein[24] have been previously reported as stem cell transplant locations in the rat. We transplanted the cells into the rat liver through the portal vein as this method is faster and easier to perform. In this study, after transplanting IPCs into diabetic rats, blood glucose levels decreased, suggesting that the transplanted cells secreted functional insulin. Thus, after transplantation, IPC grafts could reduce hyperglycemia in SD rats. At two weeks after transplantation, blood glucose levels decreased to about 18. 7 mmol/L compared to 25. 8 mmol/L in the control SD rats. The body weight of the transplanted diabetic rats increased rapidly, whereas the body weight of the untreated rats increased slowly. In vivo glucose tolerance test results showed that blood glucose levels were decreased in the cell transplantation group. Taken together, our results show that UCMSCs can differentiate into islet-like cells in vitro under certain conditions and function as IPCs both in vivo and in vitro. These results suggest that UCMSCs are a promising stem cell source for β-cell regeneration. However, there are many questions that remain unresolved, such as how to push these cells to become mature β-cells, will the antibodies destroy the insulin-producing cells, and whether tumor formation will happen. Further work is required to address these problems.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Estos resultados pueden ayudar a los profesionales de la salud en la práctica diaria para una mejor comprensión del estado de salud de los pacientes y una mejor clasificación de su estado de riesgo. [-] [CA] Els models de risc en l'àmbit de la salut són mètodes estadístics que brinden advertències primerenques sobre el risc d'una persona de patir un episodi advers en el futur. Generalment, utilitzen la informació emmagatzemada. . . [+] [CA] Els models de risc en l'àmbit de la salut són mètodes estadístics que brinden advertències primerenques sobre el risc d'una persona de patir un episodi advers en el futur. Generalment, utilitzen la informació emmagatzemada de forma rutinària en els sistemes d'informació hospitalària per a oferir una probabilitat individual de desenrotllar un resultat negatiu futur en un període determinat. Concretament, en el camp de les malalties cròniques que compartixen factors de risc comú, els models de risc es basen en l'anàlisi d'eixos factors de risc -tensió arterial elevada, glucèmia elevada, lípids sanguinis anormals, sobrecàrrega i obesitat- i les seues mesures biomètriques associades. Estes mesures es recopilen durant la pràctica clínica ben sovint de manera periòdica i, en conseqüència, s'incorporen als models de risc i recolzen la presa de decisions dels metges.

Output: contrast


Input: Claim: Environmental psychology can predict individual behavior with high accuracy. [SEP] Text: -19 PreprintsProtocolsVideosJournalsTools & a 10. 21203/rs. 2. 11709/v1This work is licensed under a CC BY 4. 0 LicenseStatus:Published21 Oct, 2020Read the published version in →Version 1posted You are reading this latest preprint versionAbstractBackground: Meningiomas, the most common adult brain tumors, recur in up to half of cases[1–3]. This requires timely intervention and therefore accurate risk assessment of recurrence is essential. Our current practice relies heavily on histological grade and extent of surgical excision to predict meningioma recurrence. However, prediction accuracy can be as poor as 50% for low or intermediate grade tumors, which constitute more than 90% of all cases. Moreover, attempts to find molecular markers, particularly for predicting recurrence of intermediate tumors have been impeded by low[4] or heterogenous[5–8] genetic signal. We therefore sought to apply systems-biology approaches to transcriptomic data to better predict meningioma recurrence. Methods: We apply gene co-expression networks to a cohort of 252 adult patients from the publicly-available genetic repository Omnibus. Resultant gene clusters (“modules”) were represented by the first principle component of their expression levels, and their ability to predict recurrence assessed with a logistic regression model. External validation was done using an independent merged cohort of 108 patients using the same modules. We used the bioinformatics database DAVID[9] to examine the gene ontology associations of each module. Results: Using gene co-expression analysis, we were able predict tumor recurrence with high accuracy using a single module which mapped to cell cycle-related functions (AUC of 0. 81 ± 0. 09 in external validation). Further, the module maintained its accuracy with removal of up to 20 of it’s most individually predictive genes, suggesting robustness against noise at the single gene level. Conclusions: With the easy accessibility of gene panels in healthcare diagnostics, our results offer a basis for routine molecular testing in meningioma management. Cancer BiologyOncologyMeningiomabioinformaticstranscriptomicssystems biologyrecurrence predictionFiguresFigure 1Figure 2Figure 3BackgroundMeningiomas constitute approximately 34% of all brain tumors, affect 3% of the adult population[10] with an incidence rate of 8.

Output: pass


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: , 2011) of histones can have profound consequences on the cell. In most cells, histone availability is tightly regulated at multiple levels, including transcriptionally, post-transcriptionally, and post-translationally (Marzluff et al. , 2008; Bannister and Kouzarides, 2011). For example, in mammalian cultured cells, transcription of canonical histones is highly upregulated during S-phase, when replication occurs, and afterwards throttling of transcription and mRNA turnover bring messages back to very low levels. And in yeast, excess histone proteins are degraded via the ubiquitin-proteasome system (Singh et al. , 2009). For early Drosophila embryos, regulation of histones is particularly challenging. On the one hand, these embryos develop incredibly rapidly: during the first ~90 min after fertilization, nuclei divide near simultaneously every ~8 min, deep within the embryo (cleavage stages); a subset of these nuclei migrates to the surface and divides four more times over the next hour (syncytial blastoderm stages). All these divisions occur near simultaneously and in the absence of cytokinesis. As a result, histone demand goes up exponentially during this period, in a fluctuating manner, as S-phases and mitoses alternate on minute time scales (the entire interphase is dedicated to DNA replication during these cycles). On the other hand, zygotic transcription is minimal during these stages, being upregulated only in late syncytial blastoderm as part of the midblastula transition (MBT). Thus, early embryos cannot control histone expression transcriptionally. Instead, they draw on abundant histone proteins and mRNAs, produced by the mother during oogenesis. Newly fertilized embryos already contain sufficient histone proteins for thousands of nuclei, and they increase histone levels further by translation of the maternal mRNAs. Thus, histone proteins are consistently overabundant. How is chromatin assembly regulated under those conditions? Previous work revealed that for three histones, the canonical histones H2A and H2B as well as H2Av, the single H2A variant in Drosophila, LDs play an important role in regulating histone availability (Li et al. , 2012).

Output: pass


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: L'objectiu d'esta tesi és proporcionar una visió nova del risc, associat a un pacient, basada en tecnologies Data-Driven que oferisquen una visió dinàmica de l'evo\-lució dels pacients respecte a la seua condició crònica. Tècnicament, suposa abordar els models de risc incorporant la perspectiva dinàmica i el comportament dels pacients als models de risc gràcies a la informació inclosa en la Història Clínica Electrònica. Els resultats obtinguts al llarg d'esta tesi mostren com les tecnologies de mineria de processos poden aportar una visió dinàmica i interactiva dels models de risc de malalties cròniques. Estos resultats poden ajudar els professionals de la salut en la pràctica diària per a una millor comprensió de l'estat de salut dels pacients i una millor classificació del seu estat de risc. [-] [EN] Risk models in the healthcare domain are statistical methods that provide early warnings about a person's risk for an adverse episode in the future. They usually use the information routinely stored in Hospital. . . [+] [EN] Risk models in the healthcare domain are statistical methods that provide early warnings about a person's risk for an adverse episode in the future. They usually use the information routinely stored in Systems to offer an individual probability for developing a future negative outcome in a given period. Concretely, in the field of chronic diseases that share common risk factors, risk models are based on the analysis of those risk factors -raised blood pressure, raised glucose levels, abnormal blood lipids, and overweight and obesity- and their associated biometric measures. These measures are collected during clinical practice frequently in a periodic manner, and accordingly, they are incorporated into the risk models to support clinicians' decision-making. Data-Driven techniques could be used to create these temporal-aware risk models, considering the patients' history included in Records, and extracting knowledge from raw data.

Output: contrast


Input: Claim: Environmental psychology can predict individual behavior with high accuracy. [SEP] Text: 36 and 3. 61 per 100,000 person years in females and males respectively [11]. For over half a century, the prediction of meningioma recurrence has relied solely upon histological features[11] (Organization grading from I to III) and degree of surgical excision [1]. While about 70-80% of fully excised WHO grade I meningiomas do not recur, 20-30% recur over follow-up with half of the recurrences occurring before the tenth year and half after ten years[12]. For WHO grade II lesions completely excised, histology predicts a recurrence of 50% over 5 years [2] and a disease specific survival rate of 69% over 10 years [3]. Given the inherent inaccuracy of histology to predict recurrence, all patients consequently require lifelong monitoring with expensive MRI imaging and clinical follow-up, essentially transforming meningioma into a “chronic disease”. Not only does this represent a significant financial burden but the stress and strain on the psychological well-bring of patients is substantial as they live with the constant uncertainty as to whether the tumor will recur, face future morbidity or require more treatment. It is therefore critical to develop better methods designed to assess the risk of recurrence that take into account the intrinsic biology of the patient’s meningioma. The genetic landscape of meningiomas is the next frontier to our understanding of their biology and its relation to disease recurrence. While some studies have identified chromosomal rearrangements [13], mutations in genes TERT [14], ATK1 [15], SMO [16] and DNA methylation [8] as correlates of tumor recurrence, none of these have successfully translated into routine clinical practice. In addition, studies on transcriptomics have been limited by low signal. However alternative methodology exists to effectively capture additive biological effects and relate them to complex clinical traits [17–19]. Such methods may help extract translatable markers of meningioma recurrence. Gene co-expression networks are an emerging technique used to detect patterns in transcriptomics by incorporating additive signal from relatively low gene expression levels [17, 18, 20]. The technique establishes gene similarity profiles based on shared connectivity and clusters into biologically similar groups called modules. A meta-gene is computed to summarize each module based on its gene expression levels and correlated to a clinical trait.

Output: pass


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: Log in or new issue alertsGet alerts Enter your Email address: Subscribe to e2016. | DOI: 10. 1097/01. COT. 0000480383. 29391. 39 —Three new studies with impressive outcomes show the promise of targeted therapies for a variety of patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to presentations here at the of Meeting. “As we move toward molecular targeted therapies linked to genetic defects, we can begin to talk about a cure for CLL. The hope is to reduce toxicity and to move combinations more upfront where they might be more effective,” said the moderator of a news conference that featured the three studies, Robert Hromas, MD of the University of Florida. Ibrutinib forsmall lymphocytic lymphoma (SLL) primarily affects older patients who often have other chronic diseases or conditions. In this population of patients, chlorambucil has been a standard first-line therapy. Fludarabine-based regimens are unsuitable for frail or older patients, said Alessandra Tedeschi, MD, of Niguarda Cà Granda in Italy, who reported the results of the open-label, multicenter, international -2 trial, which evaluated the use of ibrutinib in previously untreated 269 CLL/SLL patients, age 65 and older (Abstract 495and published simultaneously online in the Journal of Medicine—DOI: 10. 1056/NEJMoa1509388). Ibrutinib is a first-in-class, oral, covalent Bruton's tyrosine kinase inhibitor, which received FDA approval for CLL patients who had one or more prior therapies and for patients with del17p CLL. The results of the trial found that in relapsed/refractory CLL, ibrutinib led to a 78 percent reduction in the risk of disease progression and a 57 percent reduction in the risk of death as compared with ofatumumab. The patients, who had a median age of 73, were randomized to receive either continuous daily doses of ibrutinib or the chemotherapy drug chlorambucil for up to 12 treatment cycles. “By investigator assessment, ibrutinib therapy led to a 91 percent reduction in the risk of progression or death compared with chlorambucil,” Tedeschi said.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Score15 () is a key element of Finland’s national FIN-D2D diabetes prevention program, which has successfully screened over 10% of the Finnish population so far. has been used in Finland to identify high-risk individuals who might benefit from interventions or who would merit further investigation using the oral glucose tolerance test (OGTT). Among those detected by the Finnish study as being at high risk of developing diabetes, 60% of men and 45% of women had already developed abnormal glucose intolerance at baseline. 16 The incidence of diabetes at one-year follow-up was between 18% and 22% among those who had high-risk prediabetes (i. e. both IFG and IGT) at baseline. Of those who completed a lifestyle education program, 17% reduced their body weight by over 5%; as a result, their risk of developing diabetes was 69% lower than that of those with stable weight. 17 However, the generalizability of is limited by the different ethnic make-up of Canada compared to that of Finland. As a result, Canadian diabetes experts adapted to include ethnicity and other key variables (sex, education, macrosomia) to create the Questionnaire (). 18 * This paper describes three main objectives of our study: (1) to develop a risk-scoring prognostic model (similar to score) suitable for Canada’s multi-ethnic population (); (2) to validate the resulting scoring model using a test-set methodology to assess dysglycemia from measured blood tests; and (3) to compare the predictive accuracy of the new model to. * source Between 2007 and 2011, 6475 Canadian adults from seven provinces (and Island) were recruited in a screening study to detect diabetes and prediabetes using the questionnaire. Several large urban sites were deliberately included to ensure a diverse multi-ethnic sample of participants. All participants had their glycemic status confirmed with the oral glucose tolerance test (OGTT, i. e. fasting plasma glucose [FPG] and plasma glucose 2 hours after a 75 g glucose challenge). A subset of participants at three sites also had their glycated hemoglobin (HbA1c ) measured. Most participants were recruited through face-to-face encounters during opportunistic visits at community health centres;19 some were recruited through local mailouts. 20 Most participants were aged 40 to 74 years, although some sites chose to include younger Aboriginal participants and those from other non-White ethnic groups.

Output: contrast


Input: Claim: Environmental psychology can predict individual behavior with high accuracy. [SEP] Text: Highly correlated meta-genes can then be used to predict a phenotype such as recurrence. With the affordability of gene expression profiling, meta-gene based diagnostics of tumor recurrence becomes feasible. With contribution of multiple module genes a meta-gene seeks to holistically represent a biological process. This multi-gene signature provides a robust against fluctuations of individual expression levels. In the current study we hypothesized the existence of meta-genes consisting of gene modules that predict tumor recurrence with high accuracy. By annotating modules correlated with recurrent phenotypes we aim to provide further insight into the underlying biology driving tumor recurrence in addition to the clinical application. MethodsData collection and pre-processing: We identified 17 studies containing meningioma gene expression data in the Omnibus (GEO)[21] with four datasets (GSE43290, GSE1658, GSE74385, and GSE16181) including annotated tumor recurrence (Table 1). Gene expression analysis for these studies was carried out using microarray platforms Genome U133A, Genome U133 Plus 2. 0, HT-12 V4. 0, and SU 912, respectively. Each study was background corrected, log2 transformed and quantile normalized except GSE16181, which had previously been pre-processed. After this step, we filtered to include only genes common to all four studies. Discovery was done using dataset GSE16181 and external validation was done using GSE43290, GSE1658 and GSE74385 datasets merged with ComBat, a well-established Bayesian batch correction tool[22]. Notably, gene expression matrices were globally scaled to a mean of 0 and standard deviation of 1 prior to merging, as previously suggested[23]. Gene module detection and meta-gene computation: Our analysis was based on the well-established Analysis (WGCNA), which has been described in detail elsewhere[18]. We first constructed an adjacency matrix with gene-gene Pearson correlations. Per convention, soft-thresholding was introduced by raising correlations to a common power (a hyperparameter, ß), which was selected as the lowest natural number for which the network approached scale-free topology (r2 ≥ 0. 9).

Output: pass


Input: Claim: The majority of genetic therapies are still in experimental stages but show promising results. [SEP] Text: Further increasing intensity of host preparative lymphodepletion by adding total-body irradiation (TBI) of either 2 or 12 Gy prior to cell transfer in cyclophosphamide and fludarabine lymphodeleted patients was shown to generate response rates up to 52% and 72%, respectively. Of the 25 patients studied in the 12 Gy TBI arm, there were 4 complete responders and at least 2 substantial partial responders (Dudley et al. 2008). The caveat of adoptive cell therapy is its complexity of several critical preparative steps that are both labor intensive and costly which may be the major obstacle to the widespread application of this approach. Up to 4 to 6 weeks of cell culture are required to obtain adequate numbers of reactive lymphocytes for adoptive transfer. Additionally, much akin to the limitation of high dose IL-2, only patients with an excellent functional status are be able to withstand the intensity of adoptive cell therapy which may also involve TBI in addition to IL-2. On the other hand, as the data from the NCI suggest, such potent therapy in highly selected patients does have the potential to induce durable responses and a potential cure. To date, however, only small phase II clinical trials have been completed and no phase III study has been initiated. Meanwhile, further innovations beyond current TIL technology are underway. Current strategies seek to improve the yield of TIL cultures, to use vaccines to stimulate the transferred T cells in vivo, and to employ gene therapy using genetically engineered lymphocytes that express highly reactive T-cell receptors (TCRs) with specific anti-melanoma differentiation antigen activity (gp-100 or MART-1), produce IL-2 or other molecules promoting an effective immune response. The gene therapy approach is of particular interest because the anti-tumor effector T cells could be rapidly expanded for adoptive transfer. Furthermore, it could be of tremendous benefit to patients who do not have autologous reactive TIL available and would otherwise be ineligible for adoptive immunotherapy (Johnson et al. 2009; Yang et al. 2010). The objective response rates in trials employing gene therapy have been reported to be 20% to 45%, and durable tumor regression at all disease sites including the brain has also been observed (Johnson et al. 2009; Morgan et al. 2006; Robbins et al. 2011). Advertisement 3.

Output: corroborate


Input: Claim: Most biohacking techniques can entirely eliminate the risk of chronic diseases. [SEP] Text: Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19:708-23. de Group. Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population: the Hoorn Study. JAMA. 2001;285(16):2109-13. -Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Med. 2001;344:1343-50. Knowler WC, Barrett-;. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Med. 2002;346:393-403. . Risk assessment tools for identifying individuals at risk of developing type 2 diabetes. Epidemiol Rev. 2011;33:46-62. . Diabetes risk score: towards earlier detection of type 2 diabetes in general practice. Res Rev. 2000 May-Jun;16(3):164-71. . A new public health tool for risk assessment of abnormal glucose levels. Dis. 2010;7(2):1-9. . Calculator: a simple tool for detecting undiagnosed diabetes and pre-diabetes. Diabetes Care. 2008;31:1040-5. . Tool to assess likelihood of fasting glucose impairment (TAG-IT). Med. 2008;6(6):555-61. ; Health and Survey. Predicting impaired glucose tolerance using common clinical information: data from the third Survey. Diabetes Care. 2003;26(7):2058-62. . The performance of a risk score in predicting undiagnosed hyperglycemia. Diabetes Care. 2002;25:984-8. Detection of undiagnosed diabetes and other hyperglycemia states: the in Communities Study. Diabetes Care. 2003;26(5):1338-43. Lindstrom J, Tuomilehto J. Risk Score: a practical tool to predict type 2 diabetes risk. Diabetes Care. 2003;26(3):725-31. - Cardiometabolic profile of people screened for being at high risk of type 2 diabetes in a national diabetes prevention program (FIN-D2D). Diabetes. 2010;4:231-9.

Output: contrast


Input: Claim: Environmental psychology can predict individual behavior with high accuracy. [SEP] Text: The adjacency matrix was subsequently converted into a biologically-inspired topological overlap map (TOM), wherein pairwise gene similarities are based on comparing their connectivity profiles, a more meaningful measure than direct correlation[24]. Hierarchical clustering with superimposed hybrid adaptive tree cut[25], an unsupervised dendrogram cutting function, was applied to the TOM to identify biologically important gene modules. Finally, representative module “meta-genes” for each sample were calculated using principal component analysis; they are simply the projections of a sample’s modules’ gene expression values on their respective first principal components. Module investigation: We first used a multivariate logistic regression model to identify modules whose meta-gene expression levels differed significantly (p<0. 05) between recurrent and non-recurrent tumors when controlling for histological grade. In order to probe the biological function of relevant modules, we used the well-established and open-source Database for Annotation, Visualization and (DAVID)[9] to analyze their constituent gene lists. Recurrence classifier: A logistic regression classifier was used as our prediction model, with module meta-genes as regressors and recurrence as a binary response. The model was trained with the discovery cohort and tested with both 10-fold cross validation and external validation sets. Computational platform: All analysis was performed using R, an open-source platform for statistical computation and graphics[26]. ResultsWe firstly investigated the differential gene expression profile between recurrent and non-recurrent meningiomas in both cohorts, though no single genes were significantly different (log2 fold change >1 and p<0. 0001) in the validation cohort (Figure 1A). Co-expression networks revealed two gene modules (Figure 1B and C) with significant correlation to recurrence (Mann-Whitney p<0. 05): a “blue” module containing 220 genes and a “turquoise” module consisting of 299 genes. The meta-gene of each module was defined as the first principal component of its expression values[20](Supplementary figure 1). We next investigated whether the meta–genes could be used to predict meningioma recurrence and found good classifier performance with 10-fold cross validation using the “turquoise” module (AUC=0. 87 ±0. 04; Figure 2A).

Output: pass