Early symptoms and sensations as predictors of lung cancer: a machine learning multivariate model.

The aim of this study was to identify a combination of early predictive symptoms/sensations attributable to primary lung cancer (LC). An interactive e-questionnaire comprised of pre-diagnostic descriptors of first symptoms/sensations was administered to patients referred for suspected LC. Respondents were included in the present analysis only if they later received a primary LC diagnosis or had no cancer; and inclusion of each descriptor required ≥4 observations. Fully-completed data from 506/670 individuals later diagnosed with primary LC (n = 311) or no cancer (n = 195) were modelled with orthogonal projections to latent structures (OPLS). After analysing 145/285 descriptors, meeting inclusion criteria, through randomised seven-fold cross-validation (six-fold training set: n = 433; test set: n = 73), 63 provided best LC prediction. The most-significant LC-positive descriptors included a cough that varied over the day, back pain/aches/discomfort, early satiety, appetite loss, and having less strength. Upon combining the descriptors with the background variables current smoking, a cold/flu or pneumonia within the past two years, female sex, older age, a history of COPD (positive LC-association); antibiotics within the past two years, and a history of pneumonia (negative LC-association); the resulting 70-variable model had accurate cross-validated test set performance: area under the ROC curve = 0.767 (descriptors only: 0.736/background predictors only: 0.652), sensitivity = 84.8% (73.9/76.1%, respectively), specificity = 55.6% (66.7/51.9%, respectively). In conclusion, accurate prediction of LC was found through 63 early symptoms/sensations and seven background factors. Further research and precision in this model may lead to a tool for referral and LC diagnostic decision-making

Three-Year Follow-Up of Participants from a Self-Weighing Randomized Controlled Trial

Frequent self-weighing is associated with weight loss maintenance. Several years ago, we investigated frequent self-weighing’s effect on weight loss and found the participants lost a significant amount of weight. Three years after this trial's end, participants were contacted for an update on their weight and self-weighing frequency. Weight change and self-weighing frequency since the end of the study were assessed. We hypothesized that participants who maintained frequent self-weighing behavior would have maintained their weight loss. Out of 98 participants enrolled in the RCT, 37% (n = 36) participated in this follow-up study. Total weight loss during the trial for the follow-up participants was 12.7 ± 19.4 lbs (p<0.001). Three years after intervention, participants regained 0.9 ± 4.34 lbs, a value that was not statistically different from zero (p=0.75). This did not differ by gender (p=0.655). Over 75% of these participants continued to weigh themselves at least once a week. Frequent self-weighing may be an effective, low-cost strategy for weight loss maintenance. Future research should further investigate the role of self-weighing in long-term weight gain prevention

Requirement of Cognate CD4+ T-Cell Recognition for the Regulation of Allospecific CTL by Human CD4+CD127−CD25+FOXP3+ Cells Generated in MLR

Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4+ Tregs on CD8+ cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4+CD127−CD25+FOXP3+ Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechanisms were then tested using modified 51Chromium release assays (Micro-CML), MLRs and CFSE-based multi-fluorochrome flow cytometry proliferation assays. It was observed that increased numbers of CD4+CD127−CD25+FOXP3+ cells were generated after a 7 day MLR. After immunoselection for CD4+CD127−CD25+ cells, they were designated as MLR-Tregs. When added as third component modulators, MLR-Tregs inhibited the alloreactive proliferation of autologous PBMC in a concentration dependent manner. The inhibition was quasi-antigen specific, in that the inhibition was non-specific at higher MLR-Treg modulator doses, but non-specificity disappeared with lower numbers at which specific inhibition was still significant. When tested in micro-CML assays CTL inhibition occurred with PBMC and purified CD8+ responders. However, antigen specificity of CTL inhibition was observed only with unpurified PBMC responders and not with purified CD8+ responders or even with CD8+ responders plus Non-T “APC”. However, allospecificity of CTL regulation was restored when autologous purified CD4+ T cells were added to the CD8+ responders. Proliferation of CD8+ cells was suppressed by MLR-Tregs in the presence or absence of IL-2. Inhibition by MLR-Tregs was mediated through down-regulation of intracellular perforin, granzyme B and membrane-bound CD25 molecules on the responding CD8+ cells. Therefore, it was concluded that human CD4+CD127−CD25+FOXP3+ MLR-Tregs down-regulate alloreactive cytotoxic responses. Regulatory allospecificity, however, requires the presence of cognate responding CD4+ T cells. CD8+ CTL regulatory mechanisms include impaired proliferation, reduced expression of cytolytic molecules and CD25+ activation epitopes

Dynamics of spin correlations in the spin-1/2 isotropic XY chain in a transverse field

Dynamic xx spin pair correlation functions for the isotropic spin-1/2 XY chain are calculated numerically for long open chains in the presence of a transverse magnetic field at finite temperature. As an application we discuss the temperature dependence of the spin-spin relaxation time in PrCl_3.Comment: 2 pages, latex, 2 figures, abstract of the paper presented at Ampere Summer School ``Applications of Magnetic Resonance in Novel Materials'' Nafplion, Greece, 3-9 September, 2000, partially published in J. Phys. A: Math. Gen. 33, 3063 (2000

Effect of the clinical course of acute-on-chronic liver failure prior to liver transplantation on post-transplant survival

BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival. METHODS: We identified patients from the United Network for Organ Sharing database who were transplanted within 28 days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition. RESULTS: A total of 3,636 patients listed with ACLF-3 underwent LT within 28 days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0–2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0–2 (p 60 years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0–2 than among those who did not. CONCLUSIONS: Improvement from ACLF-3 at listing to ACLF 0–2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients >60 years of age. LAY SUMMARY: Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60 years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival

Effective transcription factor binding site prediction using a combination of optimization, a genetic algorithm and discriminant analysis to capture distant interactions

<p>Abstract</p> <p>Background</p> <p>Reliable transcription factor binding site (TFBS) prediction methods are essential for computer annotation of large amount of genome sequence data. However, current methods to predict TFBSs are hampered by the high false-positive rates that occur when only sequence conservation at the core binding-sites is considered.</p> <p>Results</p> <p>To improve this situation, we have quantified the performance of several Position Weight Matrix (PWM) algorithms, using exhaustive approaches to find their optimal length and position. We applied these approaches to bio-medically important TFBSs involved in the regulation of cell growth and proliferation as well as in inflammatory, immune, and antiviral responses (NF-κB, ISGF3, IRF1, STAT1), obesity and lipid metabolism (PPAR, SREBP, HNF4), regulation of the steroidogenic (SF-1) and cell cycle (E2F) genes expression. We have also gained extra specificity using a method, entitled SiteGA, which takes into account structural interactions within TFBS core and flanking regions, using a genetic algorithm (GA) with a discriminant function of locally positioned dinucleotide (LPD) frequencies.</p> <p>To ensure a higher confidence in our approach, we applied resampling-jackknife and bootstrap tests for the comparison, it appears that, optimized PWM and SiteGA have shown similar recognition performances. Then we applied SiteGA and optimized PWMs (both separately and together) to sequences in the Eukaryotic Promoter Database (EPD). The resulting SiteGA recognition models can now be used to search sequences for BSs using the web tool, SiteGA.</p> <p>Analysis of dependencies between close and distant LPDs revealed by SiteGA models has shown that the most significant correlations are between close LPDs, and are generally located in the core (footprint) region. A greater number of less significant correlations are mainly between distant LPDs, which spanned both core and flanking regions. When SiteGA and optimized PWM models were applied together, this substantially reduced false positives at least at higher stringencies.</p> <p>Conclusion</p> <p>Based on this analysis, SiteGA adds substantial specificity even to optimized PWMs and may be considered for large-scale genome analysis. It adds to the range of techniques available for TFBS prediction, and EPD analysis has led to a list of genes which appear to be regulated by the above TFs.</p

Associations of BCL-2 (RS17759659), CTLA-4 (RS231775), APO-1/FAS (RS2234767) genes polymorphisms with activity of proliferation and apoptosis in thyroid tissue of patients with nodular forms of goiter combined with autoimmune thyroiditis and thyroid adenoma

The study of apoptosis and proliferative activity in the thyroid gland (TG) tissue of patients with nodular goiter and autoimmune thyroiditis (NGAIT) and thyroid adenoma (TA) is based on the expression/density of Fas/FasL, BCL-2, p53, and Ki-67 markers assessment depending on the genetic polymorphisms of BCL-2 (rs17759659), CTLA-4 (rs231775) and APO-1/Fas (rs2234767) genes.Several mechanisms of thyroid cells' programmed killing are activated in NGAIT and TA with domination of Fas-induced apoptosis, which strongly associates with the BCL-2 gene's (rs17759659) promoter (F=25.33; p&lt;0.001) and almost six fold weaker associates with the CTLA-4 gene's (rs231775) promoter (F=4.23, p=0.017). Factors that decrease the likelihood of NGAIT and TA regardless of the CTLA-4 (rs231775) and APO-1/Fas (rs2234767) genes' genotypes are the high Ki-67 density and reduction of cells containing p53 or BCL-2 proteins (OR=0.07-0.17; 95% CI OR: 0.03-0.36; p&lt;0.001, and OR=0.08-0.11; 95% CI OR: 0.02-0.31; p&lt;0.001, re­spectively). High expression of surface Fas and FasL in lymphoid infiltration and de­struction of thyroid cells (stronger in GG-genotype carriers of the BCL-2 gene by 18.54% (pAA=0.043) and 36.18% (pAG=0.018), respectively) indicates the initiation of the external pathway of apoptosis through the caspase mechanism (effector caspase- 8)