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

Protecting the Kidney in Liver Transplant Recipients: Practice‐Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134132/1/ajt13765_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134132/2/ajt13765.pd

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

Thermodynamics and complex dielectric permittivity of mixed crystals of the Rb₁-x(NH₄)xH₂PO₄ type

We propose a pseudospin model for proton glasses of the Rb₁₋x(NH₄)xH₂PO₄(Rb₁₋x(ND₄)xD₂PO₄) type, which takes into account the energy levels of hydrogens (deuterons) around the PO₄ group, long-range interactions between the hydrogen bonds, and an internal random deformational field. Within the framework of a cluster approximation and a mean field approximation over the long-range interactions, we derive a system of equations for the state parameters for the regions which are in the ferroelectric and antiferroelectric states, as well as in the proton glass state. Within the Glauber dynamics approach, we obtain a system of equations for the frequency-dependent linear responses of polarization and the proton glass order parameter. We obtain a qualitative description of the temperature behavior of dielectric permittivities of the K₁₋x(ND₄)xD₂PO₄ and Rb₁₋x(NH₄)xH₂AsO₄ compounds at different frequencies. The origin of low-temperature peak in the imaginary part of dielectric permittivity in proton glasses is discussed.Запропонована псевдоспiнова модель протонних стекол типу Rb₁₋x(NH₄)xH₂PO₄(Rb₁₋x(ND₄)xD₂PO₄), яка враховує енергетичнi рiвнi протонiв (дейтронiв) бiля тетраедра PO₄, далекосяжну взаємодiю мiж водневими зв’язками i внутрiшнє хаотичне деформацiйне поле. В рамках кластерного наближення i наближення середнього поля по далекодiїї виведена система рiвнянь для параметрiв стану для областей, якi знаходяться в феро-, антифероелектричному станах, i в станi протонного скла. В рамках глауберiвської динамiки виведена система рiвнянь для частотнозалежних лiнiйних вiдгукiв полярiзацiї i параметра протонного скла. Отримано якiсний опис температурної поведiнки дiелектричних проникностей сполук K₁₋x(ND₄)xD₂PO₄ and Rb₁₋x(NH₄)xH₂AsO₄ при рiзних частотах. Обговорюються причини низькотемпературного пiку уявної частини дiелектричних проникностей в протонних стеклах

Constant regulation for stable CD8 T-cell functional avidity and its possible implications for cancer immunotherapy.

The functional avidity (FA) of cytotoxic CD8 T cells impacts strongly on their functional capabilities and correlates with protection from infection and cancer. FA depends on TCR affinity, downstream signaling strength, and TCR affinity-independent parameters of the immune synapse, such as costimulatory and inhibitory receptors. The functional impact of coreceptors on FA remains to be fully elucidated. Despite its importance, FA is infrequently assessed and incompletely understood. There is currently no consensus as to whether FA can be enhanced by optimized vaccine dose or boosting schedule. Recent findings suggest that FA is remarkably stable in vivo, possibly due to continued signaling modulation of critical receptors in the immune synapse. In this review, we provide an overview of the current knowledge and hypothesize that in vivo, codominant T cells constantly "equalize" their FA for similar function. We present a new model of constant FA regulation, and discuss practical implications for T-cell-based cancer immunotherapy

Mitochondrial transplantation for therapeutic use

Mitochondria play a key role in the homeostasis of the vast majority of the body’s cells. In the myocardium where mitochondria constitute 30 % of the total myocardial cell volume, temporary attenuation or obstruction of blood flow and as a result oxygen delivery to myocardial cells (ischemia) severely alters mitochondrial structure and function. These alterations in mitochondrial structure and function occur during ischemia and continue after blood flow and oxygen delivery to the myocardium is restored, and significantly decrease myocardial contractile function and myocardial cell survival. We hypothesized that the augmentation or replacement of mitochondria damaged by ischemia would provide a mechanism to enhance cellular function and cellular rescue following the restoration of blood flow. To test this hypothesis we have used a model of myocardial ischemia and reperfusion. Our studies demonstrate that the transplantation of autologous mitochondria, isolated from the patient’s own body, and then directly injected into the myocardial during early reperfusion augment the function of native mitochondria damaged during ischemia and enhances myocardial post-ischemic functional recovery and cellular viability. The transplanted mitochondria act both extracellularly and intracellularly. Extracellularly, the transplanted mitochondria enhance high energy synthesis and cellular adenosine triphosphate stores and alter the myocardial proteome. Once internalized the transplanted mitochondria rescue cellular function and replace damaged mitochondrial DNA. There is no immune or auto-immune reaction and there is no pro-arrhythmia as a result of the transplanted mitochondria. Our studies and those of others demonstrate that mitochondrial transplantation can be effective in a number of cell types and diseases. These include cardiac and skeletal muscle, pulmonary and hepatic tissue and cells and in neuronal tissue. In this review we discuss the mechanisms leading to mitochondrial dysfunction and the effects on cellular function. We provide a methodology for the isolation of mitochondria to allow for clinical relevance and we discuss the methods we and others have used for the uptake and internalization of mitochondria. We foresee that mitochondrial transplantation will be a valued treatment in the armamentarium of all clinicians and surgeons for the treatment of varied ischemic disorders, mitochondrial diseases and related disorders

Emergence of additional visible range photoluminescence due to aggregation of cyanine dye:astraphloxin on carbon nanotubes dispersed with anionic surfactant

Self-organization of organic molecules with carbon nanomaterials leads to formation of functionalized molecular nano-complexes with advanced features. We present a study of physical and chemical properties of carbon nanotube-surfactant-indocarbocyanine dye (astraphloxin) in water focusing on aggregation of the dye and resonant energy transfer from the dye to the nanotubes. Self-assembly of astraphloxin is evidenced in absorbance and photoluminescence depending dramatically on the concentrations of both the dye and surfactant in the mixtures. We observed an appearance of new photoluminescence peaks in visible range from the dye aggregates. The aggregates characterized with red shifted photoluminescence peaks at 595, 635 and 675 nm are formed mainly due to the presence of surfactant at the premicellar concentration. The energy transfer from the dye to the nanotubes amplifying near-infrared photoluminescence from the nanotubes is not affected by the aggregation of astraphloxin molecules providing important knowledge for further development of advanced molecular nano-complexes. The aggregation with the turned-on peaks and the energy transfer with amplified photoluminescence create powerful tools of visualization and/or detection of the nanotubes in visible and near-infrared spectral range, respectively, boosting its possible applications in sensors, energy generation/storage, and healthcare

Multiplex plasma protein assays as a diagnostic tool for lung cancer

Lack of the established noninvasive diagnostic biomarkers causes delay in diagnosis of lung cancer (LC). The aim of this study was to explore the association between inflammatory and cancer‐associated plasma proteins and LC and thereby discover potential biomarkers. Patients referred for suspected LC and later diagnosed with primary LC, other cancers, or no cancer (NC) were included in this study. Demographic information and plasma samples were collected, and diagnostic information was later retrieved from medical records. Relative quantification of 92 plasma proteins was carried out using the Olink Immuno‐Onc‐I panel. Association between expression levels of panel of proteins with different diagnoses was assessed using generalized linear model (GLM) with the binomial family and a logit‐link function, considering confounder effects of age, gender, smoking, and pulmonary diseases. The analysis showed that the combination of five plasma proteins (CD83, GZMA, GZMB, CD8A, and MMP12) has higher diagnostic performance for primary LC in both early and advanced stages compared with NC. This panel demonstrated lower diagnostic performance for other cancer types. Moreover, inclusion of four proteins (GAL9, PDCD1, CD4, and HO1) to the aforementioned panel significantly increased the diagnostic performance for primary LC in advanced stage as well as for other cancers. Consequently, the collective expression profiles of select plasma proteins, especially when analyzed in conjunction, might have the potential to distinguish individuals with LC from NC. This suggests their utility as predictive biomarkers for identification of LC patients. The synergistic application of these proteins as biomarkers could pave the way for the development of diagnostic tools for early‐stage LC detection

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