Miracle-dz/UniFAR-FTUs huggingface dataset:
Prognostic value of EGFR and KRAS in circulating tumor DNA in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis

EGFR (exon 19 and exon 21) mutations in patients with advanced non-small cell lung cancer (NSCLC) treated by EGFR-TKIs are associated with a better survival; while KRAS mutations predict a worse prognosis. However, there are divergent findings regarding the prognostic value of EGFR and KRAS mutations in circulating tumor DNA (ctDNA). We aimed to summarize the evidence for the use of circulating EGFR and KRAS mutations as prognostic factors in advanced NSCLC patients. We searched the network databases for studies reporting progression-free survival (PFS) and overall survival (OS) stratified by EGFR or KRAS mutations in ctDNA in advanced NSCLC patients. Thirteen studies enrolling 2,293 patients were reviewed. Correlation of circulating EGFR or KRAS mutations with patients’ prognosis was assessed by meta-analysis. The pooled analyses showed that EGFR mutations in ctDNA significantly prolong PFS (HR=0.64,95% CI 0.51-0.81, I2=0%, p=0.0002), namely, in patients treated by EGFR-TKIs. There is a trend to have a prolonged OS for advanced NSCLC patients with circulating EGFR mutations who were treated by EGFR-TKIs (HR=0.79, 95% CI 0.52-1.21, I2=0, p=0.28). KRAS mutations detected in ctDNA predict a worse PFS (HR=1.83, 95% CI 1.40-2.40, p<0.0001) and OS (HR=2.07, 95% CI 1.54-2.78, p<0.00001) in advanced NSCLC patients treated by chemotherapy. Sensitivity analyses and subgroup analyses demonstrated the stability of our conclusion. Our analysis showed that EGFR mutations in ctDNA predicted a better PFS, in particular in advanced NSCLC patients treated by EGFR-TKIs. KRAS mutations in ctDNA indicated a worse PFS and OS in patients treated by chemotherapy.
A prospective, multi‐center study of the chocolate balloon in femoropopliteal peripheral artery disease: The Chocolate BAR registry

The Chocolate BAR study is a prospective multicenter post‐market registry designed to evaluate the safety and performance of the Chocolate percutaneous transluminal angioplasty balloon catheter in a broad population with symptomatic peripheral arterial disease. The primary endpoint is acute procedural success (defined as ≤30% residual stenosis without flow‐limiting dissection); secondary long‐term outcomes include freedom from target lesion revascularization (TLR), major unplanned amputation, survival, and patency. A total of 262 patients (290 femoropopliteal lesions) were enrolled at 30 US centers between 2012 and 2014. The primary endpoint of procedure success was achieved in 85.1% of cases, and freedom from stenting occurred in 93.1%. Bail out stenting by independent adjudication occurred in 1.6% of cases and there were no flow limiting dissections. There was mean improvement of 2.1 Rutherford classes (±1.5) at 12‐months, with 78.5% freedom from TLR, 97.2% freedom from major amputation, and 93.3% freedom from all‐cause mortality. Core Lab adjudicated patency was 64.1% at 12 months. Use of the Chocolate balloon in an “all‐comers” population achieved excellent procedural outcomes with low dissection rates and bailout stent use.
PolyC-binding proteins enhance expression of the CDK2 cell cycle regulatory protein via alternative splicing

Abstract The PolyC binding proteins (PCBPs) impact alternative splicing of a subset of mammalian genes that are enriched in basic cellular functions. Here, we focus our analysis on PCBP-controlled cassette exon-splicing within the cell cycle control regulator cyclin-dependent kinase-2 (CDK2) transcript. We demonstrate that PCBP binding to a C-rich polypyrimidine tract (PPT) preceding exon 5 of the CDK2 transcript enhances cassette exon inclusion. This splice enhancement is U2AF65-independent and predominantly reflects actions of the PCBP1 isoform. Remarkably, PCBPs’ control of CDK2 ex5 splicing has evolved subsequent to mammalian divergence via conversion of constitutive exon 5 inclusion in the mouse CDK2 transcript to PCBP-responsive exon 5 alternative splicing in humans. Importantly, exclusion of exon 5 from the hCDK2 transcript dramatically represses the expression of CDK2 protein with a corresponding perturbation in cell cycle kinetics. These data highlight a recently evolved post-transcriptional pathway in primate species with the potential to modulate cell cycle control.
Dysfunctional telomeres induce p53‐dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation

Aging is associated with progressive telomere shortening, resulting in the formation of dysfunctional telomeres that compromise tissue proliferation. However, dysfunctional telomeres can limit tumorigenesis by activating p53‐dependent cellular senescence and apoptosis. While activation of both senescence and apoptosis is required for repress tumor formation, it is not clear which pathway is the major tumor suppressive pathway in vivo. In this study, we generated Eμ‐myc; Pot1b∆/∆ mouse to directly compare tumor formation under conditions in which either p53‐dependent apoptosis or senescence is activated by telomeres devoid of the shelterin component Pot1b. We found that activation of p53‐dependent apoptosis plays a more critical role in suppressing lymphoma formation than p53‐dependent senescence. In addition, we found that telomeres in Pot1b∆/∆; p53−/− mice activate an ATR‐Chk1‐dependent DNA damage response to initiate a robust p53‐independent, p73‐dependent apoptotic pathway that limited stem cell proliferation but suppressed B‐cell lymphomagenesis. Our results demonstrate that in mouse models, both p53‐dependent and p53‐independent apoptosis are important to suppressing tumor formation.
Formin-mediated actin polymerization at cell–cell junctions stabilizes E-cadherin and maintains monolayer integrity during wound repair

Cadherin-mediated cell–cell adhesion is required for epithelial tissue integrity in homeostasis, during development, and in tissue repair. Fmnl3 and mDia1 cooperate in stabilizing E-cadherin at cell–cell junctions and facilitate strong cell adhesion and monolayer cohesion during collective cell migration.
Nutrient additions to a tropical rain forest drive substantial soil carbon dioxide losses to the atmosphere

Terrestrial biosphere–atmosphere carbon dioxide (CO2) exchange is dominated by tropical forests, where photosynthetic carbon (C) uptake is thought to be phosphorus (P)-limited. In P-poor tropical forests, P may also limit organic matter decomposition and soil C losses. We conducted a field-fertilization experiment to show that P fertilization stimulates soil respiration in a lowland tropical rain forest in Costa Rica. In the early wet season, when soluble organic matter inputs to soil are high, P fertilization drove large increases in soil respiration. Although the P-stimulated increase in soil respiration was largely confined to the dry-to-wet season transition, the seasonal increase was sufficient to drive an 18% annual increase in CO2 efflux from the P-fertilized plots. Nitrogen (N) fertilization caused similar responses, and the net increases in soil respiration in response to the additions of N and P approached annual soil C fluxes in mid-latitude forests. Human activities are altering natural patterns of tropical soil N and P availability by land conversion and enhanced atmospheric deposition. Although our data suggest that the mechanisms driving the observed respiratory responses to increased N and P may be different, the large CO2 losses stimulated by N and P fertilization suggest that knowledge of such patterns and their effects on soil CO2 efflux is critical for understanding the role of tropical forests in a rapidly changing global C cycle.
Association of adrenal hormone metabolites and mortality over a 6-year follow-up in COPD patients with acute exacerbation

Abstract Background: The release of hormones from the adrenal gland is vital in acute and chronic illnesses such as chronic obstructive pulmonary disease (COPD) involving recurrent exacerbations. Using a metabolomic approach, we aim to investigate associations of different adrenal hormone metabolites with short- and long-term mortality in COPD patients. Methods: We prospectively followed 172 COPD patients (median age 75 years, 62% male) from a previous Swiss multicenter trial. At baseline, we measured levels of a comprehensive spectrum of adrenal hormone metabolites, including glucocorticoid, mineralocorticoid and androgen hormones by liquid chromatography coupled with tandem mass spectrometry (MS). We calculated Cox regression models adjusted for gender, age, comorbidities and previous corticosteroid therapy. Results: Mortality was 6.4% after 30 days and increased to 61.6% after 6 years. Higher initial androgen hormones predicted lower long-term mortality with significant results for dehydroepiandrosterone (DHEA) [adjusted hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70–0.98; p=0.026] and dehydroepiandrosterone sulfate (DHEA-S) (adjusted HR, 0.68; 95% CI, 0.50–0.91; p=0.009). An activation of stress hormones (particularly cortisol and cortisone) showed a time-dependent effect with higher levels pointing towards higher mortality at short term, but lower mortality at long term. Activation of the mineralocorticoid axis tended to be associated with increased short-term mortality (adjusted HR of aldosterone, 2.76; 95% CI, 0.79–9.65; p=0.111). Conclusions: Independent of age, gender, corticosteroid exposure and exacerbation type, adrenal hormones are associated with mortality at short and long term in patients with COPD exacerbation with different time-dependent effects of glucocorticoids, androgens and mineralocorticoids. A better physiopathological understanding of the causality of these effects may have therapeutic implications.
A CMOS finite impulse response filter with a crossover traveling wave topology for equalization up to 30 Gb/s

This paper describes a fully differential 3-tap finite impulse response filter in 90-nm CMOS. A traditional traveling wave filter topology is modified to alleviate its inherent delay-bandwidth-gain tradeoffs. Each tap gain is comprised of two transconductors whose outputs superimpose with the same group delay, similar to a distributed amplifier. This doubles the bandwidth of the filter for a given tap spacing and gain. Digital control is provided for the tap gains, an integrated pre-amplifier, and tuning varactors. Coupled differential spirals are used in the delay lines to help the design fit into an area 600 /spl mu/m/spl times/500 /spl mu/m. A 1-V supply voltage and 25-mW power consumption are enabled by the use of parallel differential pairs for sign control of the transconductances instead of Gilbert cell amplifiers. The input return loss is better than 16 dB and the output return loss is better than 9 dB up to 30 GHz. Equalization of NRZ data over a coaxial cable channel was demonstrated up to 30 Gb/s, making it faster than any previously reported CMOS equalizer.
Hand gestures support word learning in patients with hippocampal amnesia

Co‐speech hand gesture facilitates learning and memory, yet the cognitive and neural mechanisms supporting this remain unclear. One possibility is that motor information in gesture may engage procedural memory representations. Alternatively, iconic information from gesture may contribute to declarative memory representations mediated by the hippocampus. To investigate these alternatives, we examined gesture's effects on word learning in patients with hippocampal damage and declarative memory impairment, with intact procedural memory, and in healthy and in brain‐damaged comparison groups. Participants learned novel label‐object pairings while producing gesture, observing gesture, or observing without gesture. After a delay, recall and object identification were assessed. Unsurprisingly, amnesic patients were unable to recall the labels at test. However, they correctly identified objects at above chance levels, but only if they produced a gesture at encoding. Comparison groups performed well above chance at both recall and object identification regardless of gesture. These findings suggest that gesture production may support word learning by engaging nondeclarative (procedural) memory.
LIPID NANOPARTICLES: APPLICATION IN CANCER THERAPY

Several obstacles frequently encountered with anticancer drugs, such as normal tissue toxicity, stability, poor specificity and a high incidence of drug resistant tumor cells, are overcome by delivering them using Lipid Nanoparticles (LNs). LNs include Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), which have been developed by most of researchers for cancer therapy. The SLNs and NLCs because of submicron-sized particulate matter may preferentially extravasate into the tumor and be retained there to achieve passive tumor targeting. The advances in surface-engineering technology modified the surface physico-chemical properties of LNs to target them to the tissue of interest. This maximizes the amount of drug that can reach the targeted tumor sites and minimizes systemic drug toxicity. The emergence of the newer forms of LNs such as polymer– lipid hybrid nanoparticle and long-circulating SLN may further expand the role of this versatile drug carrier in cancer therapy. In the present review, an attempt has been made to highlight the importance of solid lipid nanoparticles and nanostructured lipid carriers in anticancer drug delivery. The discussion includes obstacles in cancer therapy, rationale of using lipid nanoparticles in cancer therapy, significant anticancer activity of LNs -encapsulated cytotoxic drugs, future directions for SLN and NLC- based delivery systems in cancer therapy. In the near future, LNs will be further improved to deliver anticancer compounds in a more efficient, specific and safer manner.
Using Sensors and Generators of H2O2 to Elucidate the Toxicity Mechanism of Piperlongumine and Phenethyl Isothiocyanate.

AIMS Chemotherapeutics target vital functions that ensure survival of cancer cells, including their increased reliance on defense mechanisms against oxidative stress compared to normal cells. Many chemotherapeutics exploit this vulnerability to oxidative stress by elevating the levels of intracellular reactive oxygen species (ROS). A quantitative understanding of the oxidants generated and how they induce toxicity will be important for effective implementation and design of future chemotherapeutics. Molecular tools that facilitate measurement and manipulation of individual chemical species within the context of the larger intracellular redox network present a means to develop this understanding. In this work, we demonstrate the use of such tools to elucidate the roles of H2O2 and glutathione (GSH) in the toxicity mechanism of two ROS-based chemotherapeutics, piperlongumine and phenethyl isothiocyanate. RESULTS Depletion of GSH as a result of treatment with these compounds is not an important part of the toxicity mechanisms of these drugs and does not lead to an increase in the intracellular H2O2 level. Measuring peroxiredoxin-2 (Prx-2) oxidation as evidence of increased H2O2, only piperlongumine treatment shows elevation and it is GSH independent. Using a combination of a sensor (HyPer) along with a generator (D-amino acid oxidase) to monitor and mimic the drug-induced H2O2 production, it is determined that H2O2 produced during piperlongumine treatment acts synergistically with the compound to cause enhanced cysteine oxidation and subsequent toxicity. The importance of H2O2 elevation in the mechanism of piperlongumine promotes a hypothesis of why certain cells, such as A549, are more resistant to the drug than others. INNOVATION AND CONCLUSION The approach described herein sheds new light on the previously proposed mechanism of these two ROS-based chemotherapeutics and advocates for the use of both sensors and generators of specific oxidants to isolate their effects. Antioxid. Redox Signal. 24, 924-938.
Lifetime abuse and perceived social support among the elderly: a study from seven European countries

Background Being a victim of abuse during one's life course may affect social relations in later life. The aims of this study were to: (i) examine the association between lifetime abuse and perceived social support and (ii) identify correlates of perceived social support among older persons living in seven European countries. Methods A sample of 4467 women and men aged 60-84 years living in Germany, Greece, Italy, Lithuania, Portugal, Spain and Sweden was collected through a cross-sectional population-based study. Abuse (psychological, physical, sexual, financial and injury) was assessed through interviews or interviews/self-response questionnaire based on the Conflict Tactics Scale-2 and the UK study on elder abuse. Perceived social support was assessed by the Multidimensional Scale of Perceived Social Support. Results Victims of lifetime abuse perceived poorer social support in later life. Multivariate analyses showed that high levels of perceived social support were associated with being from Greece and Lithuania (compared to Germany), being female, not living alone, consuming alcohol and physical activity. Poorer perceived social support was associated with being from Portugal, being old, having social benefits as the main source of income, experiencing financial strain and being exposed to lifetime psychological abuse and injuries. Conclusions Our findings showed that exposure to psychological abuse and injuries across the lifespan were associated with low levels of perceived social support, emphasizing the importance of detection and appropriate treatment of victims of abuse during their life course. Future research should focus on coping strategies buffering the negative effects of abuse on social relationships.
TRACE ELEMENTS ANALYSIS OF CROPS AND VEGETABLES GROWN AROUND INDUSTRIAL AREAS OF FAISALABAD AND GUJRANWALA CITIES USING INAA AND AAS

Industrial effluents pollution is a source of risk to the health of people living in industrial cities of Pakistan. Most of the untreated effluents are discharged to the nearby agricultural fields that pollutes the vegetation grown in such soil. A majority of the industries are not equipped with suitable recycling and effluent treatment plants. Consequently, toxic metals enter our food chain and results in significant health risks and serious diseases. In order to evaluate the concentration of toxic metals (namely As, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sb and Se), in crops and vegetable samples collected from the irrigated areas of Faisalabad and Gujranwala regions. Neutron activation analysis (NAA) and atomic absorption spectrometric (AAS) techniques have been used. All the observed metal concentrations were higher than the reported literature values. Moreover, the highest values of toxic metals of As (0.44±0.03 µg/g) and Co (0.5±0.01 µg/g), Mn (45.3±2.0 µg/g) and Sb (0.1±0.01 µg/g), Se (1.28±0.06 µg/g) and Pb (3.84±0.27 µg/g) were found in tomato, bitter gourd and rice samples respectively.
Design & Simulation of Ring Shape Wide Band Antenna Using DGS for Wireless Application

The design of a low-cost wideband microstrip antenna for wireless communication is shown in this paper. The antenna, which is microstrip-line fed, has a partial ground plane flushed with the feed line. The substrate is based on an inexpensive FR4 material. It has a rectangular split-ring slot enclosed inside a rectangular patch. The inclusion of the split-ring slot and the U-shaped slot in the partial ground plane gives resonance at multiple frequencies.
Porcine intestinal yeast species, Kazachstania slooffiae, a new potential protein source with favourable amino acid composition for animals

There is little information about Kazachstania slooffiae which dominates among other yeasts in the pigs' intestine. Therefore, the aims of this study were to characterise the yeast cell contents and to investigate which nitrogen sources, organic acids and alcohols may be utilised or produced by this species. The results showed that, K. slooffiae could use urea, ammonium sulphate, peptides and single amino acids and produce thereby ethanol and formic acid. However, this yeast did not metabolise amino acids, lactic, butyric, propionic and acetic acids as sole carbon source. Using a global metabolite profiling approach employing gas chromatography and high-resolution liquid chromatography mass spectrometry, was found that the amount of peptides and dehydroascorbic acid considerably increased in the fermentation residues after yeast cultivation. It is noteworthy that the cells of K. slooffiae had higher contents of nitrogen and total amino acids (especially lysine) than the cells of nutritional yeast (Saccharomyces cerevisiae). This study indicates that due to potential production of peptides and formic acid in the intestinal tract, K. slooffiae might have an impact on the gut health. Moreover, from a nutritional standpoint, the cells of this yeast can be a good source of protein with useful amino acid composition for animal.
Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.
Ultraviolet-induced birefringence in hydrogen-loaded optical fiber

A precision phase-shifting approach to fabricate various phase-shifted gratings using different combinations of polarized ultraviolet (UV) light is demonstrated. In doing so, the difference between s- and p-polarized light reported by others is confirmed. However, we reveal added complexity for the role of hydrogen and deuterium in the UV-induced process. Previous arguments for the origins are systematically ruled out by reviewing existing literature. We note that the birefringence is made up of at least two components with different thermal stabilities, one consistent simply with molecular hydrogen being present in the system. Overall the birefringence, by deduction, is associated with anisotropy in hydrogen reactions within the fiber. As a result they lead, through known mechanisms of dilation in glass, to anisotropic stress relaxation that can be annealed out, with or without hydrogen remaining, at low temperatures close to 125 °C.