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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

Sternal wound complications following sternotomy need a multidisciplinary approach in high-risk postoperative cardiac surgical patients. Poorly controlled pain during surgical management of such wounds increases cardiovascular stress and respiratory complications. Multimodal analgesia including intravenous opioids, non-opioid analgesics, and regional anesthesia techniques, like central neuraxial blocks and fascial plane blocks, have been described. Pecto-intercostal fascial plane block (PIFB), a novel technique, has been effectively used in patients undergoing cardiac surgery. Under ultrasound (US) guidance PIFB is performed with the aim of depositing local anesthetic between two superficial muscles, namely the pectoralis major muscle and the external intercostal muscle. The authors report a series of five cases where US-guided bilateral PIFB was used in patients undergoing sternal wound debridement. Patients had excellent analgesia intraoperatively as well as postoperatively for 24 hours with minimal requirement of supplemental analgesia. None of the patients experienced complications due to PIFB administration. The authors concluded that bilateral PIFB can be effectively used as an adjunct to multimodal analgesia with general anesthesia and as a sole anesthesia technique in selected cases of sternal wound debridement.

As the world moves towards a sustainable future, there is a need for efficient integration of intermittent energy sources (IES) sources with intelligent energy grids. Electricity from IES (such as wind, solar, hydro, etc.) relies on various environmental factors and introduces significant uncertainties. This, in turn, impacts the financial viability of the investment plan for energy utilities and demands the deployment of efficient electricity price forecasting (EPF) approaches. Many existing EPF approaches show limited performance due to significant nonlinearity, high volatility, and continuous evolutions of exogenous variables. For such applications, data-driven approaches such as deep learning (DL) have shown promising forecasting capabilities in recent years. Therefore, this work comprehensively analyses the performance of various DL architectures for EPF across five major global deregulated electricity markets. Furthermore, to improve the performance, we propose a distinct approach by integrating Monte Carlo dropouts and weighted constraints in a DL architecture. The performance of model is assessed against regression-based models and benchmark DL architectures in terms of error matrices and computational time. The results demonstrate that the presented methodology enables the identification of the most appropriate DL architecture and demonstrates improved forecasting performance for electricity markets when compared against benchmarks.

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Background: In India, neonatal mortality contributes to over 64% of infant deaths, mostly occurring during the first week of life. Mortality rate in second month of life is also higher than at later ages. Delay in identification of warning signs of neonatal illness naturally postpones the initiation of treatment and referral to hospital. Materials and Methods: The study aimed to explore the perception of care givers regarding danger signs of illness and practices followed in young infants. Care givers who cared for the sick young infants during last six months were recruited using a convenient sampling technique and qualitative research approach. Five semi-structured interviews and one FGD were conducted using an interview and FGD guide. Data was analyzed manually by reading and rereading the transcribed verbatim leading to the emergence of themes, subthemes, and codes. Results: Data explored that excessive crying was perceived as a danger sign by entire mothers, and many of them were unable to recognize important warning signs. The delay in decision making for medical care-seeking also shows dwindling awareness. Additionally, mothers were adapting few unhygienic practices as home remedies leading to worsening the symptoms and making a call for additional infections which needs to be addressed by the health authorities at community level. Conclusion: Pronounced efforts are expected to raise mindfulness of mothers toward the significance of early identification of neonatal danger signs to stave off the high magnitude of neonatal mortality. Inclusion of excessive crying as neonatal danger sign is recommended as well.

Introduction: Left ventricular (LV) diastolic dysfunction is common on preoperative screening among patients undergoing surgery. There is no simple screening test at present to suspect LV diastolic dysfunction. This study was aimed to test the hypothesis, whether elastic recoil signal (ERS) on tissue Doppler imaging of mitral annulus (MA TDI) can be used as a qualitative test to differentiate patients from normal LV diastolic function versus patients with LV diastolic dysfunction. Methods: This was a prospective cross-sectional observational study of patients admitted for elective surgeries. Normal diastolic function and categorization of LV diastolic dysfunction into severity grades I, II, or III were performed as per the American Society of Echocardiography/ European Associationof Cardio Vascular Imaging (ASE/EACVI) recommendations for LV diastolic dysfunction. Results: There were 41 (61%) patients with normal LV diastolic function and 26 (39%) patients with various grades of LV diastolic dysfunction. In 38 out of 41 patients with normal LV diastolic function, the characteristic ERS was identified. The ERS was absent in all the patients with any grade of LV diastolic dysfunction. Consistency of identification of ERS on echocardiography was tested with a good interobserver variability coefficient of 0.94 (P-value

INTRODUCTION: Autism is a heterogeneous neurodevelopmental disorder that influences a child's ability to think, learn, communicate, and interact socially and possess behavioral problems. It has also been observed to be associated with several medical conditions, including certain chromosomal disorders like Down syndrome (DS). Several studies have shown autistic individuals with DS. The main objective of the present study is to screen for chromosomal abnormalities in autistic children with DS characteristics in the North Karnataka population, India. MATERIALS AND METHODS: Chromosome analysis of peripheral blood of four DS children with autistic characteristics was performed to examine the chromosomal abnormalities, which were confirmed by fluorescent in situ hybridization. RESULTS: Childhood Autism Rating Scale score was calculated initially to assess the severity of autism. All four cases were found to have autism with DS. Out of four cases, three (75%) were found to be trisomy 21 and 1 (25%) had a trisomy 21 mosaic condition. CONCLUSION: Our study confirms the chromosomal abnormality present in autistic children with DS characteristics and these findings will contribute in several ways to the diagnosis and treatment of the genetic cause of autism with other comorbidities or vice versa.

Abstract Background Bovine mastitis continues to remain as the most challenging disease in dairy cattle, as a result improvement of selection methods has great economic relevance while a deeper understanding of the genetic mechanisms regulating milk production traits and mastitis is of general scientific interest. Objectives This study aimed to evaluate the association of SNPs of the LAP3 and SIRT1 genes with estimated breeding values (EBVs) of milk production traits and clinical mastitis in dairy cattle of Indian origin. Methods DNA samples from 263 animals (Sahiwal and Karan Fries cattle) were genotyped by PCR‐RFLP to assess their pattern of genetic variation. EBVs of milk production traits and phenotypic records of incidences of clinical mastitis were used for association analysis. Results A total of 9 SNPs were identified, including three (rs110932626: A>G, rs716493845: C>T and rs43702363: C>T) in intron 12, four (g.24904G>C, rs110839532: G>T, rs43702361: T>C and rs41255599: C>T) in exon 13 and within 3’UTR of LAP3 gene and two (rs110250233: G>A and rs42140046: C>G) in the promoter region of SIRT1 gene. Eight of these identified SNPs were chosen for subsequent genotyping and association analyses. Association analysis revealed that SNP rs41255599: C>T was significantly associated with lactation milk yield, 305‐day milk yield, 305‐day fat yield, 305‐day solid not fat yield, lactation length and incidence of clinical mastitis (p G and rs43702363: C>T showed significant association with 305‐day milk yield. Conclusion Overall, these findings provide evidence for association of the LAP3 gene with milk production traits and clinical mastitis in dairy cattle, indicating the potential role of LAP3 variants in these traits.

Background and Aims: Left ventricular (LV) systolic dysfunction is a common cause of hemodynamic disturbance perioperatively and is associated with increased morbidity and mortality. Echocardiographic evaluation of left ventricular systolic function (LVSF) has great clinical utility. This study was aimed to test the hypothesis that LVSF assessed by an anesthetist using mitral valve E Point Septal Separation (EPSS) has a significant correlation with that assessed using modified Simpson's method perioperatively. Methods: This prospective observational study included 100 patients scheduled for elective surgeries. Transthoracic echocardiography (TTE) was performed preoperatively within 24 hours of surgery by an anesthetist as per American Society of Echocardiography (ASE) guidelines. EPSS measurements were obtained in parasternal long-axis view while volumetric assessment of LV ejection fraction (EF) used apical four-chamber view. Bivariate analysis of EPSS and LV EF was done by testing Pearson correlation coefficient. Receiver Operating Characteristic (ROC) curve constructed to obtain area under curve (AUC) and Youden's Index. Results: The mean value of mitral valve EPSS was 7.18 ± 3.95 mm. The calculated mean LV EF value using volumetric analysis was 56.31 ± 11.92%. LV dysfunction as per ASE guidelines is present in 28% of patients. EPSS was statistically significantly related to LV EF negatively with a Pearson coefficient of -0.74 (P < 0.0001). AUC of ROC curve 0.950 (P < 0.0001) suggesting a statistically significant correlation between EPSS and LV EF. Youden's index of EPSS value 7 mm was obtained to predict LV systolic dysfunction. Conclusion: Mitral valve EPSS shows a significant negative correlation with gold standard LVEF measurement for LVSF estimation. It can very well be used to assess LVSF perioperatively by anesthetists with brief training.

A novel nano-formulation (NF) that sensitizes Acinetobacter baumannii (AB) to otherwise ineffective colistin is described in the present study. Infections due to multidrug resistant (MDR) AB represent a major therapeutic challenge, especially in situations of pre-existing colistin resistance (colR). Subsequently, boosting the effectiveness of colistin would be a better alternative tactic to treat AB infections rather than discovering a new class of antibiotics. We have previously demonstrated an NF comprising self-assembled guanidinium and ionic silver nanoparticles [AD-L@Ag(0)] to have anti-biofilm and bactericidal activity. We report NF AD-L@Ag(0) for the very first time for the potentiation of colistin in Gram-negative colistin-resistant bacteria. Our results implied that a combination of clinically relevant concentrations of colistin and AD-L@Ag(0) significantly decreased colistin-resistant AB bacterial growth and viability, which otherwise was elevated in the presence of only colistin. In this study, we have described various combinations of minimum inhibitory concentration (MIC) of colistin (MICcol, 1/2 MICcol, and 1/4 MICcol) and that of AD-L@Ag(0) [MICAD-L@Ag(0), 1/2 MICAD-L@Ag(0), and 1/4 MICAD-L@Ag(0)] and tested them against MDR AB culture. The results (in broth as well as in solid media) signified that AD-L@Ag(0) was able to potentiate the anti-microbial activity of colistin at sub-MIC concentrations. Furthermore, the viability and metabolic activity of bacterial cells were also measured by CTC fluorescence assay and ATP bioluminescence assay. The results of these assays were in perfect concordance with the scores of cultures (colony forming unit and culture turbidity). In addition, quantitative real-time PCR (qRT-PCR) was performed to unveil the expression of selected genes, DNAgyrA, DNAgyrB, and dac. These genes introduce negative supercoiling in the DNA, and hence are important for basic cellular processes. These genes, due to mutation, modified the Lipid A of bacteria, further resisting the uptake of colistin. Therefore, the expression of these genes was upregulated when AB was treated with only colistin, substantiating that AB is resistant to colistin, whereas the combinations of MICcol + MICAD-L@Ag(0) downregulated the expression of these genes, implying that the developed formulation can potentiate the efficiency of colistin. In conclusion, AD-L@Ag(0) can potentiate the proficiency of colistin, further enhancing colistin-mediated death of AB by putatively disrupting the outer membrane (OM) and facilitating bacterial death.

Numerous human pathogens, especially Gram-negative bacteria, are able to enter the viable-but-non-culturable (VBNC) state when they are exposed to environmental stressors and pose the risk of being resuscitated and causing infection after the removal of the trigger. Widely used food preservatives like weak organic acids are potential VBNC inducers in food processing and packaging facilities but have only been reported for food-borne pathogens. In the present study, it is demonstrated for the first time that one such agent, formic acid (FA), can induce a VBNC state at food processing, storage, and distribution temperatures (4, 25, and 37°C) with a varied time of treatment (days 4–10) in pathogenic Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. The use of hospital-associated pathogens is critical based on the earlier reports that demonstrated the presence of these bacteria in hospital kitchens and commonly consumed foods. VBNC induction was validated by multiple parameters, e.g., non-culturability, metabolic activity as energy production, respiratory markers, and membrane integrity. Furthermore, it was demonstrated that the removal of FA was able to resuscitate VBNC with an increased expression of multiple virulence and Antimicrobial Resistance (AMR) genes in both pathogens. Since food additives/preservatives are significantly used in most food manufacturing facilities supplying to hospitals, contamination of these packaged foods with pathogenic bacteria and the consequence of exposure to food additives emerge as pertinent issues for infection control, and control of antimicrobial resistance in the hospital setting.

Cognitive radios are expected to play an important role in capturing the constantly growing traffic interest on remote networks. To improve the usage of the radio range, a cognitive radio hub detects the weather, evaluates the open-air qualities, and then makes certain decisions and distributes the executives’ space assets. The cognitive radio works in tandem with artificial intelligence and artificial intelligence methodologies to provide a flexible and intelligent allocation for continuous production cycles. The purpose is to provide a single source of information in the form of a survey research to enable academics better understand how artificial intelligence methodologies, such as fuzzy logics, genetic algorithms, and artificial neural networks, are used to various cognitive radio systems. The various artificial intelligence approaches used in cognitive radio engines to improve cognition capabilities in cognitive radio networks are examined in this study. Computerized reasoning approaches, such as fuzzy logic, evolutionary algorithms, and artificial neural networks, are used in the writing audit. This topic also covers cognitive radio network implementation and the typical learning challenges that arise in cognitive radio systems.

The premises for the potential success of molecular breeding is the ability to identify major genes associated with important dairy related traits. The present study was taken up with the objectives to identify single nucleotide polymorphism (SNP) of bovine MASP2 and SIRT1 genes and its effect on estimated breeding values (EBVs) and to estimate genetic parameters for lactation milk yield (LMY), 305-day milk yield (305dMY), 305-day fat yield (305dFY), 305-day solid not fat yield (305dSNFY) and lactation length (LL) in Sahiwal dairy cattle to devise a promising improvement strategy. Genetic parameters and breeding values of milk production traits were estimated from 935 Sahiwal cattle population (1979-2019) reared at National Dairy Research Institute at Karnal, India. A total of 7 SNPs, where one SNP (g.499C>T) in exon 2 and four SNPs (g.576G>A, g.609T>C, g.684G>T and g.845A>G) in exon 3 region of MASP2 gene and 2 SNPs (g.-306T>C and g.-274G>C) in the promoter region of SIRT1 gene were identified in Sahiwal cattle population. Five of these identified SNPs were chosen for further genotyping by PCR-RFLP and association analysis. Association analysis was performed using estimated breeding values (n = 150) to test the effect of SNPs on LMY, 305dMY, 305dFY, 305dSNFY and LL. Association analysis revealed that, three SNP markers (g.499C>T, g.609T>C and g.-306T>C) were significantly associated with all milk yield traits. The estimates for heritability using repeatability model for LMY, 305dMY, 305dFY, 305dSNFY and LL were low, however the corresponding estimates from first parity were 0.20±0.08, 0.17±0.08, 0.13±0.09, 0.13±0.09 and 0.24, respectively. The repeatability estimates were moderate to high indicating consistency of performance over the parities and hence reliability of first lactation traits. Genetic correlations among the traits of first parity were high (0.55 to 0.99). From the results we could conclude that optimum strategy to improve the Sahiwal cattle further would be selecting the animals based on their first lactation 305dMY. Option top include the significant SNP in selection criteria can be explored. Taken together, a 2-stage selection approach, select Sahiwal animals early for the SNP and then on the basis of first lactation 305dMY will help to save resources.

Records on first lactation test day traits pertaining to Sahiwal cattle maintained at ICAR-National Dairy Research Institute over a period of 29 years (1988-2016) were utilized in this study. Test day traits, viz. test day milk yields (TDMY), test day fat yields (TDFY) and test day solid not fat yields (TDSNFY) were recorded at monthly intervals and a total of 11 test days were included up to 305 days lactation. Effect of different genetic and non-genetic factors on test day traits was assessed using least-squares mixed model. Random effect of sire and fixed effect of period of calving as well as season of calving had significant effect on different test day traits, however, age group at first calving had no significant effect in the present study. Paternal half-sib correlation method was used to estimate the heritability of different test day traits. Heritability estimates as observed for different test day traits varied from low to high. Heritability for test day milk yields, test day fat yields and test day SNF yields ranged from 0.06 (TDMY8) to 0.40(TDMY2), 0.09 (TDFY11) to 0.62 (TDFY10) and 0.06 (TDSNFY5) to 0.44 (TDSNFY2), respectively. Highest heritability of test day milk yield and test day solid not fat yield in second test day suggested that this test day could be used as early selection criteria for these two traits.

TUSC3 resides on chromosome 8p which is frequently deleted in advanced stage tumors. Here, the authors show that TUSC3 loss mediated by miR-224/-520c promotes NSCLC metastasis where it enhances ATF-6α-dependent UPR and HRD-1 dependent ERAD, which in turn suppress p53-NM23H1/2 tumor suppressor pathway.

Background and Objectives: Empagliflozin, a sodium glucose cotransporter-2 inhibitor, was recently evaluated in a randomized, controlled trial (RCT) in drug-naïve Type 2 diabetes mellitus (T2DM) patients managed on diet and exercise therapy. Efficacy and safety of empagliflozin in Indian subgroup of patients from a 76-week extension study of the initial multicentric RCT are reported in this article. Materials and Methods: In this study, patients were randomized to empagliflozin 10 mg (E10, n = 24), empagliflozin 25 mg (E25, n = 29), placebo (n = 28) and sitagliptin 100 mg (S100, n = 27). Exploratory efficacy endpoints were changed from baseline to week 76 in glycosylated hemoglobin (HbA1c, %) and fasting blood glucose (mg/dL) along with body weight (kg) and blood pressure (BP) (mmHg) reduction. Safety analysis included clinically relevant adverse events (AEs). Results: In 108 randomized patients, adjusted mean reduction in HbA1c compared to placebo was significant with E10 (−0.81, 95% confidence interval (CI) −1.33, −0.28; P = 0.0029) and E25 (−1.11, 95% CI − 1.60, −0.61; P < 0.0001). HbA1c below 7% at week 76 was achieved in significantly higher number of patients with E10 (20.8%, P < 0.0001) and E25 (28.0%, P < 0.0001). There was significant reduction in adjusted mean weight as compared to placebo with E10 (−1.41, 95% CI − 2.51, −0.31; P = 0.0125) and E25 (−1.50, 95% CI − 2.54, −0.46; P = 0.0051) but nonsignificant with S100 (−0.75 95% CI − 1.86, −0.36; P = 0.1842). BP reduction was numerically higher with empagliflozin compared to placebo. AEs were similar in all treatment groups except for genital infections which were more common in E10 (20.8%) but not in E25 (3.4%) as compared to placebo (3.6%). All treatments were well tolerated with no severe AEs. Conclusion: Treatment with empagliflozin was well tolerated and resulted in sustained glycemic efficacy over long-term (76 weeks) in drug-naïve Indian T2DM patients.

This study was undertaken to determine if crosstalk among the transient receptor potential (TRP) melastatin 8 (TRPM8), TRP vanilloid 1 (TRPV1), and vascular endothelial growth factor (VEGF) receptor triad modulates VEGF-induced Ca2+ signaling in human corneal keratocytes. Using RT-PCR, qPCR and immunohistochemistry, we determined TRPV1 and TRPM8 gene and protein coexpression in a human corneal keratocyte cell line (HCK) and human corneal cross sections. Fluorescence Ca2+ imaging using both a photomultiplier and a single cell digital imaging system as well as planar patch-clamping measured relative intracellular Ca2+ levels and underlying whole-cell currents. The TRPV1 agonist capsaicin increased both intracellular Ca2+ levels and whole-cell currents, while the antagonist capsazepine (CPZ) inhibited them. VEGF-induced Ca2+ transients and rises in whole-cell currents were suppressed by CPZ, whereas a selective TRPM8 antagonist, AMTB, increased VEGF signaling. In contrast, an endogenous thyroid hormone-derived metabolite 3-Iodothyronamine (3-T1AM) suppressed increases in the VEGF-induced current. The TRPM8 agonist menthol increased the currents, while AMTB suppressed this response. The VEGF-induced increases in Ca2+ influx and their underlying ionic currents stem from crosstalk between VEGFR and TRPV1, which can be impeded by 3-T1AM-induced TRPM8 activation. Such suppression in turn blocks VEGF-induced TRPV1 activation. Therefore, crosstalk between TRPM8 and TRPV1 inhibits VEGFR-induced activation of TRPV1.

The study aims at examining how fiscal deficits affect the performance of the stock market in India by using annual data from 1988–2012. The study makes use of Ng-Perron unit root tests to check the non-stationarity property of the series; the Auto Regressive Distributed Lag (ARDL) bounds test and a Vector Error Correction Model (VECM) for testing both short and long run dynamic relationships. The variance decomposition (VDC) is used to predict the exogenous shocks of the variables. The findings of the bounds test reveal that the estimated equation and the series are co-integrated. The ARDL results suggest a long run negative relationship exists between budget deficit and stock prices and do not show any significant relationship in the short run. The VECM result shows that fiscal deficits influence the stock price only in the short run. The results of the Variance Decomposition show that stock price movement in the long run is mostly explained by shocks of fiscal deficits. The study implies that the government must adopt appropriate macroeconomic policies to reduce budget deficit, which will result in stock market growth and in turn will lead to the financial development of the country.

Extracellular ATP is among molecules promoting microglia activation and inducing the release of extracellular vesicles (EVs), which are potent mediators of intercellular communication between microglia and the microenvironment. We previously showed that EVs produced under ATP stimulation (ATP-EVs) propagate a robust inflammatory reaction among astrocytes and microglia in vitro and in mice with subclinical neuroinflammation (Verderio et al., 2012). However, the proteome of EVs released upon ATP stimulation has not yet been elucidated. In this study we applied a label free proteomic approach to characterize the proteome of EVs released constitutively and during microglia activation with ATP. We show that ATP drives sorting in EVs of a set of proteins implicated in cell adhesion/extracellular matrix organization, autophagy-lysosomal pathway and cellular metabolism, that may influence the response of recipient astrocytes to EVs. These data provide new clues to molecular mechanisms involved in microglia response to ATP and in microglia signaling to the environment via EVs.

Platinum-based therapy is most often used to treat advanced cases of head and neck cancers, but only a small fraction of the patient population responds to cisplatin, with a median survival time of less than a year. Although gene signatures and molecular etiology of head and neck cancers have been previously described, none of them are predictive indicators of cisplatin treatment response in particular. Therefore, currently, there is a lack of clinically employable predictive indicators of the disease beyond HPV status to specifically predict patients' response to platinum-based therapy. It beckons a substantial effort to look for predictive indicators of cisplatin treatment response. In this regard, CD24 expression level appears to be a significant molecular phenotype of cisplatin-resistant residual cells in laryngeal carcinoma lines. CD24 expression level directly affects cisplatin sensitivity and affects the expression of critical apoptotic, stem and drug resistance genes. A relatively small retrospective patient tumor analysis suggests that CD24 high tumors go on to show an unfavorable response to cisplatin treatment. Overall, based on the strength of further analysis, CD24 presents a strong rationale to be utilized as a predictive indicator to stratify head and neck cancer patients for platinum-based therapy. It also provides a rationale for using CD24 as a therapeutic adjuvant target along with standard cisplatin therapy.

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.