Prevalence and predictors of water-borne diseases among elderly people in India: evidence from Longitudinal Ageing Study in India, 2017-18.

BACKGROUND: India suffers from a high burden of diarrhoea and other water-borne diseases due to unsafe water, inadequate sanitation and poor hygiene practices among human population. With age the immune system becomes complex and antibody alone does not determine susceptibility to diseases which increases the chances of waterborne disease among elderly population. Therefore the study examines the prevalence and predictors of water-borne diseases among elderly in India. METHOD: Data for this study was collected from the Longitudinal Ageing Study in India (LASI), 2017-18. Descriptive statistics along with bivariate analysis was used in the present study to reveal the initial results. Proportion test was applied to check the significance level of prevalence of water borne diseases between urban and rural place of residence. Additionally, binary logistic regression analysis was used to estimate the association between the outcome variable (water borne diseases) and the explanatory variables. RESULTS: The study finds the prevalence of water borne disease among the elderly is more in the rural (22.5%) areas compared to the urban counterparts (12.2%) due to the use of unimproved water sources. The percentage of population aged 60 years and above with waterborne disease is more in the central Indian states like Chhattisgarh and Madhya Pradesh followed by the North Indian states. Sex of the participate, educational status, work status, BMI, place of residence, type of toilet facility and water source are important determinants of water borne disease among elderly in India. CONCLUSION: Elderly people living in the rural areas are more prone to waterborne diseases. The study also finds state wise variation in prevalence of waterborne diseases. The elderly people might not be aware of the hygiene practices which further adhere to the disease risk. Therefore, there is a need to create awareness on basic hygiene among this population for preventing such bacterial diseases.

pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving in vitro and in vivo drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC50) of PDAC cells when encapsulated in pHNPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that pHNP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.

Chemical Architecture of Block Copolymers Differentially Abrogate Cardiotoxicity and Maintain the Anticancer Efficacy of Doxorubicin.

The molecular architecture of pH-responsive amphiphilic block copolymers, their self-assembly behavior to form nanoparticles (NPs), and doxorubicin (DOX)-loading technique govern the extent of DOX-induced cardiotoxicity. We observed that the choice of pH-sensitive tertiary amines, surface charge, and DOX-loading techniques within the self-assembled NPs strongly influence the release and stimulation of DOX-induced cardiotoxicity in primary cardiomyocytes. However, covalent conjugation of DOX to a pH-sensitive nanocarrier through a "conditionally unstable amide" linkage (PCPY-cDOX; PC = polycarbonate and PY = 2-pyrrolidine-1-yl-ethyl-amine) significantly reduced the cardiotoxicity of DOX in cardiomyocytes as compared to noncovalently encapsulated DOX NPs (PCPY-eDOX). When these formulations were tested for drug release in serum-containing media, the PCPY-cDOX systems showed prolonged control over drug release (for ∼72 h) at acidic pH compared to DOX-encapsulated nanocarriers, as expected. We found that DOX-encapsulated nanoformulations triggered cardiotoxicity in primary cardiomyocytes more acutely, while conjugated systems such as PCPY-cDOX prevented cardiotoxicity by disabling the nuclear entry of the drug. Using 2D and 3D (spheroid) cultures of an ER + breast cancer cell line (MCF-7) and a triple-negative breast cancer cell line (MDA-MB-231), we unravel that, similar to encapsulated systems (PCPY-eDOX-type) as reported earlier, the PCPY-cDOX system suppresses cellular proliferation in both cell lines and enhances trafficking through 3D spheroids of MDA-MB-231 cells. Collectively, our studies indicate that PCPY-cDOX is less cardiotoxic as compared to noncovalently encapsulated variants without compromising the chemotherapeutic properties of the drug. Thus, our studies suggest that the appropriate selection of the nanocarrier for DOX delivery may prove fruitful in shifting the balance between low cardiotoxicity and triggering the chemotherapeutic potency of DOX.

Downregulation of miR-506-3p Facilitates EGFR-TKI Resistance through Induction of Sonic Hedgehog Signaling in Non-Small-Cell Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs). Treatment resistance remains the primary obstacle to the successful treatment of NSCLC. Although drug resistance mechanisms have been studied extensively in NSCLC, the regulation of these mechanisms has not been completely understood. Recently, increasing numbers of microRNAs (miRNAs) are implicated in EGFR-TKI resistance, indicating that miRNAs may serve as novel targets and may hold promise as predictive biomarkers for anti-EGFR therapy. MicroRNA-506 (miR-506) has been identified as a tumor suppressor in many cancers, including lung cancer; however, the role of miR-506 in lung cancer chemoresistance has not yet been addressed. Here we report that miR-506-3p expression was markedly reduced in erlotinib-resistant (ER) cells. We identified Sonic Hedgehog (SHH) as a novel target of miR-506-3p, aberrantly activated in ER cells. The ectopic overexpression of miR-506-3p in ER cells downregulates SHH signaling, increases E-cadherin expression, and inhibits the expression of vimentin, thus counteracting the epithelial-mesenchymal transition (EMT)-mediated chemoresistance. Our results advanced our understanding of the molecular mechanisms underlying EGFR-TKI resistance and indicated that the miR-506/SHH axis might represent a novel therapeutic target for future EGFR mutated lung cancer treatment.

The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling.

Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC.

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.

BACKGROUND: In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity. METHODS: We analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells. RESULTS: Present studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways. CONCLUSIONS: These studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.

The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review.

Renal Cell Carcinoma (RCC) is the most prominent kidney cancer derived from renal tubules and accounts for roughly 85% of all malignant kidney cancer. Every year, over 60,000 new cases are registered, and about 14,000 people die from RCC. The incidence of this has been increasing significantly in the U.S. and other countries. An increased understanding of molecular biology and the genomics of RCC has uncovered several signaling pathways involved in the progression of this cancer. Significant advances in the treatment of RCC have been reported from agents approved by the Food and Drug Administration (FDA) that target these pathways. These agents have become drugs of choice because they demonstrate clinical benefit and increased survival in patients with metastatic disease. However, the patients eventually relapse and develop resistance to these drugs. To improve outcomes and seek approaches for producing long-term durable remission, the search for more effective therapies and preventative strategies are warranted. Treatment of RCC using natural products is one of these strategies to reduce the incidence. However, recent studies have focused on these chemoprevention agents as anti-cancer therapies given they can inhibit tumor cell grow and lack the severe side effects common to synthetic compounds. This review elaborates on the current understanding of natural products and their mechanisms of action as anti-cancer agents. The present review will provide information for possible use of these products alone or in combination with chemotherapy for the prevention and treatment of RCC.

The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The average survival of resected patients is between 12 and 20 months, with a high probability of relapse. Standard chemo and radiation therapies do not offer significant improvement of the survival of these patients. Furthermore, novel treatment options aimed at targeting oncogenes or growth factors in pancreatic cancer have proved unsuccessful. Thereby, identifying new biomarkers that can detect early stages of this disease is of critical importance. Among these biomarkers, microRNAs (miRNAs) have supplied a profitable recourse and become an attractive focus of research in PDAC. MiRNAs regulate many genes involved in the development of PDAC through mRNA degradation or translation inhibition. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of PDAC therapies. This review summarizes the reports describing miRNAs involvement in cellular processes involving pancreatic carcinogenesis and their utility in diagnosis, survival and therapeutic potential in pancreatic cancer.

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition.

Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-ß/SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-ß in breast carcinogenesis.

Interests shape how adolescents pay attention: the interaction of motivation and top-down attentional processes in biasing sensory activations to anticipated events.

The voluntary allocation of attention to environmental inputs is a crucial mechanism of healthy cognitive functioning, and is probably influenced by an observer's level of interest in a stimulus. For example, an individual who is passionate about soccer but bored by botany will obviously be more attentive at a soccer match than an orchid show. The influence of monetary rewards on attention has been examined, but the impact of more common motivating factors (i.e. the level of interest in the materials under observation) remains unclear, especially during development. Here, stimulus sets were designed based on survey measures of the level of interest of adolescent participants in several item classes. High-density electroencephalography was recorded during a cued spatial attention task in which stimuli of high or low interest were presented in separate blocks. The motivational impact on performance of a spatial attention task was assessed, along with event-related potential measures of anticipatory top-down attention. As predicted, performance was improved for the spatial target detection of high interest items. Further, the impact of motivation was observed in parieto-occipital processes associated with anticipatory top-down spatial attention. The anticipatory activity over these regions was also increased for high vs. low interest stimuli, irrespective of the direction of spatial attention. The results also showed stronger anticipatory attentional and motivational modulations over the right vs. left parieto-occipital cortex. These data suggest that motivation enhances top-down attentional processes, and can independently shape activations in sensory regions in anticipation of events. They also suggest that attentional functions across hemispheres may not fully mature until late adolescence.

The Production, Assessment, and Utility of 3D-Printed Video Laryngoscopes in Eastern India: A Low-Cost Alternative to Conventional Video Laryngoscopes.

Introduction Recognizing the limitations of traditional direct laryngoscopes, particularly in difficult airway situations, video laryngoscopy has emerged as a potentially safer and more effective alternative. This study evaluated the utility of two 3D-printed video laryngoscopes: a standard geometry video laryngoscope (SGVL), resembling the traditional Macintosh blade, and a hyper-angulated video laryngoscope (HAVL) with a more curved design. Their performance was compared to a standard Macintosh direct laryngoscope across various intubation parameters. By leveraging the cost-effectiveness of 3D printing with polylactic acid, the study aimed to assess the potential of this technology to improve airway management across diverse clinical settings and varying levels of physician expertise. Methods This prospective randomized crossover study compared the effectiveness of 3D-printed video laryngoscopes (VL) and a standard direct laryngoscope in intubation. After obtaining IRB approval, physicians from various specialties across multiple centers participated. Participants received training on SGVL, HAVL, and DL intubation using an instructional video and hands-on practice. The training was standardized for all participants. The primary outcome measures were time to successful intubation, number of attempts, and time to visualize vocal cords. Participants were randomized to use all three laryngoscopes on a manikin, with a maximum of two attempts per scope. A 30-minute break separated each laryngoscope evaluation. Successful intubation was defined as the single insertion of each laryngoscope and bougie, followed by endotracheal tube placement and confirmation of lung inflation. Results Ninety-eight doctors, mostly from the EM team (73.5%) and ICU team (23.4%). Teams consist of consultants, residents, and medical officers of the concerned departments. Forty-eight of the participants (49%) were novice operators (<25 intubations). Successful first-attempt intubation in those with <1 year of experience with intubation (n=33) was highest for SGVL (97%) compared to DL (82%) and HAVL (67%). Participants who learned intubation through self-directed learning exhibited a higher acceptance of VL and achieved 100% success on their first attempt. Among those who followed modules or workshops, 97% had successful first-attempt intubation with VL. The average time taken to visualize the vocal cords was lower in SGVL compared to DL (5.6 vs. 7.5 seconds) (p<0.001). The HAVL also had a lower average time compared to the DL (7.1 vs. 7.5 secs) (p<0.001). However, the time taken to intubate using DL (24.2 ±8.7 sec) was similar to SGVL (28.1 ±13 sec). Lastly, the intubation time using HAVL was the longest (49.6 ±35.5 sec). The time to intubate with DL and SGVL had Spearman's rho of 0.64 (p<0.001), and DL and HAVL had 0.59 (p<0.001). Conclusions The ease of use and its cost-effective nature make 3D-printed VLs beneficial in situations where traditional VLs may not be available, especially in simulation and training.

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers.

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.

pH-responsive targeted nanoparticles release ERK-inhibitor in the hypoxic zone and sensitize free gemcitabine in mutant K-Ras-addicted pancreatic cancer cells and mouse model.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis.

CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could be mediated through the interaction with the αvß3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance.

The role of CCNs in controlling cellular communication in the tumor microenvironment.

The Cellular communication network (CCN) family of growth regulatory factors comprises six secreted matricellular proteins that promote signal transduction through cell-cell or cell-matrix interaction. The diversity of functionality between each protein is specific to the many aspects of healthy and cancer biology. For example, CCN family proteins modulate cell adhesion, proliferation, migration, invasiveness, apoptosis, and survival. In addition, the expression of each protein regulates many biological and pathobiological processes within its microenvironment to regulate angiogenesis, inflammatory response, chondrogenesis, fibrosis, and mitochondrial integrity. The collective range of CCN operation remains fully comprehended; however, understanding each protein's microenvironment may draw more conclusions about the abundance of interactions and signaling cascades occurring within such issues. This review observes and distinguishes the various roles a CCN protein may execute within distinct tumor microenvironments and the biological associations among them. Finally. We also review how CCN-family proteins can be used in nano-based therapeutic implications.

Oscillatory alpha-band mechanisms and the deployment of spatial attention to anticipated auditory and visual target locations: supramodal or sensory-specific control mechanisms?

Oscillatory alpha-band activity (8-15 Hz) over parieto-occipital cortex in humans plays an important role in suppression of processing for inputs at to-be-ignored regions of space, with increased alpha-band power observed over cortex contralateral to locations expected to contain distractors. It is unclear whether similar processes operate during deployment of spatial attention in other sensory modalities. Evidence from lesion patients suggests that parietal regions house supramodal representations of space. The parietal lobes are prominent generators of alpha oscillations, raising the possibility that alpha is a neural signature of supramodal spatial attention. Furthermore, when spatial attention is deployed within vision, processing of task-irrelevant auditory inputs at attended locations is also enhanced, pointing to automatic links between spatial deployments across senses. Here, we asked whether lateralized alpha-band activity is also evident in a purely auditory spatial-cueing task and whether it had the same underlying generator configuration as in a purely visuospatial task. If common to both sensory systems, this would provide strong support for "supramodal" attention theory. Alternately, alpha-band differences between auditory and visual tasks would support a sensory-specific account. Lateralized shifts in alpha-band activity were indeed observed during a purely auditory spatial task. Crucially, there were clear differences in scalp topographies of this alpha activity depending on the sensory system within which spatial attention was deployed. Findings suggest that parietally generated alpha-band mechanisms are central to attentional deployments across modalities but that they are invoked in a sensory-specific manner. The data support an "interactivity account," whereby a supramodal system interacts with sensory-specific control systems during deployment of spatial attention.

Cysteine-rich 61-connective tissue growth factor-nephroblastoma-overexpressed 5 (CCN5)/Wnt-1-induced signaling protein-2 (WISP-2) regulates microRNA-10b via hypoxia-inducible factor-1α-TWIST signaling networks in human breast cancer cells.

MicroRNAs (miRNAs) are naturally occurring single-stranded RNA molecules that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in regulating processes commonly altered during tumorigenesis and metastatic growth. These include cell proliferation, differentiation, apoptosis, migration, and invasion. Among the several miRNAs, miRNA-10b (miR-10b) expression is increased in metastatic breast cancer cells and positively regulates cell migration and invasion through the suppression of the homeobox D10 (HOXD10) tumor suppressor signaling pathway. In breast metastatic cells, miR-10b expression is enhanced by a transcription factor TWIST1. We find that miR-10b expression in breast cancer cells can be suppressed by CCN5, and this CCN5 effect is mediated through the inhibition of TWIST1 expression. Moreover, CCN5-induced inhibition of TWIST1 expression is mediated through the translational inhibition/modification of hypoxia-inducible factor-1α via impeding JNK signaling pathway. Collectively, these studies suggest a novel regulatory pathway exists through which CCN5 exerts its anti-invasive function. On the basis of these findings, it is plausible that reactivation of CCN5 in miR-10b-positive invasive/metastatic breast cancers alone or in combination with current therapeutic regimens could provide a unique, alternative strategy to existing breast cancer therapy.

Rural-urban differentials in the prevalence of diarrhoea among older adults in India: Evidence from Longitudinal Ageing Study in India, 2017-18.

INTRODUCTION: Diarrhoeal diseases are common among children and older adults. Yet, majority of the scientific studies deal with children, neglecting the other vulnerable and growing proportion of the population-the older adults. Therefore, the present study aims to find rural-urban differentials in the prevalence of diarrhoea among older adults in India and its states. Additionally, the study aims to find the correlates of diarrhoea among older adults in India. The study hypothesizes that there are no differences in the prevalence of diarrhoea in rural and urban areas. METHODS: Data for this study was utilized from the recent Longitudinal Ageing Study in India (2017-18). The present study included eligible respondents aged 60 years and above (N = 31,464). Descriptive statistics along with bivariate analysis was presented to reveal the preliminary results. In addition, binary logistic regression analysis was used to fulfil the study objectives. RESULTS: About 15% of older adults reported that they suffered from diarrhoea in the last two years. The prevalence of diarrhoea among older adults was found to be highest in Mizoram (33.5 per cent), followed by Chhattisgarh (30.7 per cent) and Bihar (30.2 per cent). There were significant rural-urban differences in the prevalence of diarrhoea among older adults in India (difference: 7.7 per cent). The highest rural-urban differences in the prevalence of diarrhoea were observed among older adults who were 80+ years old (difference: 13.6 per cent), used unimproved toilet facilities (difference: 12.7 per cent), lived in the kutcha house (difference: 10.2 per cent), and those who used unclean source of cooking fuel (difference: 9 per cent). Multivariate results show that the likelihood of diarrhoea was 17 per cent more among older adults who were 80+ years compared to those who belonged to 60-69 years' age group [AOR: 1.17; CI: 1.04-1.32]. Similarly, the older female had higher odds of diarrhoea than their male counterparts [AOR: 1.19; CI: 1.09-1.30]. The risk of diarrhoea had declined with the increase in the educational level of older adults. The likelihood of diarrhoea was significantly 32 per cent more among older adults who used unimproved toilet facilities than those who used improved toilet facilities [AOR: 1.32; CI: 1.21-1.45]. Similarly, older adults who used unimproved drinking water sources had higher odds of diarrhoea than their counterparts [AOR: 1.45; CI: 1.25-1.69]. Moreover, older adults who belonged to urban areas were 22 per cent less likely to suffer from diarrhoea compared to those who belonged to rural areas [AOR: 0.88; CI: 0.80-0.96]. CONCLUSION: The findings of this study reveal that diarrhoea is a major health problem among older adults in India. There is an immediate need to address this public health concern by raising awareness about poor sanitation and unhygienic practices. With the support of the findings of the present study, policy makers can design interventions for reducing the massive burden of diarrhoea among older adults in rural India.

Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis.

BACKGROUND: Despite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood. RESULTS: We show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP) cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1. CONCLUSIONS: In conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

Association of anthropometric measures of obesity and physical activity with cardio-vascular diseases among older adults: Evidence from a cross-sectional survey, 2017-18.

BACKGROUND: With the increase in elderly population, the risk of cardiovascular diseases (CVD) among Indian older adults is also increasing. The present paper tries to assess how different anthropometric measures of obesity and physical activity affects cardiovascular disease risk among older adults in India. METHODS: The data from Longitudinal Ageing Study in India (LASI) has been used. The total sample size for the present study is 31,464 older adults aged 60 years and above. Chi-square test and binary logistic regression has been used to measure the association of obesity measures and CVD prevalence. RESULTS: About 35.2% (n = 11,058) of the older adults suffered from CVD. Moreover, 22.2% (n = 6,217) of the older adults were obese/overweight, 23.7% (n = 6,651) had high risk waist circumference and 77.0% (n = 21,593) had high risk waist-Hip ratio. The likelihood of CVD was 60%, 50%, and 34% significantly higher among older adults who were obese/overweight [Adjusted odds ratio (AOR): 1.60; CI: 1.48-1.72], had high risk waist circumference [AOR: 1.50; CI: 1.39-1.62] and high risk waist-Hip ratio [AOR: 1.34; CI: 1.25-1.44], respectively compared to older adults with normal BMI and those who do not have a high risk waist circumference and high risk waist hip ratio. Moreover, older adults who never did physical activity had 22 per cent higher risk of CVD than those who did frequent [AOR: 1.22; CI: 1.13-1.32] physical activity. CONCLUSION: The burden of overweight and obesity along with physical inactivity increases the risk of CVD in older adults. These findings highlight the urgent need for framing direct and indirect strategies to control obesity in order to reduce the burden of CVD among older adults in India.