Improving Consumption

The information systems (IS) research relevance debate was sparked by concerns that the research community is delivering products that are only sometimes considered useful. Symptoms of the problem include the marketability of IS graduates, our failure to lead industry, the proliferation of journals and conferences with overlapping themes, and a rewards system that is geared towards outputs. Relevance, in my view, is a function of addressing the right problem and packaging the results in a manner suitable for consumption. My recommendations therefore include: identifying the fundamental and applied areas; recognizing our limitations in these areas; providing research summaries; clarifying the research channels by avoiding overlaps in conferences and journals; and altering the rewards and control systems such that they are biased towards contribution to the discipline

Connecting to the Next Generation Mobile Desktop

Mobile phones have evolved over the years from a plain device that allowed voice communication to the present day smart phones that are capable of variety of tasks. Much touted smart phone lacks some of the rudimentary business as well as other functions that are available in a traditional laptop/desktop. This article proposes a new system called Next Generation Mobile Desktop (NGMD) that provides desktop equivalent functions on a functional mobile phone. Proposed NGMD leverage some of the emerging technologies to offer enhanced services to the user. This article discusses some of the existing as well as new mobile technologies and then proposes the architecture for the NGMD. This article also discusses some of the services offered by NGMD and provides illustrative examples of them. We believe NGMD capable phones would dominate the corporate market and free up the user from carrying multiple devices while on the road

Identification of pathogenic virus sequences in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is by far the most common type of pancreatic cancer. It constitutes about 90% of tumors of the exocrine pancreas. The aggressive nature of PDAC along with a lack of diagnostic markers contributes to high lethality of this disease, which is nearly identical to its incidence. Studies from malignancies such as hepatocellular carcinoma and cervical cancer, along with the fact that liver and pancreas are in a close proximity, provided a plausible basis for the hypothesis of virus association in PDAC tumor development. However, there have been no established reports about virus(es) associated with pancreatic cancer. The present study identified a new cancer-associated virus in human PDAC samples, called Meleagrid herpesvirus-1 (MeHV-1), or also known commonly as herpesvirus of turkeys, by two different and independent approaches: experimental genomic subtraction and digital microRNAome subtraction between healthy and PDAC patients. In the first approach, a genome-wide experimental comparison of DNA from PDAC tissues to DNA from tissues of healthy individuals was performed by representational difference analysis (RDA). Using this technique, differences in sequence composition were selectively isolated and amplified with very high sensitivity. Virus sequences associated with the occurrence of pancreatic cancer were detected by this process. The second approach, performed in parallel, involved a sequence analysis of the complete microRNA (miRNA) content of PDAC tissue samples. The sequencing data was digitally compared to databases of human and viral sequences so as to identify viral miRNAs. Because of the limited number of molecules, this analysis form did not need any experimental selection and amplification in order to achieve a sufficiently enough sensitivity to find viral microRNAs. The common results of the two analyses strongly suggested that MeHV-1 plays a crucial role in PDAC tumor progression. One of the viral microRNAs – hvt-miR-H14-3p – was studied in detail at the functional level by both in vitro and in vivo experiments in order to define the molecular mechanism of action with regard to its effect on pancreatic tumor carcinogenesis. The key findings from this work include: 1. Identification of MeHV-1 DNA sequences in the PCR difference products (DPs) resulting from RDA on genomic DNA from PDAC and healthy tissues. 2. A tumor-specific MeHV-1 signature was also identified in the miRNA sequence analysis of tumor DNA, using an independent methodological approach. 3. RT-qPCR analyses showed that hvt-miR-H14-3p from MeHV-1 was expressed at significantly higher levels in PDAC and chronic pancreatitis (CP) tissues – CP being a chronic inflammation of the pancreas and a well-known risk factor of PDAC – than in healthy tissues. This observation was further verified using independent digital PCR platforms. 4. Metastatic and non-metastatic PDAC cell lines overexpressing hvt-miR-H14-3p showed a significant increase in migration and invasion compared to the respective controls, interestingly, without any significant change in proliferation. 5. Hvt-miR-H14-3p was found targeting cellular p27, down-regulating its expression. 6. The functional consequences of viral sequences identified in vitro could also be confirmed in vivo in NOD scid gamma mice. In conclusion, this study is very significant in elucidating functional consequences of viral sequences in PDAC for the definition of relevant molecular effects responsible for carcinogenesis

Envisioning the Next Generation Cellular Client

The cellular revolution has been accompanied by a gradual evolution in functionality. The Motorola handie-talkie introduced in the early 1940‟s was a five pound behemoth that barely worked. Contemporary phones have become ubiquitous devices that are outfitted with camera, video, GPS, internet and e-mail. Fourth generation phones are expected to provide high speed internet access for data as well as multi-media through protocols that subsume existing standards. Beyond this, the capabilities of 4G phones have not been spelled out in detail. In this paper we outline our vision of a feature rich next generation phone that is backed up by an infrastructure of service offerings

Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy

The recent interest to modulate autophagy in cancer therapy has been hampered by the dual roles of this conserved catabolic process in cancer, highlighting the need for tailored approaches. Since RAS isoforms have been implicated in autophagy regulation and mutation of the KRAS oncogene is highly frequent in colorectal cancer (CRC), we questioned whether/how mutant KRAS alleles regulate autophagy in CRC and its implications. We established two original models, KRAS-humanized yeast and KRAS-non-cancer colon cells and showed that expression of mutated KRAS up-regulates starvation-induced autophagy in both. Accordingly, KRAS down-regulation inhibited autophagy in CRC-derived cells harboring KRAS mutations. We further show that KRAS-induced autophagy proceeds via up-regulation of the MEK/ERK pathway in both colon models and that KRAS and autophagy contribute to CRC cell survival during starvation. Since KRAS inhibitors have proven difficult to develop, our results suggest using autophagy inhibitors as a combined/alternative therapeutic approach in CRCs with mutant KRAS.This work was supported by FCT/MEC through Portuguese funds (PIDDAC) - PEst-OE/BIA/UI4050/2014 and FCT I.P. through the strategic funding UID/BIA/04050/2013 as well as by FCT through projects PTDC/BIA-BCM/69448/2006 and FCT-ANR/BEX-BCM/0175/2012, as well as fellowships to S.A. (SFRH/BD/64695/2009) and S.R.C. (SFRH/BPD/89980/2012).info:eu-repo/semantics/publishedVersio

Hydroxychloroquine for chronic myeloid leukemia: complete cure on the horizon?

No abstract available

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders

ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression

Opioid overdose deaths and potentially inappropriate opioid prescribing practices (PIP): A spatial epidemiological study

INTRODUCTION: Opioid overdose deaths quintupled in Massachusetts between 2000 and 2016. Potentially inappropriate opioid prescribing practices (PIP) are associated with increases in overdoses. The purpose of this study was to conduct spatial epidemiological analyses of novel comprehensively linked data to identify overdose and PIP hotspots. METHODS: Sixteen administrative datasets, including prescription monitoring, medical claims, vital statistics, and medical examiner data, covering \u3e98% of Massachusetts residents between 2011-2015, were linked in 2017 to better investigate the opioid epidemic. PIP was defined by six measures: \u3e /=100 morphine milligram equivalents (MMEs), co-prescription of benzodiazepines and opioids, cash purchases of opioid prescriptions, opioid prescriptions without a recorded pain diagnosis, and opioid prescriptions through multiple prescribers or pharmacies. Using spatial autocorrelation and cluster analyses, overdose and PIP hotspots were identified among 538 ZIP codes. RESULTS: More than half of the adult population (n = 3,143,817, ages 18 and older) were prescribed opioids. Nearly all ZIP codes showed increasing rates of overdose over time. Overdose clusters were identified in Worcester, Northampton, Lee/Tyringham, Wareham/Bourne, Lynn, and Revere/Chelsea (Getis-Ord Gi*; p \u3c 0.05). Large PIP clusters for \u3e /=100 MMEs and prescription without pain diagnosis were identified in Western Massachusetts; and smaller clusters for multiple prescribers in Nantucket, Berkshire, and Hampden Counties (p \u3c 0.05). Co-prescriptions and cash payment clusters were localized and nearly identical (p \u3c 0.05). Overlap in PIP and overdose clusters was identified in Cape Cod and Berkshire County. However, we also found contradictory patterns in overdose and PIP hotspots. CONCLUSIONS: Overdose and PIP hotspots were identified, as well as regions where the two overlapped, and where they diverged. Results indicate that PIP clustering alone does not explain overdose clustering patterns. Our findings can inform public health policy decisions at the local level, which include a focus on PIP and misuse of heroin and fentanyl that aim to curb opioid overdoses

Why is autophagy important in human diseases?

The process of macroautophagy (referred to hereafter as autophagy), is generally characterized by the prominent formation of autophagic vesicles in the cytoplasm. In the past decades, studies of autophagy have been vastly expanded. As an essential process to maintain cellular homeostasis and functions, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and thus misregulation of autophagy can result in a variety of pathological conditions in human beings. Although our understanding of regulatory pathways that control autophagy is still limited, an increasing number of studies have shed light on the importance of autophagy in a wide range of physiological processes and human diseases. The goal of the reviews in the current issue is to provide a general overview of current knowledge on autophagy. The machinery and regulation of autophagy were outlined with special attention to its role in diabetes, neurodegenerative disorders, infectious diseases and cancer