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In low latitude regions, due to impact of abrupt climate change/human interference, significant changes in vegetation, particularly the destruction of the highly fragile mangrove ecosystem has been noticed in different tropical areas of the world. In this study, a sediment core collected from the Kali Estuary has been used to determine the vegetation distribution of the Western Ghats since the late Holocene. Pollen and magnetic susceptibility data have been used as proxies to achieve objectives of the study. There has been a dramatic decrease in mangroves, evergreen (tree taxa) and deciduous forest pollens and the abundance of herbaceous/savanna type grassland pollen over the past 3.5 ka. This is supported by the significant decrease of the low-frequency magnetic susceptibility (χlf) of the core reflecting the decrease in the summer monsoon rainfall. Therefore, the post-3.5 ka time period marks the beginning of the recolonization of vegetation. Rarefied diversity pattern plots were used to evaluate abundance and evenness in the pollen data as a result of the late-Holocene climate change. A significant increase in the diversity of herbaceous/savanna grassland taxa in the post-3.5 ka sequence of the core indicates the regional expansion of the agriculture in the Kali River basin. In contrast, the reduction in the taxonomic diversity of mangroves and arboreal taxa implies less-conducive environmental conditions for their growth, with further reduction due to anthropogenic interference. The magnetic susceptibility of the core measured at one cm interval indicates the general decrease in the intensity of the summer monsoon rainfall.

Background: Urinary tract infections (UTI) are one of the most common infections in the community and hospitals. Uropathogens colonize the urinary tract and may ascend to bladder causing cystitis, if left untreated reach kidneys through ureters can be responsible for acute pyelonephritis and cause renal damage. Aims: The aim of the present study is to determine the prevalence of urinary tract infections and antibiotic susceptibility pattern in a tertiary care hospital. Settings & Design: This is an observational study conducted in Microbiology department, Hind Institute of Medical Sciences, Barabanki. Materials and Methods: A total of 623 urine(mid-stream) samples were collected from indoor and outdoor departments of hospital and culture was done on UTI chromogenic agar using semiquantitative method. Antibiotic sensitivity test was performed using Kirby Bauer disc diffusion method. Results: Prevalence of urinary tract infections is 29% in the study. (43%) is the most common micro-organism isolated followed by (13%), (11%), (10.4%), (8.8%), (3.3%), (1.6%), CONS & (1.1%) and (6.6%). The females(56.6%) are more commonly affected than males. Conclusion: In the present study, beta-lactamase inhibitors and aminoglycosides were effective drugs against gram negative bacteria. Vancomycin and linezolid were sensitive in gram positive bacteria. Nitrofurantoin is the promising drug in cases of uncomplicated UTI, and safe to use in pregnancy. High recurrence rates and antimicrobial resistance are responsible for increasing the burden of disease. It is advised to use the antibiotics judiciously as per the hospital antibiotic policy which will help prevent multidrug resistance micro-organism further reducing morbidity and mortality. Keywords: Escherichia coli, Urinary tract infections, Uropathogens.

Introduction: Health care workers (HCW) including medical as well as paramedical workers are a potential source of carrier of infection for the patients admitted in different intensive care units (ICU). The anterior nares are the main reservoir of Staphylococcus although other body sites are frequently colonised with it, such as hands, skin, axillae, and intestinal tract. The body parts of health care workers as well as the equipments and accessories used by them are likely to transmit infections. Materials and Methods: A prospective study was conducted to evaluate the infections in different ICUs. A total of 288 parallel nasal and hands swabs were collected. These samples were cultured as per standard protocols and antibiotic sentivity was also carried out. For antibiotic sensitivity Kirby disc diffusion method on Mueller Hinton agar plate was used. Coagulase negative Staphylococcus was the bacteria isolated and subjected to sensitivity towards different antibiotics. Results: Of the 288 samples 90 samples (31.3%) were positive while 198 (68.7%) were negative. The distribution of the positive samples from Medical ICUs – 47 cases, Paediatric ICUs – 21 and, Surgical ICUs – 22 cases. Conclusion: Coagulase negative Staphylococci were predominantly isolated from culture and increasing antibiotic resistance is also observed. The most effective antibiotics were Tobramycin, Teicoplanin and Linezolid while Penicillin, Gentamycin and Erythromycin showed highest resistance. HCW themselves as well as the accessories used by them are an important potential source of infection for the admitted patients. Regular disinfection of these accessories should be strictly followed in each and every ICU. Keywords: Nosocomial, Cons, Healthcare workers, Nasal carrier, ICU.

The causative agent of novel coronavirus disease (COVID-19) is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 possesses RNA as a genetic material with 79% of the match with the bat SARS-CoV genome, which became epidemic in 2002. The SARS-CoV-2 peripheral Spike-Fc protein binds specifically to the ACE2 receptors present on bronchial epithelial cells and alveolar pneumocytes to downmodulates its expression which leads to severe acute respiratory failure. The disease is super infectious from human to human and the symptoms are similar to flu. The old aged and immunocompromised population are severely affected, and healthcare providers globally applied various strategies for treatment including the repurposing of drugs including antimalarial drug, hydroxychloroquine and anti-viral drugs.Herein, we described the SARS-CoV-2 pandemic, immune responses, possible drug targets, vaccines under the trials and correlated the possibility of trained immunity induced by BCG vaccination over control of SARS-CoV-2 infection. The countries with constraint BCG vaccination policy are struggling badly compared to countries with BCG vaccination policy. The BCG vaccination policy supports either lowering the total number of COVID-19 cases or the increasing recovery rate.

A sudden, unprecedented failure of USP rabbit pyrogen tests for multiple 10% IGIV-C lots prompted a thorough investigation of the root cause for this phenomenon. All microbe-related testing, including Limulus amebocyte lysate test for endotoxin, proved negative, and no deficiencies were discovered in manufacturing. Plasma pool composition analysis revealed that a single plasma donor ("Donor X″) was common to all pyrogenic IGIV-C lots and that as little as one unit of "Donor X″ plasma (in a pool of ∼4500 units) was sufficient to cause IGIV-C lot failure in the USP rabbit pyrogen test. Whole plasma and Protein A-purified IgG from "Donor X″ caused a temperature increase in rabbits; however, all IgG samples tested pyrogen-negative in two in vitro cell-based pyrogen tests. Flow cytometry showed that "Donor X″ IgG bound strongly to rabbit white blood cells (WBC) but minimally to human WBC. Exclusion of "Donor X″ plasma from manufacturing marked the end of IGIV-C lots registering positive in the USP rabbit pyrogen test. This failure of multiple 10% IGIV-C lots to pass the USP rabbit pyrogen test was demonstrated to be due to the highly unusual anti-rabbit-leukocyte specificity of IgG from a single donor.

A series of new room-temperature ionic liquids (RTILs) based on biodegradable pyridinium carboxamide cation and conformationally flexible NTf2 anion have been synthesised. The variation of thermo-physical properties of these RTILs with alkyl chain length size has been studied and compared with corresponding parental pyridinium NTf2 ILs. A drastic change in thermophysical properties has been noted on the introduction of the amide functionality on pyridinium cation moiety. The crucial role of amide functionality is also important concerning biodegradability as it acts as an active site for an enzymatic attack, helpful toward biodegradation. Besides, the dependence of thermal and physical properties on alkyl chain length is also noteworthy. A detailed DFT based theoretical studies substantiate the experimental observation of chain length dependence melting point variation and successfully correlated that with stabilisation energy. Conformational dynamics of NTf2 anion (between transoid and cisoid) has been elucidated by Raman spectroscopic studies. Interestingly, the data demonstrate that the conformation of NTf2 anion depends on the chain length of the cation, clearly indicating anionic interaction with the hydrophobic region of the cation. This information is crutial as it vindicates the fact that multiple weak interaction do exist in ILs making it a complex nonostructured system composed of ions.

Pollen in the surface sediment collected in a transect from sea to land in the Coringa mangrove wetland was analysed to determine the spatial and quantitative composition of the pollen record for palaeoecological interpretation. Autochthonous pollen preservation of the existing mangrove species was predominant in the sediments and serves as a potential indicator of coastal wetlands. The low quantity of allochthonous and parautochthonous pollen in the sediment reflects the regional plant community. Statistical analysis of the palynological data shows a high association between pollen from Avicennia marina and Clerodendrum inerme and their vegetation. Aegiceras corniculatum, Sonneratia, Ceriops decandra, Xylocarpus mekongenesis, Cocos nucifera, Azadirachta indica, Syzygium, Chenopodiaceae, Poaceae and Cyperaceae show overrepresentation. Ordination techniques for individual species using fidelity and dispersibility indices and regression analyses suggest four different floristic groups, of (i) high dispersibility-moderate fidelity taxa; (ii) high dispersibility-low fidelity taxa; (iii) moderate dispersibility-low fidelity taxa; and (iv) low dispersibility-high fidelity taxa. Species with high fidelity and moderate-low dispersibility indices could be used to identify the vegetation types in sedimentary sequences. The presence of discriminatory taxa (Avicennia marina, Sonneratia sp.), even in small quantities, helps in accurate identification of the local vegetation. Results indicate that while mangrove pollen is transported over short distances, non-mangrove pollen and spores are transported from longer distances. Thus, the status of mangrove and non-mangrove pollen in the sediments provides a clue to the (palaeo)coastal ecology and the (palaeo)climatic conditions.

BACKGROUND: Carbapenemase-producing microorganisms are becoming a major concern among hospital-acquired infections. There is also increased multidrug resistance seen among these isolates. AIMS: We have conducted this study to determine the prevalence of New Delhi metallo-beta-lactamase-1 (NDM-1) gene-producing Escherichia coli among hospitalized patients in a tertiary care hospital in Northern India. SETTINGS AND DESIGN: The study was conducted in the Department of Microbiology with the tertiary care hospital settings. It was a prospective cross-sectional observational study conducted during January 2014–August 2014. MATERIALS AND METHODS: A total of 500 nonduplicate E. coli samples were processed. The isolates with reduced susceptibility to ertapenem, i.e., zone diameter between 19 and 21 mm, were considered carbapenemase producers. These isolates were subjected to modified Hodge test for phenotypic confirmation. Polymerase chain reaction was performed on all the screened isolates for molecular detection of NDM-1 gene. STATISTICAL ANALYSIS USED: Chi-square test was used to analyze the data and P < 0.05 was considered statistically significant. RESULTS: Out of 500 E. coli isolates, 61 (12.2%) were screened for carbapenemase production. 47 (9.4%) isolates were positive by modified Hodge test and 36 (7.2%) isolates showed the presence of blaNDM-1 gene (P < 0.05). CONCLUSION: There is an increased prevalence of NDM-1 gene-producing E. coli isolates. These carbapenemase-producing isolates are more resistant to other group of antibiotics (aminoglycosides, fluoroquinolones along with β-lactam group). Early detection of blaNDM-1 gene can help in choosing the effective treatment options for hospitalized patients in time, thereby reducing the risk of mortality.

Background Human rabies immunoglobulin (RIG) is an integral part of post-exposure prophylactic treatment of rabies (along with rabies vaccination). Infiltration of most, if not all, of the RIG dose at the wound site is recommended. RIG produced by a caprylate/chromatography manufacturing process (RIG-C; HyperRAB) increased the potency and purity of this product over the existing licensed RIG from a solvent/detergent process (RIG-S/D; HyperRAB-S/D). Methods A series of studies were conducted to characterize the content and purity of RIG-C. A single-dose pharmacokinetic study in rabbits was performed to compare intramuscular (IM) immunoglobulin products manufactured by two different purification processes, solvent/detergent (IGIM-S/D) and caprylate/chromatography (IGIM-C). Results RIG-C was found to be a highly purified IgG formulation with high monomer content and formulated with twice the anti-rabies potency of RIG-S/D while maintaining the same overall protein concentration. RIG-C facilitates IM administration at the wound site by halving the injection volume. The new caprylate/chromatography process eliminated detectible levels of pro-coagulant impurities and IgA that were carried through in the prior S/D process. These impurities have been associated with thrombotic complications and allergic reactions in susceptible patients. After single dose administration, IGIM-C was pharmacokinetically equivalent to IGIM-S/D in rabbits. Conclusion RIG-C is a more potent RIG formulation with less impurities yielding a safer and more convenient product with similar pharmacokinetic profile.

The article describes an efficient method for the preparation of silver nanoparticles ink for its application in printed electronics. The effective formulation using polyvinylpyrrolidone (PVP) and triethylamine leads to highly stable silver nano-ink. The spincoated silver nanoparticulate films fabricated using the as-prepared nano-ink exhibit bulk-like conductivity at moderate annealing temperature of 60C -100C. Additionally; pen-on-paper type of conventional writing is successfully demonstrated with modifying the formulation of such nano-inks. The viscosity of as-prepared Ag nano-ink can be easily altered by varying the concentration of binders and solvents to suit its end applications. Such flexibility coupled with high conductivity and amphiphilic nature makes this silver nano-ink highly useful in various advanced printing techniques. Copyright © 2016 VBRI Press.

There is a large body of research on cognitive interventions for older adults the review which suggests the following: (1) Cognition remediation therapy is indicated for healthy elderly, and in mild cognitive impairment (MCI), early dementia, brain disease and injury, and severe mental illness (SMI). (2) Studies on healthy elderly demonstrate that with cognitive training (CT), cognitive stimulation (CS), and/or cognitive rehabilitation (CR) age-related cognitive decline can be reversed, at least partially if not fully, even in advanced age, with improved social functioning and quality of life. Better results are obtained if cognitive remediation therapy (CRT) is combined with vocational/psychosocial rehabilitation. Generalization of training to activities of daily living (ADL) and to secondary outcome measures such as quality of life and self-esteem are issues that need to be addressed in older adults. (3) Research in MCI has indicated that CRT, especially memory training, has some role. Future studies should place focus on the assessment of dose-response relationship, training generalization, and ecologically relevant approaches. (4) Findings of earlier work in early-stage dementia were frustrating, more recent work, especially randomized controlled trials of high quality, has provided a ray of rope with respect to effectiveness of CT and CR. Further well-designed studies are required to provide more definitive evidence. (5) Significant therapeutic effects of CR have been observed on cognitive function and ADL in the elderly patients with stroke. Routine screening for stroke patients and those with brain injury for cognitive impairment is recommended. (6) Available research provides evidence that cognitive remediation benefits people with SMI, and when combined with psychiatric rehabilitation this benefit generalizes to functioning. Elderly with SMI need special focus. Further needs to be carried out on older people with SMI.

Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. The combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We have now developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by (1)H-NMR, MALDI, and mass spectrometry; and optimal nanoplex formulations were characterized for surface charge, size, and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si, and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth, and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation, and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anticancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.

Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/β-catenin-signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc). Wild-type and Alb/AEG-1 mice did not develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis, whereas Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc, the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of prosurvival and epithelial-mesenchymal transition-signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed. Specifically, Alb/AEG-1/c-Myc mice overexpressed maternally imprinted noncoding RNAs (ncRNAs), such as Rian, Meg-3, and Mirg, which are implicated in hepatocarcinogenesis. Knocking down these ncRNAs significantly inhibited proliferation and invasion by Alb/AEG-1/c-Myc hepatocytes.Our studies reveal a novel cooperative oncogenic effect of AEG-1 and c-Myc that might explain the mechanism of aggressive HCC. Alb/AEG-1/c-Myc mice provide a useful model to understand the molecular mechanism of cooperation between these two oncogenes and other molecules involved in hepatocarcinogenesis. This model might also be of use for evaluating novel therapeutic strategies targeting HCC.

Multi-walled-carbon nanotubes (MWNTs) are widely explored as carriers for drug delivery due to their facile transport through cellular membranes and are reportedly found to be effective against cancer. In the present study, we have evaluated cellular uptake of Docetaxel (DTX) conjugated MWNTs from human breast cancer cells (MCF-7 and MDA-mb-231) and have provided primary results on cytotoxicity of the same. Efficient internalization of the drug conjugate (DTX-MWNTs) inside the cell was corroborated with the help of confocal microscopy, transmission electron microscopy and flow cytometry. The comparison of cytotoxicity of the conjugate and DTX was done by MTT assay. Results of the study indicated increased efficacy of the conjugates over the drug in terms of their cytotoxicity. It was observed that such conjugation of drug to MWNTs can be explored as a strategy to improve therapeutic index of cytotoxic drugs such as DTX and thereby enriching cancer therapies of coming time.

The staphylococcal nuclease and tudor domain containing 1 (SND1) is a multifunctional protein overexpressed in breast, prostate, colorectal and hepatocellular carcinomas and malignant glioma. Molecular studies have revealed the multifaceted activities of SND1 involved in regulating gene expression at transcriptional as well as post-transcriptional levels. Early studies identified SND1 as a transcriptional co-activator. SND1 is also a component of RNA-induced silencing complex (RISC) thus mediating RNAi function, a regulator of mRNA splicing, editing and stability, and plays a role in maintenance of cell viability. Such diverse actions allow the SND1 to modulate a complex array of molecular networks, thereby promoting carcinogenesis. Here, we describe the crucial role of SND1 in cancer development and progression, and highlight SND1 as a potential target for therapeutic intervention.

Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Because AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1–deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of AKT, ERK, and β-catenin, compared with wild-type control animals. However, AEG-1–deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL6 production and STAT3 activation, two key mediators of HCC development, were also deficient along with other biologic and epigenetics findings in the tumor microenvironment, confirming that AEG-1 supports an NF-κB–mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development. Cancer Res; 74(21); 6184–93. ©2014 AACR.

Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)–mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. Cancer Res; 74(16); 4364–77. ©2014 AACR.

Hepatocellular carcinoma (HCC) is a vicious and highly vascular cancer with a dismal prognosis. It is a life-threatening illness worldwide that ranks fifth in terms of cancer prevalence and third in cancer deaths. Most patients are diagnosed at an advanced stage by which time conventional therapies are no longer effective. Targeted molecular therapies, such as the multikinase inhibitor sorafenib, provide a modest increase in survival for advanced HCC patients and display significant toxicity. Thus, there is an immense need to identify novel regulators of HCC that might be targeted effectively. The insulin-like growth factor (IGF) axis is commonly abnormal in HCC. Upon activation, the IGF axis controls metabolism, tissue homeostasis, and survival. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein of a family of low-affinity IGF-binding proteins termed "IGFBP-related proteins" that have been identified as a potential tumor suppressor in HCC. IGFBP7 has been implicated in regulating cellular proliferation, senescence, and angiogenesis. In this review, we provide a comprehensive discussion of the role of IGFBP7 in HCC and the potential use of IGFBP7 as a novel biomarker for drug resistance and as an effective therapeutic strategy.

AEG-1 is an oncogene that is overexpressed in all cancers, including hepatocellular carcinoma. AEG-1 plays a seminal role in promoting cancer development and progression by augmenting proliferation, invasion, metastasis, angiogenesis and chemoresistance, all hallmarks of aggressive cancer. AEG-1 mediates its oncogenic function predominantly by interacting with various protein complexes. AEG-1 acts as a scaffold protein, activating multiple protumorigenic signal transduction pathways, such as MEK/ERK, PI3K/Akt, NF-κB and Wnt/β-catenin while regulating gene expression at transcriptional, post-transcriptional and translational levels. Our recent studies document that AEG-1 is fundamentally required for activation of inflammation. A comprehensive and convincing body of data currently points to AEG-1 as an essential component critical to the onset and progression of cancer. The present review describes the current knowledge gleaned from patient and experimental studies as well as transgenic and knockout mouse models, on the impact of AEG-1 on hepatocarcinogenesis.

Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) and lysine-rich CECAM-1 co-isolated protein (LYRIC), is now established as a positive regulator of tumorigenesis (1). Using immunohistochemistry in a large cohort of patient samples, elevated AEG-1 protein expression has been documented in a variety of cancers (1). AEG-1 expression gradually increases with disease progression and displays a negative correlation with patient survival. The AEG-1 gene is located in human chromosome 8q22, which is amplified in breast and liver cancers (2, 3). AEG-1 is a downstream gene in the Ha-Ras signaling pathway that activates PI3K/Akt and leads to transcriptional upregulation of AEG-1 by c-Myc (4). AEG-1 is a target of miRNA-375, a tumor suppressor in diverse cancers (5). Thus AEG-1 expression might be increased by a variety of mechanisms during carcinogenesis. Gain- and loss-of-function studies in diverse cell lines confirm the importance of AEG-1 in the development and progression of cancer. In multiple cancer cell lines that express low levels of AEG-1 and are poorly aggressive, AEG-1 overexpression results in a significant increase in in vitro proliferation, anchorage-independent growth, migration and invasion and in vivo tumorigenesis, metastasis and angiogenesis in nude mice xenograft models (1). As a corollary, RNAi-mediated inhibition of AEG-1 in aggressive cell lines expressing high levels of AEG-1 significantly inhibits aforementioned in vitro and in vivo oncogenic phenotypes. AEG-1 overexpression results in activation of multiple pro-survival signal transduction pathways, and profoundly contributes to chemoresistance and tumor angiogenesis, major hallmarks of aggressive cancers (1). Thus AEG-1 plays a fundamental role in aggressive progression of the carcinogenic process. The molecular mechanism by which AEG-1 induces these profound changes is gradually being clarified. AEG-1 is a 582 amino acids protein with a transmembrane domain and multiple nuclear localization signals (NLS) (1). In cancer cells, AEG-1 is detected in the cytoplasm as well as on the cell membrane and in the nucleus (2). Depending upon location, AEG-1 interacts with different protein complexes regulating diverse functions. AEG-1 interacts with NF-κB and CBP promoting NF-κB-mediated transcription (6) while it interacts with YY1 along with CBP to repress transcription (7). In the cytoplasm, AEG-1 is a component of the RNA-induced silencing complex (RISC) and assists oncomiR-mediated degradation of tumor suppressor mRNAs (8). AEG-1 facilitates translation of specific mRNAs, such as the mRNA for the multidrug resistance gene (MDR1), which contributes to chemoresistance (9). The membrane-located AEG-1 promotes interaction of cancer cells with lung endothelium thus augmenting metastasis (3). The identification of the diverse interacting partners indicates that AEG-1 may be a scaffold protein mediating formation of multi-protein complexes in different intracellular compartments. AEG-1 plays an important role in hepatocarcinogenesis (2). AEG-1 mRNA and protein overexpression as well as amplification of AEG-1 gene was detected in a large percentage of Hepatocellular carcinoma (HCC) patients (2). To better comprehend the role of AEG-1 in hepatocarcinogenesis and to decipher the underlying molecular mechanism(s) in an in vivo context, we have generated a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG-1). We document that compared to wild-type (WT) mice, the hepatocarcinogenic process is significantly amplified in Alb/AEG-1 mice. We unravel novel aspects of AEG-1, including induction of steatosis, protection from senescence and activation of coagulation pathways, which contribute to its tumor promoting functions. This is the first study analyzing AEG-1 function in vivo and Alb/AEG-1 mouse provides a useful model to further understand the hepatocarcinogenic process and evaluate emerging novel therapies for this invariably fatal disease.

PurposeThis study is designed to determine the antioxidant profile of the crude aqueous and organic (Ethyl acetate) extract of 11 plants. These plants are mainly distributed in north eastern (NE) zones of India. Extracts of the aerial and/or underground parts have been applied in traditional medicine for the treatment of different diseases hence they have gained sufficient importance in alternate medicinal therapy.Design/methodology/approachThe present study was carried out to evaluate the antioxidant activities of extracts NE in vitro systems to gain mechanistic insights.FindingsResults from antioxidant assays together with authentic antioxidant standards revealed that aqueous extract (AqEx) showed strong superoxide radical scavenging activity, reducing power, and ferrous ion‐chelating ability. The ranges of total phenolic contents was determined and found from 2.0860 to 7.1193 in aqueous extract and 1.7716 to 5.4330 mg (GAEq/100 g) in ethylacetate extract. The results revealed that total flavonoid contents in the selected plant from NE and the range of the extract varied from 0.1769 to 1.6990 mg (QEq/100 g), respectively.Originality/valueThe present study focuses on the antioxidant activity of 11 extracts of Indian origin. The plant extracts are also screened for flavonoid contents and total phenolics.

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.

Astrocyte elevated gene-1 (AEG-1), also known as MTDH (metadherin) or LYRIC, is an established oncogene. However, the physiological function of AEG-1 is not known. To address this question, we generated an AEG-1 knock-out mouse (AEG-1KO) and characterized it. Although AEG-1KO mice were viable and fertile, they were significantly leaner with prominently less body fat and lived significantly longer compared with wild type (WT). When fed a high fat and cholesterol diet (HFD), WT mice rapidly gained weight, whereas AEG-1KO mice did not gain weight at all. This phenotype of AEG-1KO mice is due to decreased fat absorption from the intestines, not because of decreased fat synthesis or increased fat consumption. AEG-1 interacts with retinoid X receptor (RXR) and inhibits RXR function. In enterocytes of AEG-1KO mice, we observed increased activity of RXR heterodimer partners, liver X receptor and peroxisome proliferator-activated receptor-α, key inhibitors of intestinal fat absorption. Inhibition of fat absorption in AEG-1KO mice was further augmented when fed an HFD providing ligands to liver X receptor and peroxisome proliferator-activated receptor-α. Our studies reveal a novel role of AEG-1 in regulating nuclear receptors controlling lipid metabolism. AEG-1 may significantly modulate the effects of HFD and thereby function as a unique determinant of obesity.

We assessed genomic instability of 3.4 kb DYZ1 repeat arrays in patients encompassing prostate cancer (PC), cases of repeated abortion (RA) and males exposed to natural background radiation (NBR) using real-time PCR and fluorescence in situ hybridization (FISH). Normal males showed DYZ1 copies ranging from 3000 to 4300, RA, 0-2237; PC, 550; and males exposed to NBR, 1577-5700. FISH showed organizational variation of DYZ1 in these samples substantiating the data obtained from real-time PCR. Of the 10 RA samples, 7 were found to be affected of which, 5 showed deletion of 265 bp from nt 25 to 290 and 773 bp from 1347 to 2119 and 2 showed deletion of 275 bp from nt 3128 to 3402. Copy number variation of DYZ1 in these males correlated with genetic constrains/anomalies. Although precise mechanisms of genomic instability of DYZ1 remains unclear, we construe that this repeat plays a critical role in maintaining the structural integrity of the Y chromosome, possibly by absorbing the load of mutations. This may be used as a marker system to analyze genetic integrity of the DYZ1 repeat array(s) across the spectrum of patients.

Mutations in the SRY gene encompassing the HMG box have been well characterized in gonadal dysgenesis, male infertility and other types of sex chromosome related anomalies (SCRA). However, no information is available on copy number status of this gene under such abnormal conditions. Employing 'Taqman Probe Assay' specific to the SRY gene, we screened 16 DNA samples from patients with SCRA and 36 samples from males exposed to high levels of natural background radiation (HNBR). Patients with SCRA showed 2-16 copies of the SRY gene of which, one, Oxen (49, XYYYY) had eight copies with sequences different from one another. Of the 36 HNBR samples, 12 had one copy whereas 24 harboured 2-8 copies of the SRY gene. A HNBR male 33F had one normal and one mutated copy of this gene. Analysis of 25 DNA samples from blood and semen of normal males showed only one copy of this gene. Despite multiple copies in affected males, fluorescence in-situ hybridization (FISH) with SRY probe detected a single signal on the Y chromosome in HNBR males suggesting its possible localized tandem duplication. Copy number status of the other Y-linked loci is envisaged to augment DNA diagnostics facilitating genetic counselling to affected patients.

The protein phosphatases PP1(c), PP2A(c) and PP2Calpha are shown to dephosphorylate protein kinase Cdelta (PKCdelta) in vitro; of these PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells. However the observation that binding of Mg-ATP to PKCdelta could protect the enzyme from dephosphorylation by PP2A(c) in vitro indicates that an additional input/factor is required for dephosphorylation in vivo.

Hepatocellular carcinoma (HCC) is a highly fatal disease mandating development of novel, targeted therapies to elicit prolonged survival benefit to the patients. Insulin-like growth factor-binding protein-7 (IGFBP7), a secreted protein belonging to the IGFBP family, functions as a potential tumor suppressor for HCC. In the present study, we evaluated the therapeutic efficacy of a replication-incompetent adenovirus expressing IGFBP7 (Ad.IGFBP7) in human HCC. Ad.IGFBP7 profoundly inhibited viability and induced apoptosis in multiple human HCC cell lines by inducing reactive oxygen species (ROS) and activating a DNA damage response (DDR) and p38 MAPK. In orthotopic xenograft models of human HCC in athymic nude mice, intravenous administration of Ad.IGFBP7 profoundly inhibited primary tumor growth and intrahepatic metastasis. In a nude mice subcutaneous model, xenografts from human HCC cells were established in both flanks and only left-sided tumors received intratumoral injection of Ad.IGFBP7. Growth of both left-sided injected tumors and right-sided uninjected tumors were markedly inhibited by Ad.IGFBP7 with profound suppression of angiogenesis. These findings indicate that Ad.IGFBP7 might be a potent therapeutic eradicating both primary HCC and distant metastasis and might be an effective treatment option for terminal HCC patients.

Background: The aim of this study was to review the management of ventriculoperitoneal (VP) shunt complications in children. Patients and Methods: During the last 5 years (January 1, 2006 to December 31, 2010), 236 VP shunt operations were performed in children under 12 years of age; of these, 40 (16.94%) developed shunt complications and those who underwent VP shunt revisions were studied. Results: This prospective study included 40 (28 boys and 12 girls) children and required 48 shunt revisions. Complications following VP shunts that required shunt revisions were peritoneal catheter/peritoneal end malfunction (18), shunt/shunt tract infections (7), extrusion of peritoneal catheter through anus (5), ventricular catheter malfunction (4), cerebrospinal fluid (CSF) leak from abdominal wound (4), shunt system failure (2), ventricular end/shunt displacement (2), CSF pseudocysts peritoneal cavity (2), extrusion of peritoneal catheter from neck, chest, abdominal scar and through umbilicus, one each. Four-fifth of these shunt complications occurred within 6 months of previous surgery. Surgical procedures done during shunt revisions in order of frequency were revision of peritoneal part of shunt (27, 56.25%), revision of entire shunt system (6, 12.5%), extra ventricular drainage and delayed re-shunt (5, 10.41%), shunt removal and delayed re-shunt (5, 10.41%), opposite side shunting (2, 4.16%), cysts excision and revision of peritoneal catheter (2, 4.16%) and revision of ventricular catheter (1, 2.08%). The mortalities following VP shunt operations were 44 (18.64%) and following shunt revisions were 4 (10%). Conclusions: VP shunt done for hydrocephalus in children is not only prone for complications and need for revision surgery but also associated with considerable mortality.

Ten Indian herbs (Manjisth, Tagar, Kulfa, Khuskhus, Gokharu, Carrot, Kasni, Bathua, Soya ke Beej, Pudina), popularly used for medicinal purpose, were extracted in sonicator by methanol and water for the estimation of polyphenols and flavonoids. Antioxidant capacities (AOC) of extracts were evaluated based on their ability to scavenge the DPPH radical and FRAP Assay. The results showed that methanolic extract of all the plant materials had very high antioxidant activity. Amongst them, Pudina extract in the methanol showed highest value of AOC by both FRAP and DPPH methods (33 percent and 1.36 mg QEq / 100 g). Total phenol and flavonoids content were also evaluated for these extracts. It varied from 0.8736 to 6.3918 mg GAE / 100 g and 0.3642 to 1.9876 mg QE / 100 g. Total ash content and acid insoluble content of soya showed highest value i.e. 14.55 percent and 92.92 percent.

Anthocyanins are natural colorants which have gained a growing interest due to their extensive range of colors and beneficial health effects. The red and blue shades of 15 flowers were extracted with 1 % acidic methanol and these extracts were then screened for Total Anthocyanin content (TAC) using the pH method. In this paper the overall anthocyanin content of red and blue flowers was determined at room temperature (25°C). TAC accounts for the antioxidant activity of red and blue flowers. A quantitative relationship between acid-base and redox chemistry was also drawn.

BackgroundThe most frequently observed major consequences of ionizing radiation are chromosomal lesions and cancers, although the entire genome may be affected. Owing to its haploid status and absence of recombination, the human Y chromosome is an ideal candidate to be assessed for possible genetic alterations induced by ionizing radiation. We studied the human Y chromosome in 390 males from the South Indian state of Kerala, where the level of natural background radiation (NBR) is ten-fold higher than the worldwide average, and that from 790 unexposed males as control.ResultsWe observed random microdeletions in the Azoospermia factor (AZF) a, b and c regions in >90%, and tandem duplication and copy number polymorphism (CNP) of 11 different Y-linked genes in about 80% of males exposed to NBR. The autosomal homologues of Y-linked CDY genes largely remained unaffected. Multiple polymorphic copies of the Y-linked genes showing single Y-specific signals suggested their tandem duplication. Some exposed males showed unilocus duplication of DAZ genes resulting in six copies. Notably, in the AZFa region, approximately 25% of exposed males showed deletion of the DBY gene, whereas flanking genes USP9Y and UTY remained unaffected. All these alterations were detected in blood samples but not in the germline (sperm) samples.ConclusionsExposure to high levels of NBR correlated with several interstitial polymorphisms of the human Y chromosome. CNPs and enhanced transcription of the SRY gene after duplication are envisaged to compensate for the loss of Y chromosome in some cells. The aforesaid changes, confined to peripheral blood lymphocytes, suggest a possible innate mechanism protecting the germline DNA from the NBR. Genome analysis of a larger population focusing on greater numbers of genes may provide new insights into the mechanisms and risks of the resultant genetic damages. The present work demonstrates unique signatures of NBR on human Y chromosomes from Kerala, India.

In the present study the comparative data of total phenol and total flavonoid contents along with antioxidant activity were assessed in native Canna indica. Total phenolic contents were analyzed by a Folin-Ciocalteu reagent and antioxidant activity was analyzed by DPPH assay and TEAC assay, in crude methanolic extracts of red, yellow varieties of Canna indica and red variety of Hibiscus rosa sinensis. DPPH assay of crude extracts taking pyrogallol as standard show that fresh red canna extract has best results for radical scavenging. Stability of color content of canna towards pH and its pKa were assessed. Colorimetric analysis of crude extracts showed red canna extract to be the best in terms of its tinctorial strength, a pre-requisite for a food dye. On the basis of the results obtained, red canna flowers were found to serve as a potential source of natural antioxidant and a natural food colorant.

The incidence of hepatocellular carcinoma (HCC) is rising in the US with parallel increase in mortality rate. Lack of effective therapy for advanced HCC mandates development of novel targeted therapies to counteract this fatal malady. Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) and LYRIC, plays a pivotal role in hepatocarcinogenesis and serves as an ideal target for anti-HCC therapy. AEG-1 interacts with retinoid X receptor (RXR) and inhibits retinoic acid-induced gene expression and cell death. Retinoic acid has been evaluated for HCC treatment without promising result. Overexpression of AEG-1 might underlie the poor performance of retinoic acid in HCC clinical trials. We documented that combination of a lentivirus expressing AEG-1 shRNA (lenti.shAEG-1) and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We now have developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). PAMAM has a net positive charge that complexes with the net negative charge of the siRNA backbone, PEG increases stability of the nanoplexes and increases circulation time and the galactose binds to asialoglycoprotein receptors that are upregulated on liver cells. The polymer conjugate was characterized by 1H-NMR and optimal nanoplex formulations were characterized for surface charge and size using a zetasizer Nano ZS. We established orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) in the livers of athymic nude mice and monitored tumor development by bioluminescence imaging (BLI). One week after tumor establishment mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si and PAMAM-AEG-1si+ATRA by 8 i.v. injections over 4 weeks, and sacrificed 2 weeks after the last injection. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. Measurement of liver weight at the end of the experiment corroborated these findings. Analysis of AEG-1 mRNA in tumor samples showed a marked decrease in AEG-1 level by PAMAM-AEG-1si indicating efficacy of in vivo knockdown. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anti-cancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC and need to be evaluated stringently in endogenous mouse models of HCC for a potential Phase I/II clinical trial. Citation Format: Jyoti Srivastava, Devaraja Rajasekaran, Ayesha Siddiq, Rachel Gredler, Chadia L. Robertson, Maaged A. Akiel, Xue-Ning Shen, Kareem A.N. Ebeid, Aliasger K. Salem, Paul B. Fisher, Devanand Sarkar. A novel combinatorial therapy for hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5400. doi:10.1158/1538-7445.AM2015-5400

Ionizing radiations are known to induce tumors, chromosomal lesions and minisatellite length variations, yet no correlation has been demonstrated between radiation exposure and indels or copy number polymorphism (CNP) of the genes. We studied the impact of natural background radiation (NBR) on the human Y chromosome owing to its haploid status and clonal inheritance. We analyzed the AZFc region using the DNA from blood and semen of 100 males living near the coastal peninsula in Kerala (India), exposed to NBR along with other 50 normal fertile males. STS mapping of AZFc region showed random microdeletions without conclusive gr/gr or b1/b3 phenotypes. Using a highly specific novel Taqman assay based on sY587 sequence, we detected four copies of the DAZ genes in normal males and 4-16 in those exposed to NBR. Amongst NBR exposed males with multiples copies of the DAZ genes, 75% showed varying FISH signals for DAZ genes with cosmid 18E8 whereas 30% showed mosaicism in terms of presence/absence of the signals in 6-8% cells and unexpected number of signals in 9-12% interphase nuclei. Startlingly, all germline samples studied were found to be free from AZFc microdeletions and CNP of the DAZ genes. Since the DAZ genes are heavily implicated with the germ cell development, the cells with DAZ deletion/duplication are unlikely to survive. Alternatively, an innate mechanism may be operative to protect the germline from the effects of NBR.

Classical and novel protein kinase C (PKC) isoforms are down-regulated as a result of chronic activation by certain tumour promoters and physiological stimuli; however, the mechanisms leading to down-regulation are not fully understood. In the present study, we have studied the PMA ('TPA')-induced degradation of PKCΔ in NIH 3T3 cells under culture conditions where PKCΔ displays cell-cycle-dependent down-regulation. In contrast with previous studies, a hyperphosphorylated form of this PKC isoform, promoted by calyculin A, was rapidly degraded in PMA-treated cells. Similarly, the presence of calyculin A enhanced the down-regulation of PKCΔ observed on G1/S-phase progression through the cell cycle. Analysis of phosphorylation-site mutants indicated that the T-loop Thr505 phosphorylation site was critical for induced degradation.

The oncogene Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in a wide variety of human cancers. In vitro and in vivo nude mouse xenograft studies have established the tumor-promoting role of AEG-1. Activation of multiple signaling pathways, such as NF-κB, PI3K/Akt, Wnt/β-catenin and MEK/ERK, has been attributed to mediate oncogenesis by AEG-1. To better understand the role AEG-1 plays in the onset and progression of cancer and to identify key mechanism(s) of AEG-1 action, we generated a novel AEG-1 knockout mouse (AEG-1-/-). We studied hepatocarcinogenesis in this model because AEG-1 is overexpressed in more than 90% of human hepatocellular carcinoma (HCC) patients and is believed to play a key regulatory role in progression of the disease. AEG-1-/- mice were viable with normal development. We first compared the aging associated phenotype of WT and AEG-1-/- mice. At 16 months of age spontaneous tumor development in lungs and liver was observed in some cohorts of untreated WT mice (n=20). Such tumorigenesis was not detected in any of the AEG-1-/- mice. Additionally, age-associated inflammatory infiltrates were observed in the internal organs of WT but not AEG-1-/- mice. To initiate HCC, WT and AEG-1-/- mice were treated with diethylnitrosamine (DEN) at 2 weeks of age. At 32 weeks WT mice showed a marked hepatocarcinogenic response while AEG-1-/- mice exhibited profound resistance to tumor formation. The hepatocarcinogenic response was further evaluated by DEN initiation followed by daily phenobarbital treatment. WT mice exhibited an intensified hepatocarcinogenic response evidenced by large necrotic liver tumors at 28 weeks of age with a 52% rate of lung metastasis. AEG-1-/- mice remained remarkably resistant even to this combinatorial treatment with no distant metastasis. No difference in the activation of Akt, ERK and β-catenin signaling was observed between WT and AEG-1-/- mice indicating that these pathways may not be regulated by AEG-1 under physiological conditions. However, marked inhibition of NF-κB activation was observed in AEG-1-/- mice. Lipopolysaccharide (LPS)-induced NF-κB luciferase reporter activity, nuclear translocation of p65 subunit of NF-κB and induction of IL-1β and IL-6 were markedly attenuated in primary hepatocytes and macrophages isolated from AEG-1-/- versus WT mice. Chronic inflammation and NF-κB activation play a causal role in hepatocarcinogenesis. Inhibition of NF-κB activation in hepatocytes and macrophages profoundly abrogates HCC development in mouse models. Our findings in AEG-1-/- mice confirm a fundamental role of AEG-1 in NF-κB activation. Here we demonstrate that lack of AEG-1 protects from generalized inflammation thereby suppressing spontaneous as well as experimental tumorigenesis. AEG-1-/-mice might be a useful model to study inflammation and cancer in diverse organ systems. Citation Format: Chadia L. Robertson, Jyoti Srivastava, Ayesha Siddiq, Rachel Gredler, Devaraja Rajasekaran, Maaged Akiel, Xue-Ning Shen, Knarik Arkun, Shobha Ghosh, Mark A. Subler, Jolene Windle, Paul B. Fisher, Devanand Sarkar. Analyzing the role of Astrocyte Elevated Gene-1 (AEG-1) in hepatocarcinogenesis using a knockout mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 72. doi:10.1158/1538-7445.AM2014-72

Violence against women can be addressed through a fundamental rights lens. It is a violation of human dignity and, in its worst form; it violates the right to life. A descriptive study was carried out among 30 married women, at a selected hospital in Varanasi. Participants were selected through convenient sampling. Data was collected through interview, by using Socio demographic proforma and structured domestic violence questionnaire. The result showed that the overall prevalence of domestic violence among women was 23(76.7%). Although, there was no correlation between domestic violence and Expenditure, Disability, Burden, Duration of illness. Domestic violence was higher amongst the group of middle educated and house maker women in area of Uttar Pradesh. 30% of the sample belonged to diagnostic category of schizophrenia. This was followed by Depression in nearly 16.7%. Most of the cases, 86.7% precipitating factor were present and 60% cases past mental illness was absent, so effective actions should be taken to stop Domestic Violence at no time.

Background Domestic violence against women is the most pervasive human rights violation in the world today. According to UNiTE to End Violence against Women (2009) by UN Women, In the United States, one-third of women murdered each year are killed by intimate partners. In South Africa, a woman is killed every 6 hours by an intimate partner. The Objective To assess the magnitude and causes of domestic violence with mental illness & normal women. Material & Methods The sample of study comprised of 50 women with mental illness and 50 normal women. Mental illness patients diagnosed according to with Axis one psychiatric Disorder DSM IV-TR, who were selected from the Psychiatry OPD and ward of the S.S. Hospital, BHU and normal women were be selected from the accompany with patients of Sir Sunder Lal Hospital. The patients were assessed on the structured questionnaire on Domestic Violence. RESULTS The domestic violence present in married women with mental illness was 72% and normal women were 36%. Perceived causes of domestic violence in married women with mental illness were more compared to those with normal women. The health care personnel should be given an opportunity to update their knowledge regarding domestic violence and there is need education for domestic violence and cessation, so that they can help the women to protect/prevent domestic violence. Language: en

The aim of this work was to determine the role of the ob gene in the obese phenotype observed in the Aston University Strain of ob/ob mouse and the Japanese Kuo Kondo (KK) mouse. After RT-PCR amplification of the ob RNA, the transcript was cloned into the vector pCR3 and three individual clones from each strain were sequenced. It was confirmed that the Aston University strain of ob/ob mice shared the same C-T mutation found in the Jackson Laboratory C57BL/6J ob/ob strain whereas the Japanese KK mice showed wild-type ob gene expression. This study indicates that the ob mutation has survived unchanged following the separation of the two strains of ob/ob mice, and secondly, that the molecular basis of the obese phenotype in the KK mice is not due to mutations in the ob gene.

The oncogene Astrocyte Elevated Gene-1 (AEG-1), also known as Metadherin (MTDH), is overexpressed in a diverse array of cancers, including hepatocellular carcinoma (HCC), and plays an important role in promoting tumor development and progression. Protein-protein interaction predominantly mediates the tumor promoting effects of AEG-1. We now describe screening of a human liver cDNA library by yeast two hybrid assay resulting in identification of Retinoid X Receptor (RXR) as an AEG-1-interacting protein. Site-directed mutagenesis assays identified an LXXLL motif in the N-terminus of AEG-1 mediating interaction with RXR. We employed human HCC cell lines stably overexpressing AEG-1 or with knockdown of AEG-1 and mouse hepatocytes isolated from a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG-1) and from AEG-1 knockout (AEG-1 KO) mouse for our studies. Luciferase reporter assays in these cells demonstrate that AEG-1 profoundly inhibits RXR-mediated transcriptional regulation of its heterodimer partner, such as Retinoic Acid Receptor (RAR), Thyroid Hormone Receptor (TR), Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR), in the presence or absence of their corresponding ligands. In this study, we focus on retinoic acid (RA) and thyroid hormone (T3) function. AEG-1 markedly inhibits expression of RA- and T3-induced genes. Overexpressed AEG-1 in cancer cells and in transgenic hepatocytes accumulates in the cytoplasm and inhibits RXR function by trapping RXR in the cytoplasm precluding its nuclear translocation. Additionally, AEG-1 induces phosphorylation of RXR, via ERK and p38 MAPK pathways. Phosphorylated RXR has low transcriptional activity, functions as dominant negative inhibitor of RXR and might facilitate hepatocarcinogenesis by AEG-1. Indeed, chromatin immunoprecipitation (ChIP) assay using RA-target genes, RARB and HOXA1, shows decreased DNA binding of RXR, even upon ligand-treatment. Overexpression of AEG-1 significantly protects human HCC cells, mouse hepatocytes and human promyelocytic leukemia cells from the killing effects of retinoic acid and its synthetic analogs. By inhibiting the expression of T3-regulated gene type I deiodinase (DIO1), AEG-1 abrogates peripheral conversion of inactive T4 to active T3 which is reflected by significantly low T3 level in the circulation of Alb/AEG-1 mice compared to WT mice. Since AEG-1 is upregulated in a wide-variety of cancers it might play an important role in regulating a diverse array of RXR-dependent signaling pathways that are critical for regulating the oncogenic process. Synthetic retinoids are being evaluated as chemopreventive agents for HCC as well as a therapeutic modality for PML. AEG-1 expression level might determine the sensitivity of the patients to these retinoids. Additionally AEG-1 might play a key role in ‘low T3 syndrome’ associated with cancer. Citation Format: Jyoti Srivastava, Chadia L. Robertson, Rachel Gredler, Ayesha Siddiq, Devaraja Rajasekaran, Prasanna K. Santhekadur, Paul B. Fisher, Devanand Sarkar. Astrocyte Elevated Gene-1 (AEG-1) interacts with retinoid X receptor (RXR) and abrogates its function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5437. doi:10.1158/1538-7445.AM2013-5437

In vitro tissue culture and nude mice xenograft models have firmly established the role of Astrocyte elevated gene-1 (AEG-1) as a positive regulator of tumorigenesis, including hepatocarcinogenesis. To better appreciate the role of AEG-1 in hepatocarcinogenesis and to dissect the underlying molecular mechanism, we have created a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1). Wild-type (WT) and Alb/AEG-1 mice were challenged with a hepatocarcinogen, N-nitrosodiethylamine (DEN), at 2 weeks of age. At 28 weeks of age, Alb/AEG-1 mice, but not WT mice, developed multinodular HCC with steatotic features and highly elevated serum liver enzymes. Affymetrix microarray analyses identified modulation of expression of genes associated with invasion, metastasis, angiogenesis and fatty acid synthesis in DEN-treated Alb/AEG-1 mice versus their WT counterparts. Hepatocytes isolated from Alb/AEG-1 mice demonstrated profound chemoresistance and dramatically evaded reduction in cell viability upon growth factor deprivation, which was associated with activation of multiple pro-survival signaling pathways. Compared to the WT hepatocytes, Alb/AEG-1 hepatocytes demonstrated marked resistance towards senescence, which was associated with abrogation of activation of a DNA damage response. Conditioned media (CM) from Alb/AEG-1 hepatocytes, but not form WT hepatocytes, induced marked angiogenesis. Mass spectrometric analysis of CM revealed noticeable increases in coagulation factors by AEG-1, which are known to play a significant role in regulating tumor invasion, angiogenesis and metastasis. siRNA-mediated knockdown of coagulation factor XII resulted in profound inhibition of AEG-1-induced angiogenesis. Our studies reveal novel aspects of AEG-1 functions, such as induction of steatosis, inhibition of senescence, a known anti-cancer mechanism, and activation of coagulation pathway to augment an aggressive hepatocarcinogenic phenotype. The Alb/AEG-1 mouse will be a useful model to decipher AEG-1 function in the context of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies directed towards HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1324. doi:1538-7445.AM2012-1324

Aim: The aim of this study was to review our experience with tube thoracostomy in the management of empyema thoracis in children. Patients and Methods: This retrospective study included 46 children (26 boys and 20 girls) who were admitted and managed for empyema thoracis, between January 1, 2010 and December 31, 2010 at the author’s department of paediatric surgery. Results: During the last 12 months, 46 children aged below 12 years were treated for empyema thoracis: Five (10.86%) were infants, 22 (47.82%) were 1 to 5 years and 19 (41.30%) were 6 to 12 years of age. All the patients presented with complaints of cough, fever and breathlessness of variable durations. Twenty three (50%) children had history of pneumonia and treatment prior to development of empyema. Thirty five (76.08%) children had right-sided and 11 (23.91%) had left-sided empyema. Thirty nine (84.78%) children were successfully treated with tube thoracostomy, systemic antibiotics and other supportive measures. Seven (15.21%) children failed to respond with above and needed decortications. Most commonly isolated bacteria were Pseudomonas (n = 12) and Staphylococcus aureus (n = 7). The average length of hospital stay in patients with tube thoracostomy was 15.35 days, and in patients who needed decortications was 16.28 days following thoracotomy. There was no mortality amongst above treated children. Conclusions: Majority of children with empyema thoracis are manageable with tube thoracostomy, antibiotics, physiotherapy and other supportive treatment. Few of them who fail to above measures need more aggressive management.

Highlights • SND1 augments AT1R receptor level by posttranscriptional regulation. • SND1 activates TGFβ signaling which promotes the epithelial–mesenchymal transition. • Migration and invasion by human hepatocellular carcinoma (HCC) cells are augmented by SND1. • A correlation is observed between SND1 and AT1R expression in HCC patients., Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in human hepatocellular carcinoma (HCC) patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R) levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGFβ signaling pathway, promoting epithelial–mesenchymal transition (EMT) and migration and invasion by human HCC cells. A positive correlation was observed between SND1 and AT1R expression levels in human HCC patients. Small molecule inhibitors of SND1, alone or in combination with AT1R blockers, might be an effective therapeutic strategy for late-stage aggressive HCC.