Scipedia: Collection of EBioMedicine

Implications of Genetic and Epigenetic Alterations of CDKN2A (p16 ) in Cancer

Scipedia content — Thu, 06 Apr 2017 12:11:57 +0200

Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK) 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.

Leaving History Behind: CD4/CD8 Ratio as a Diagnostic Tool in Sarcoidosis

Scipedia content — Thu, 06 Apr 2017 12:11:53 +0200

Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas

Scipedia content — Thu, 06 Apr 2017 12:11:47 +0200

Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patients HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients.

Corrigendum to “Syk and ye shall find” [EBioMedicine 2 (11) (2015) 190-1591]

Scipedia content — Thu, 06 Apr 2017 12:11:41 +0200

Accumulation of MxB/Mx2-resistant HIV-1 Capsid Variants During Expansion of the HIV-1 Epidemic in Human Populations

Scipedia content — Thu, 06 Apr 2017 12:11:36 +0200

Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution.

The Effect of Latency Reversal Agents on Primary CD8 + T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication

Scipedia content — Thu, 06 Apr 2017 12:11:27 +0200

Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4 + T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4 + T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8 + T cells were not able to eliminate autologous resting CD4 + T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8 + T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8 + T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8 + T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.

LEDGIN-mediated Inhibition of Integrase–LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV

Scipedia content — Thu, 06 Apr 2017 12:11:17 +0200

Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.

Oral Anticoagulants and Renal Impairment: The Convoluting Dilemma

Scipedia content — Thu, 06 Apr 2017 12:11:10 +0200

What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins

Scipedia content — Thu, 06 Apr 2017 12:11:02 +0200

The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.

Catecholamines Facilitate Fuel Expenditure and Protect Against Obesity via a Novel Network of the Gut-Brain Axis in Transcription Factor Skn-1 -deficient Mice

Scipedia content — Thu, 06 Apr 2017 12:10:54 +0200

Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis. This system is referred to as the gut-brain axis. Here we show that both brush cells and type II taste cells are eliminated in the gastrointestinal tract of transcription factor Skn-1 knockout (KO) mice. Despite unaltered food intake, Skn-1 KO mice have reduced body weight with lower body fat due to increased energy expenditure. In this model, 24-h urinary excretion of catecholamines was significantly elevated, accompanied by increased fatty acid β-oxidation and fuel dissipation in skeletal muscle and impaired insulin secretion driven by glucose. These results suggest the existence of brain-mediated energy homeostatic pathways originating from brush cells and type II taste cells in the gastrointestinal tract and ending in peripheral tissues, including the adrenal glands. The discovery of food-derived factors that regulate these cells may open new avenues the treatment of obesity and diabetes. Taste signals and nutrient stimuli sensed by the gastrointestinal tract are transmitted to the brain to regulate feeding behavior and energy homeostasis along the gut-brain axis. We propose the concept that taste-receiving cells in the oral cavity and/or food-borne chemicals-receiving brush cells in the gut are involved in regulation of the body weight and adiposity via the brain. The discovery of food-derived factors that regulate these cells may open new avenues for the treatment of obesity and diabetes.

Low Circulating Amino Acids and Protein Quality: An Interesting Piece in the Puzzle of Early Childhood Stunting

Scipedia content — Thu, 06 Apr 2017 12:10:48 +0200

A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics

Scipedia content — Thu, 06 Apr 2017 12:10:38 +0200

Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened > 320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.

A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib

Scipedia content — Thu, 06 Apr 2017 12:10:02 +0200

Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that β-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that β-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo . Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance. We further demonstrate that β-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi.

Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-analysis

Scipedia content — Thu, 06 Apr 2017 12:09:50 +0200

The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deekss funnel plot was used to detect publication bias. Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64–0.75), specificity, 0.83 (95%CI 0.78–0.86), PLR, 4.04 (95%CI 3.13–5.20), NLR, 0.36 (95%CI 0.30–0.44), and DOR, 11.17 (95%CI 7.31–17.07). The area under the SROC curve was 0.84 (95%CI 0.81–0.87). There was no evidence of publication bias. Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors.

Deciphering “B-others”: Novel fusion genes driving B-cell acute lymphoblastic leukemia

Scipedia content — Thu, 06 Apr 2017 12:09:46 +0200

Gut Bacteria Metabolism Impacts Immune Recovery in HIV-infected Individuals

Scipedia content — Thu, 06 Apr 2017 12:09:37 +0200

While changes in gut microbial populations have been described in human immuno-deficiency virus (HIV)-infected patients undergoing antiretroviral therapy (ART), the mechanisms underlying the contributions of gut bacteria and their molecular agents (metabolites and proteins) to immune recovery remain unexplored. To study this, we examined the active fraction of the gut microbiome, through examining protein synthesis and accumulation of metabolites inside gut bacteria and in the bloodstream, in 8 healthy controls and 29 HIV-infected individuals (6 being longitudinally studied). We found that HIV infection is associated to dramatic changes in the active set of gut bacteria simultaneously altering the metabolic outcomes. Effects were accentuated among immunological ART responders, regardless diet, subject characteristics, clinical variables other than immune recovery, the duration and type of ART and sexual preferences. The effect was found at quantitative levels of several molecular agents and active bacteria which were herein identified and whose abundance correlated with HIV immune pathogenesis markers. Although, we cannot rule out the possibility that some changes are partially a random consequence of the disease status, our data suggest that most likely reduced inflammation and immune recovery is a joint solution orchestrated by both the active fraction of the gut microbiota and the host.

Ethnicity matters: A Systematic Review and Meta-Analysis of the Non-Linear Relationship Between Alcohol Consumption and Prevalence and Incidence of Hepatic Steatosis

Scipedia content — Thu, 06 Apr 2017 12:09:21 +0200

Fatty liver (hepatic steatosis) is one of the most common diseases globally, with increasing prevalence. The role of alcohol consumption in the development of hepatic steatosis has not been systematically examined. We searched Medline, Embase, and ProQuest Dissertations & Theses Global for original data on the relationship between alcohol consumption and hepatic steatosis measured by non-invasive imagery, excluding studies conducted in participants

One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study

Scipedia content — Thu, 06 Apr 2017 12:09:14 +0200

Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79–82.86], p = 0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

Chronic Kidney Disease, Time in Therapeutic Range and Adverse Clinical Outcomes in Anticoagulated Patients with Non-valvular Atrial Fibrillation: Observations from the SPORTIF Trials

Scipedia content — Thu, 06 Apr 2017 12:09:06 +0200

Chronic kidney disease (CKD) is highly prevalent in atrial fibrillation (AF) patients and associated with an increased risk of adverse outcomes. Our objectives were to study clinical features associated with CKD in AF patients and the impact of CKD on anticoagulation control, as reflected by time in therapeutic range (TTR). We also determined the impact of CKD and TTR in predicting adverse outcomes. We analysed pooled datasets from SPORTIF III and V trials, including 3646 patients assigned to warfarin with data on renal function. CKD (creatinine clearance 70%, whilst diabetes mellitus, aspirin use and CKD were inversely associated with TTR > 70%. On Cox regression analysis, CKD was an independent predictor for stroke (p = 0.006) and death (p 70% was independently associated with a lower risk of stroke (p = 0.024), death (p = 0.001) and major bleeding (p = 0.001). CKD is highly prevalent amongst AF patients and a risk factor for stroke and death. Adjusting for CKD, good quality anticoagulation control (TTR > 70%) was an independent predictor for lower risks of stroke, death and major bleeding.

Liver Flukes and the Microbiota in Cancer

Scipedia content — Thu, 06 Apr 2017 12:09:01 +0200