Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype.

Cancer cells exhibit dramatic alterations of chromatin organization at cis-regulatory elements, but the molecular basis, extent, and impact of these alterations are still being unraveled. Here, we identify extensive genome-wide modification of sites bearing the active histone mark H3K4me2 in primary human colorectal cancers, as compared with corresponding benign precursor adenomas. Modification of certain colorectal cancer sites highlighted the activity of the transcription factor CNOT3, which is known to control self-renewal of embryonic stem cells (ESC). In primary colorectal cancer cells, we observed a scattered pattern of CNOT3 expression, as might be expected for a tumor-initiating cell marker. Colorectal cancer cells exhibited nuclear and cytoplasmic expression of CNOT3, suggesting possible roles in both transcription and mRNA stability. We found that CNOT3 was bound primarily to genes whose expression was affected by CNOT3 loss, and also at sites modulated in certain types of colorectal cancers. These target genes were implicated in ESC and cancer self-renewal and fell into two distinct groups: those dependent on CNOT3 and MYC for optimal transcription and those repressed by CNOT3 binding and promoter hypermethylation. Silencing CNOT3 in colorectal cancer cells resulted in replication arrest. In clinical specimens, early-stage tumors that included >5% CNOT3(+) cells exhibited a correlation to worse clinical outcomes compared with tumors with little to no CNOT3 expression. Together, our findings implicate CNOT3 in the coordination of colonic epithelial cell self-renewal, suggesting this factor as a new biomarker for molecular and prognostic classification of early-stage colorectal cancer. Cancer Res; 77(3); 766-79. ©2016 AACR

A common genetic network underlies substance use disorders and disruptive or externalizing disorders

Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders

Atlantoaxial subluxation as an early manifestation in an adolescent with undifferentiated spondyloarthritis: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Atlantoaxial instability has been described as a manifestation of ankylosing spondylitis (juvenile and adult onset), reactive arthritis, juvenile idiopathic arthritis, and rheumatoid arthritis; however, it has rarely been reported as an early manifestation of these disorders. We present this case report to increase awareness of the condition in the hope that earlier recognition of this disease may prevent further serious injury.</p> <p>Case presentation</p> <p>We report the case of a 17-year-old Hispanic adolescent woman who was initially diagnosed with undifferentiated spondyloarthritis due to peripheral arthritis, enthesitis, a positive human leukocyte antigen B27 result, and inflammatory spinal pain lasting two months. Our patient experienced persistent and worsening occipitocervical pain and signs of myelopathy three months after diagnosis; consequently, we found atlantoaxial instability along with cervical spine bone erosion and pannus formation. She was treated surgically with a C1-2 posterior instrumented fusion and at six weeks post-operatively was started on tumor necrosis factor α blockade. Her occipitocervical symptoms subsided following surgery and initiation of immunomodulation.</p> <p>Conclusions</p> <p>Our report serves to emphasize to pediatric and adult general practitioners, pediatricians, internists, family physicians, pediatric and adult rheumatologists and spine surgeons that atlantoaxial subluxation may be an early manifestation of spondyloarthritis, and that the condition is treatable by surgical intervention and immunomodulation.</p

Past Achievements and Future Challenges in 3D Photonic Metamaterials

Photonic metamaterials are man-made structures composed of tailored micro- or nanostructured metallo-dielectric sub-wavelength building blocks that are densely packed into an effective material. This deceptively simple, yet powerful, truly revolutionary concept allows for achieving novel, unusual, and sometimes even unheard-of optical properties, such as magnetism at optical frequencies, negative refractive indices, large positive refractive indices, zero reflection via impedance matching, perfect absorption, giant circular dichroism, or enhanced nonlinear optical properties. Possible applications of metamaterials comprise ultrahigh-resolution imaging systems, compact polarization optics, and cloaking devices. This review describes the experimental progress recently made fabricating three-dimensional metamaterial structures and discusses some remaining future challenges

Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis

A previous systematic review reported that topical NSAIDs were effective in relieving pain in chronic conditions like osteoarthritis and tendinitis. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review. Studies were identified by searching electronic databases, and writing to manufacturers. We identified randomised, double blind trials comparing topical NSAID with either placebo or another active treatment, in adults with chronic pain. The primary outcome was a reduction in pain of approximately 50% at two weeks, and secondary outcomes were local and systemic adverse events and adverse event-related withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative harm and number-needed-to-harm (NNH) were calculated, and the effects of trial quality, validity and size, outcome reported, and condition treated, were examined by sensitivity analyses. Twelve new trials were added to 13 trials from a previous review. Fourteen double blind placebo-controlled trials had information from almost 1,500 patients. Topical NSAID was significantly better than placebo with relative benefit 1.9 (95% confidence interval 1.7 to 2.2), NNT 4.6 (95% confidence interval 3.8 to 5.9). Results were not affected by trial quality, validity or size, outcome reported, or condition treated. Three trials with 764 patients comparing a topical with an oral NSAID found no difference in efficacy. Local adverse events (6%), systemic adverse events (3%), or the numbers withdrawing due to an adverse event were the same for topical NSAID and placebo. Topical NSAIDs were effective and safe in treating chronic musculoskeletal conditions for two weeks. Larger and longer trials are necessary to fully elucidate the place of topical NSAIDs in clinical practice

Multiplex Real-Time PCR Assay Using TaqMan Probes for the Identification of Trypanosoma cruzi DTUs in Biological and Clinical Samples

Background: Trypanosoma cruzi has been classified into six Discrete Typing Units (DTUs), designated as TcI–TcVI. In order to effectively use this standardized nomenclature, a reproducible genotyping strategy is imperative. Several typing schemes have been developed with variable levels of complexity, selectivity and analytical sensitivity. Most of them can be only applied to cultured stocks. In this context, we aimed to develop a multiplex Real-Time PCR method to identify the six T. cruzi DTUs using TaqMan probes (MTq-PCR).Methods/Principal Findings: The MTq-PCR has been evaluated in 39 cultured stocks and 307 biological samples from vectors, reservoirs and patients from different geographical regions and transmission cycles in comparison with a multi-locus conventional PCR algorithm. The MTq-PCR was inclusive for laboratory stocks and natural isolates and sensitive for direct typing of different biological samples from vectors, reservoirs and patients with acute, congenital infection or Chagas reactivation. The first round SL-IR MTq-PCR detected 1 fg DNA/reaction tube of TcI, TcII and TcIII and 1 pg DNA/reaction tube of TcIV, TcV and TcVI reference strains. The MTq-PCR was able to characterize DTUs in 83% of triatomine and 96% of reservoir samples that had been typed by conventional PCR methods. Regarding clinical samples, 100% of those derived from acute infected patients, 62.5% from congenitally infected children and 50% from patients with clinical reactivation could be genotyped. Sensitivity for direct typing of blood samples from chronic Chagas disease patients (32.8% from asymptomatic and 22.2% from symptomatic patients) and mixed infections was lower than that of the conventional PCR algorithm.Conclusions/Significance: Typing is resolved after a single or a second round of Real-Time PCR, depending on the DTU. This format reduces carryover contamination and is amenable to quantification, automation and kit production.This work received financial support from the Ministry of Science and Technology of Argentina [PICT 2011-0207 to AGS] and the National Scientific and Technical Research Council in Argentina (CONICET) [PIP 112 2011-010-0974 to AGS]. Work related to evaluation of biological samples was partially sponsored by the Pan-American Health Organization (PAHO) [Small Grants Program PAHO-TDR]; the Drugs and Neglected Diseases Initiative (DNDi, Geneva, Switzerland), Wellcome Trust (London, United Kingdom), SANOFI-AVENTIS (Buenos Aires, Argentina) and the National Council for Science and Technology in Mexico (CONACYT) [FONSEC 161405 to JMR]

The post-vaccine microevolution of invasive Streptococcus pneumoniae

The 7-valent pneumococcal conjugated vaccine (PCV7) has affected the genetic population of Streptococcus pneumoniae in pediatric carriage. Little is known however about pneumococcal population genomics in adult invasive pneumococcal disease (IPD) under vaccine pressure. We sequenced and serotyped 349 strains of S. pneumoniae isolated from IPD patients in Nijmegen between 2001 and 2011. Introduction of PCV7 in the Dutch National Immunization Program in 2006 preluded substantial alterations in the IPD population structure caused by serotype replacement. No evidence could be found for vaccine induced capsular switches. We observed that after a temporary bottleneck in gene diversity after the introduction of PCV7, the accessory gene pool re-expanded mainly by genes already circulating pre-PCV7. In the post-vaccine genomic population a number of genes changed frequency, certain genes became overrepresented in vaccine serotypes, while others shifted towards non-vaccine serotypes. Whether these dynamics in the invasive pneumococcal population have truly contributed to invasiveness and manifestations of disease remains to be further elucidated. We suggest the use of whole genome sequencing for surveillance of pneumococcal population dynamics that could give a prospect on the course of disease, facilitating effective prevention and management of IPD

Altered multisensory temporal integration in obesity

Eating is a multisensory behavior. The act of placing food in the mouth provides us with a variety of sensory information, including gustatory, olfactory, somatosensory, visual, and auditory. Evidence suggests altered eating behavior in obesity. Nonetheless, multisensory integration in obesity has been scantily investigated so far. Starting from this gap in the literature, we seek to provide the first comprehensive investigation of multisensory integration in obesity. Twenty male obese participants and twenty male healthy-weight participants took part in the study aimed at describing the multisensory temporal binding window (TBW). The TBW is defined as the range of stimulus onset asynchrony in which multiple sensory inputs have a high probability of being integrated. To investigate possible multisensory temporal processing deficits in obesity, we investigated performance in two multisensory audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Results showed a wider TBW in obese participants as compared to healthy-weight controls. This holds true for both the simultaneity judgment and the temporal order judgment tasks. An explanatory hypothesis would regard the effect of metabolic alterations and low-grade inflammatory state, clinically observed in obesity, on the temporal organization of brain ongoing activity, which one of the neural mechanisms enabling multisensory integration

Gene Expression Analysis Implicates a Death Receptor Pathway in Schizophrenia Pathology

An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH