Análisis multiescala de las comunidades de coral hermatípico del Pacífico Central Mexicano

The Mexican Central Pacific is located in a zone of oceanographic transition between two biogeographic provinces with particular conditions that affect the associated fauna. The objective of this study was to evaluate the variation of hermatypic coral assemblages in this region and to determine their relationship with the heterogeneity of the benthonic habitat and spatial variables. A total of 156 transects were carried out at 41 sites in the years 2010 and 2011. The sampling effort returned 96.7% of the coral richness expected for the area, with a total of 15 species recorded. The results showed that richness, diversity and cover of corals varied only at the site and state scales. However, the composition and coverage of all coral species, as well as the benthonic habitat structure, differed significantly across the study scales (i.e. sites, zones and states). Canonical redundancy analysis showed that variation in the richness, diversity and assemblages of corals was explained by the cover of live corals, articulated calcareous algae, sandy substrate, sponges and fleshy macroalgae. This study suggests that local scale (i.e. site) variation in the coral assemblages of the Mexican Central Pacific is the result of the heterogeneity of the benthonic habitat, while geomorphological and oceanographic characteristics play a greater role at regional scale.El Pacífico Central Mexicano se localiza en una zona de transición oceanográfica entre dos provincias biogeográficas con condiciones ambientales particulares que afectan la fauna asociada. El objetivo del estudio fue evaluar la variación de las comunidades de coral hermatípico de esta región y determinar su relación con la heterogeneidad del hábitat bentónico y variables espaciales. Se realizaron 156 transectos en 41 sitios en los años 2010 y 2011. El esfuerzo de muestreo representó el 96.7% de la riqueza de coral esperada para el área, con un total de 15 especies registradas. Los resultados mostraron que la riqueza, diversidad y cobertura de corales variaron sólo en las escalas de sitio y de estado. En cambio, la composición y cobertura de todas las especies de coral, así como la estructura del hábitat bentónico, fueron significativamente diferentes en todas las escalas estudiadas (i.e. sitio, zona y estado). Los análisis de redundancia canónica mostraron que la variación de la riqueza, diversidad y de las comunidades de corales eran explicadas por la cobertura de coral vivo, algas calcáreas articuladas, sustrato arenoso, esponjas y macroalgas carnosas. Este trabajo sugiere que la variación de las comunidades de coral en el Pacífico Central Mexicano a escala local (i.e. sitio) se debe a la heterogeneidad del hábitat bentónico, mientras que a escala regional, las características geomorfológicas y oceanográficas desempeñan un papel más importante

Ensamblajes bacterianos asociados a especies de coral del Pacífico central mexicano

The functional role of coral-associated bacteria and their contribution to coral health is still largely unknown. The first necessary step to address this gap in the knowledge is based on characterization of the microbial assemblage of the coral and the species-specific, temporal and spatial variation in its diversity. Branched corals (e.g., genus Pocillopora), are the main builders of coral reefs worldwide. This study evaluated the bacteria associated with the mucus and tissues of Pocillopora damicornis and Pocillopora verrucosa, as well as that of the seawater and surrounding sediments, in 6 sites of the Mexican Central Pacific during summer and winter seasons. The molecular techniques DGGE and RFLP were used with the 16S rDNA to assess the most abundant bacterial OTUs. The relationships between the bacterial-coral assemblage and environmental and spatial variables of the reef surroundings were also evaluated, using the multivariate analyses. Twenty different Operational Taxonomic Units (OTU) were obtained, with the highest number presented by the sediments. Specificity of bacterial groups was found for each coral species, as well as between the tissue and mucus of each species. The results showed that the bacterial dominant groups were similar between seasons, but these showed significant spatial variations among substrates within sites, as well as per substrate across all sites. The environmental variables that explained the variation of the dominant bacterial groups in corals and sea water were the coverages of fleshy macroalgae, live coral and sponge. In contrast, variation in the sediments was explained by the coverages of sand, rubble and rock.El papel funcional de las bacterias asociadas a corales y su contribución a la salud del coral es aún desconocido en gran medida. Es necesario que primero se caracterice el ensamblaje microbiano del coral y sus cambios en la diversidad a través de las especies de coral, el espacio y tiempo. Los corales ramificados (e.g., género Pocillopora) son los principales constructores arrecifales a nivel mundial. Este estudio evaluó la estructura bacteriana asociada al mucus y tejidos de Pocillopora damicornis y Pocillopora verrucosa, así como del agua de mar y sedimentos circundantes en 6 sitios del Pacífico central mexicano. Se emplearon las técnicas DGGE y RFLP del ADNr 16S para generar los perfiles de bandeo o evaluar la diversidad. Además, se evaluó la relación del ensamblaje bacteriano-coral con variables ambientales y espaciales del entorno arrecifal (de cada sitio), utilizando análisis multivariados. Se obtuvieron 20 Unidades Taxonómicas Operacionales (OTU) diferentes, siendo los sedimentos los que presentaron mayor número. Se encontró una especificidad de grupos bacterianos para cada especie de coral, así como entre el tejido y mucus de cada especie. Los resultados mostraron que los grupos de bacterias dominantes variaron entre sustratos y entre sitios, encontrando, sólo una variación espacial significativa. Las variables ambientales que explican la variación de los grupos bacterianos dominantes en corales y agua de mar fueron las coberturas de macroalgas carnosas, coral vivo y esponja. En cambio, la variación en los sedimentos fue explicada por las coberturas de arena, escombro y roc

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks