Genetic diversity of soil invertebrates corroborates timing estimates for past collapses of the West Antarctic Ice Sheet

During austral summer field seasons between 1999 and 2018, we sampled at 91 locations throughout southern Victoria Land and along the Transantarctic Mountains for six species of endemic microarthropods (Collembola), covering a latitudinal range from 76.0°S to 87.3°S. We assembled individual mitochondrial cytochrome oxidase subunit 1 (COI) sequences (= 866) and found high levels of sequence divergence at both small (600 km) spatial scales for four of the six Collembola species. We applied molecular clock estimates and assessed genetic divergences relative to the timing of past glacial cycles, including collapses of the West Antarctic Ice Sheet (WAIS). We found that genetically distinct lineages within three species have likely been isolated for at least 5.54 My to 3.52 My, while the other three species diverged more recently (<2 My). We suggest that Collembola had greater dispersal opportunities under past warmer climates, via flotation along coastal margins. Similarly increased opportunities for dispersal may occur under contemporary climate warming scenarios, which could influence the genetic structure of extant populations. As Collembola are a living record of past landscape evolution within Antarctica, these findings provide biological evidence to support geological and glaciological estimates of historical WAIS dynamics over the last ca. 5 My

Salvage brachytherapy in prostate local recurrence after radiation therapy: predicting factors for control and toxicity

PURPOSE: To evaluate efficacy and toxicity after salvage brachytherapy (BT) in prostate local recurrence after radiation therapy. METHODS AND MATERIALS: Between 1993 and 2007, we retrospectively analyzed 56 consecutively patients (pts) undergoing salvage brachytherapy. After local biopsy-proven recurrence, pts received 145 Gy LDR-BT (37 pts, 66%) or HDR-BT (19 pts, 34%) in different dose levels according to biological equivalent doses (BED2 Gy). By the time of salvage BT, only 15 pts (27%) received ADT. Univariate and multivariate analyses were performed to identify predictors of biochemical control and toxicities. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCv3.0). RESULTS: Median follow-up after salvage BT was 48 months. The 5-year FFbF was 77%. HDR and LDR late grade 3 GU toxicities were observed in 21% and 24%. Late grade 3 GI toxicities were observed in 2% (HDR) and 2.7% (LDR). On univariate analysis, pre-salvage prostate-specific antigen (PSA) > 10 ng/ml (p = 0.004), interval to relapse after initial treatment < 24 months (p = 0.004) and salvage HDR-BT doses BED2 Gy level < 227 Gy (p = 0.012) were significant in predicting biochemical failure. On Cox multivariate analysis, pre-salvage PSA, and time to relapse were significant in predicting biochemical failure.HDR-BT BED2 Gy (α/β 1.5 Gy) levels ≥ 227 (p = 0.013), and ADT (p = 0.049) were significant in predicting grade ≥ 2 urinary toxicity. CONCLUSIONS: Prostate BT is an effective salvage modality in some selected prostate local recurrence patients after radiation therapy. Even, we provide some potential predictors of biochemical control and toxicity for prostate salvage BT, further investigation is recommended

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

A school-based program implemented by community providers previously trained for the prevention of eating and weight-related problems in secondary-school adolescents : the MABIC study protocol

Background: The prevention of eating disorders and disordered eating are increasingly recognized as public health priorities. Challenges in this field included moving from efficacy to effectiveness and developing an integrated approach to the prevention of a broad spectrum of eating and weight-related problems. A previous efficacy trial indicated that a universal disordered eating prevention program, based on the social cognitive model, media literacy educational approach and cognitive dissonance theory, reduced risk factors for disordered eating, but it is unclear whether this program has effects under more real-world conditions. The main aim of this effectiveness trial protocol is to test whether this program has effects when incorporating an integrated approach to prevention and when previously-trained community providers implement the intervention. Methods/design: The research design involved a multi-center non-randomized controlled trial with baseline, post and 1-year follow-up measures. Six schools from the city of Sabadell (close to Barcelona) participated in the intervention group, and eleven schools from four towns neighboring Sabadell participated in the control group. A total of 174 girls and 180 boys in the intervention group, and 484 girls and 490 boys in the control group were registered in class lists prior to baseline. A total of 18 community providers, secondary-school class tutors, nurses from the Catalan Government's Health and School Program, and health promotion technicians from Sabadell City Council were trained and delivered the program. Shared risk factors of eating and weight-related problems were assessed as main measures. Discussion: It will be vital for progress in disordered eating prevention to conduct effectiveness trials, which test whether interventions are effective when delivered by community providers under ecologically valid conditions, as opposed to tightly controlled research trials. The MABIC project will provide new contributions in this transition from efficacy to effectiveness and new data about progress in the integrated approach to prevention. Pending the results, the effectiveness trial meets the effectiveness standards set down by the Society for Prevention Research. This study will provide new evidence to improve and enhance disordered eating prevention programs

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Vitamin D represses EMT in human colon cancer cells

Resumen del trabajo presentado al "6th International EMT Meeting: Symposium VI. Cancer and EMT I" celebrado en Alicante (España) del 13 al 16 de noviembre de 2013.The active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1,25(OH)2D3) is a pleiotropic secosteroid hormone with wide regulatory actions. 1,25(OH)2D3 acts via the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors, which binds specific DNA sequences in its target genes and modulates their transcription rate. Additionally, 1,25(OH)2D3 activates rapid, non-genomic signaling pathways. We have reported that 1,25(OH)2D3 inhibits proliferation and induces differentiation of human colon carcinoma cells via the control of a high number of genes and the antagonism of the Wnt/beta-catenin pathway (Pálmer et al., J. Cell Biol., 2001; Cancer Res., 2003). 1,25(OH)2D3 increases the expression of CDH1/E-cadherin RNA and protein through the activation of a rapid non-genomic pathway (Ca2+-RhoA-ROCK-MSK1) and the subsequent increase in transcription (Ordóñez-Morán et al., J. Cell Biol., 2008). Additionally, it induces other proteins involved in epithelial adhesion structures such as the tight junctions components claudin-7, occludin and ZO-1. These effects are partially mediated by the induction of CST5/cystatin D, a protease inhibitor that regulates gene expression within the cell nucleus, and KDM6B/JMJD3 histone H3 lysine 27 demethylase, and by the repression of SPROUTY-2, a modulator of tyrosine kinase receptor signalling (Alvarez-Díaz et al., J. Clin. Invest., 2009; Barbáchano et al., Oncogene, 2010; Pereira et al., Human Mol. Genet., 2011). In addition, CST5/cystatin D and KDM6B/JMJD3 downregulate SNAI1, SNAI2, ZEB1 and ZEB2 genes. Moreover, SPROUTY-2 represses miR-200b/c leading to ZEB1 upregulation, and also several adhesion and polarity genes and ESRP1, an inhibitor of EMT. Remarkably, a reciprocal inhibitory loop exists between 1,25(OH)2D3 and EMT, as SNAIL1 and SNAIL2/SLUG repress VDR expression (Pálmer et al., Nat. Med., 2004; Larriba et al., Carcinogenesis, 2009). Altogether, our results show that 1,25(OH)2D3 represses EMT in human colon carcinoma cells through several mechanisms that affect the expression of EMT regulators and of epithelial adhesion and polarity genes. Conversely, the EMT inducers SNAIL1/2 inactivate the vitamin D system via VDR downregulation.Peer Reviewe

SPROUTY-2 regulation and tumorigenic action in colon cancer

Resumen del póster presentado al XXXVI Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Madrid del 3 al 6 de septiembre de 2013.-- et al.SPROUTY-2 (SPRY2) is a modulator of receptor tyrosine kinase signalling, and therefore of cell growth and differentiation, with cell type-dependent tumor promoting or suppressive effects. Previously we reported that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1alpha, 25-dihydroxyvitamin D3 through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1alpha, 25-dihydroxyvitamin D3-induced E-cadherin expression. Recent data indicate that in human colon cancer cells SPRY2 expression is induced by beta-catenin in cooperation with the transcription factor FOXO3a instead of TCF/LEF1 proteins. In colon cancer patients, SPRY2 is upregulated in undifferentiated high grade tumors and at the invasive front of low grade carcinomas, and SPRY2 protein expression correlates with nuclear beta-catenin and FOXO3a colocalization. Importantly, the amount of SPRY2 protein correlates with shorter overall survival of colon cancer patients. We have found that SPRY2 dysregulates tight junction and epithelial polarity genes via microRNA-200-dependent upregulation of the transcriptional repressor ZEB1, which provides a mechanistic basis for the tumorigenic role of SPRY2 in colon cancer. In conclusion, our data reveal SPRY2 as a novel Wnt/beta-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.Peer Reviewe

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETECTIVE Study)

There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised. To develop consensus statements for all domains of DAT. A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed. A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion. Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials. Patient summary: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers