Right ventricular function in transcatheter mitral and tricuspid valve edge-to-edge repair

Since transcatheter edge-to-edge repair (TEER) has become a valuable therapy in the treatment of both, mitral (MR) and tricuspid regurgitation (TR), the question of optimized patient selection has gained growing importance. After years of attributing rather little attention to the right ventricle (RV) and its function in the setting of valvular heart failure, this neglect has recently changed. The present review sought to summarize anatomy and function of the RV in a clinical context and aimed at presenting the current knowledge on how the RV influences outcomes after TEER for atrioventricular regurgitation. The anatomy of the RV is determined by its unique shape, which necessitates to use three-dimensional imaging methods for detailed and comprehensive characterization. Complex parameters such as RV to pulmonary artery coupling (RVPAc) have been developed to combine information of RV function and afterload which is primary determined by the pulmonary vasculature and LV filling pressure. Beyond that, TR, which is closely related to RV function also plays an important role in the setting of TEER. While mitral valve transcatheter edge-to-edge repair (M-TEER) leads to reduction of concomitant TR in some patients, the prognostic value of TR in the setting of M-TEER remains unclear. Overall, this review summarizes the current state of knowledge of the outstanding role of RV function and associated TR in the setting of TEER and outlines the unsolved questions associated with right-sided heart failure

Concomitant percutaneous coronary intervention in patients undergoing transcatheter aortic valve implantation

Background Patients undergoing transcatheter aortic valve implantation (TAVI) frequently have coronary artery disease requiring percutaneous coronary intervention (PCI). Usually, PCI and TAVI are performed in two separate procedures and current studies are investigating potential benefits regarding the order. However, the two interventions may also be performed simultaneously, thereby limiting the risk associated with repeated vascular access. Data evaluating benefit and harm of concomitant procedures are scarce. Aims Therefore, this study aimed to evaluate concomitant PCI (coPCI) in TAVI patients regarding Valve Academic Research Consortium 3 (VARC-3) endpoints and long-term mortality. Methods A total of 2233 consecutive TAVI patients from the EVERY-VALVE registry were analyzed according to the VARC-3 endpoint definitions. A total of 274 patients had undergone TAVI and concomitant PCI (coPCI group). They were compared to 226 TAVI patients who had received PCI within 60 days before TAVI in a stepwise approach (swPCI group) and to the remaining 1733 TAVI patients who had not undergone PCI recently (noPCI group). Results Overall median age was 81.4 years, median Society of Thoracic Surgeons score was 4.0%. Patients in the coPCI and in the swPCI group were predominantly male with reduced left-ventricular ejection fraction. Rates of VARC-3 composite endpoints technical success and 30-day device success were comparable between all three groups. Mortality rates at 3 years after TAVI were similar (coPCI, 34.2% vs. swPCI, 31.9% vs. noPCI, 34.0% p = 0.84). Conclusions coPCI during TAVI seems comparable in a retrospective analysis. Compared to a stepwise approach, it has similar rates of composite endpoints technical success and device success as well as long-term mortality

Adjustable Intragastric Balloons: A 12-Month Pilot Trial in Endoscopic Weight Loss Management

Intragastric balloons are associated with (1) early period intolerance, (2) diminished effect within 3–4 months, and (3) bowel obstruction risk mandating removal at 6 months. The introduction of an adjustable balloon could improve comfort and offer greater efficacy. A migration prevention function, safely enabling prolonged implantation, could improve efficacy and weight maintenance post-extraction. The first implantations of an adjustable balloon with an attached migration prevention anchor are reported. The primary endpoint was the absence of bowel perforation, obstruction, or hemorrhage. Eighteen patients with mean BMI of 37.3 were implanted with the Spatz Adjustable Balloon system (ABS) for 12 months. Balloon volumes were adjusted for intolerance or weight loss plateau. Mean weight loss at 24 weeks was 15.6 kg with 26.4% EWL (percent of excess weight loss) and 24.4 kg with 48.8% EWL at 52 weeks. Sixteen adjustments were successfully performed. Six downward adjustments alleviated intolerance, yielding additional mean weight loss of 4.6 kg. Ten upward adjustments for weight loss plateau yielded a mean additional weight loss of 7 kg. Seven balloons were removed prematurely. Complications necessitating early removal included valve malfunction (1), gastritis (1), Mallory–Weiss tear (1), NSAID (2× dose/2 weeks) perforating ulcer (1), and balloon deflation (1). Two incidents of catheter shear from the chain: one passed uneventfully and one caused an esophageal laceration without perforation during extraction. The Spatz ABS has been successfully implanted in 18 patients. (1) Upward adjustments yielded additional weight loss. (2) Downward adjustments alleviated intolerance, with continued weight loss. (3) Preliminary 1-year implantation results are encouraging

Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma : the role of survivin

Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/ CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant antitumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/ CRM1 inhibition as a novel therapeutic option for DMPM

Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations

Background: Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS). Objective: To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators. Design, setting and participants: Whole-exome sequencing profiles were generated for Gleason score (GS) = 3 + 3 biopsies obtained from 54 PCa patients enrolled in two AS protocols. Patients were selected as representative of a nonindolent population, consisting of 27 patients who dropped out from AS due to upgrading (ie, finding of GS > 3 + 3 at a follow-up biopsy) within 2 yr, and a potentially indolent population, consisting of 27 patients in AS for 654 yr without any evidence of reclassification. Outcome measurements and statistical analysis: The genomic alteration landscape of core biopsies was analyzed using an integrated computational pipeline and correlated with patient reclassification due to upgrading. Results and limitations: Of all the GS = 3 + 3 biopsies of the study cohort, 34% showed clear evidence of somatic copy number aberrations along the genome. Of these, 39% came from the potentially indolent and 61% from the nonindolent population. Single-nucleotide variants demonstrated low allelic fractions and included a common F133C mutation in the SPOP gene. The minimally altered genomic landscape of the study cohort presented a distinct set of monoallelic deletions, including on 8p, 13q, 16q, and 21q, and rare amplifications of 8q, which were observed in both AS patient populations. Concerning lesions typically associated with adverse outcome, PTEN deletions and MYC amplification, though observed in a small number of cases, were detected exclusively or preferentially, respectively, in nonindolent patients. Such molecular findings were confirmed by immunohistochemistry on the same tissue blocks. The small sample size and the retrospective nature of the analysis represent the main study limitations. Conclusions: Genomic features enriched in aggressive tumors can be detected in GS = 3 + 3 core biopsies of AS patients. Patient summary: PTEN and MYC alterations at the time of diagnosis would deserve investigation in larger cohorts of AS patients to assess their potential as biomarkers for a more precise/earlier identification of patients at risk of reclassification. The presence of adverse outcome-related genomic lesions, such as PTEN deletion and MYC amplification, in GPS = 3 + 3 diagnostic core biopsies of prostate cancer patients could be considered for a more precise/earlier selection of patients not suitable for active surveillance

MiR-205 enhances radiation sensitivity of prostate cancer cells by impairing DNA damage repair through PKCϵ and ZEB1 inhibition

Background: Radiotherapy is one of the main treatment options for non-metastatic prostate cancer (PCa). Although treatment technical optimization has greatly improved local tumor control, a considerable fraction of patients still experience relapse due to the development of resistance. Radioresistance is a complex and still poorly understood phenomenon involving the deregulation of a variety of signaling pathways as a consequence of several genetic and epigenetic abnormalities. In this context, cumulative evidence supports a functional role of microRNAs in affecting radioresistance, suggesting the modulation of their expression as a novel radiosensitizing approach. Here, we investigated for the first time the ability of miR-205 to enhance the radiation response of PCa models. Methods: miR-205 reconstitution by a miRNA mimic in PCa cell lines (DU145 and PC-3) was used to elucidate miR-205 biological role. Radiation response in miRNA-reconstituted and control cells was assessed by clonogenic assay, immunofluorescence-based detection of nuclear \u3b3-H2AX foci and comet assay. RNAi was used to silence the miRNA targets PKC\u3f5 or ZEB1. In addition, target-protection experiments were carried out using a custom oligonucleotide designed to physically disrupt the pairing between the miR-205 and PKC\u3f5. For in vivo experiments, xenografts generated in SCID mice by implanting DU145 cells stably expressing miR-205 were exposed to 5-Gy single dose irradiation using an image-guided animal micro-irradiator. Results: miR-205 reconstitution was able to significantly enhance the radiation response of prostate cancer cell lines and xenografts through the impairment of radiation-induced DNA damage repair, as a consequence of PKC\u3f5 and ZEB1 inhibition. Indeed, phenocopy experiments based on knock-down of either PKC\u3f5 or ZEB1 reproduced miR-205 radiosensitizing effect, hence confirming a functional role of both targets in the process. At the molecular level, miR-205-induced suppression of PKC\u3f5 counteracted radioresistance through the impairment of EGFR nuclear translocation and the consequent DNA-PK activation. Consistently, disruption of miR-205-PKC\u3f5 3'UTR pairing almost completely abrogated the radiosensitizing effect. Conclusions: Our results uncovered the molecular and cellular mechanisms underlying the radiosensitizing effect of miR-205. These findings support the clinical interest in developing a novel therapeutic approach based on miR-205 reconstitution to increase PCa response to radiotherapy

LEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation

Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. At molecular level, MIR205HG directly binds the promoters of its target genes, which have an Alu element in proximity of the Interferon-Regulatory Factor (IRF) binding site, and represses their transcription likely buffering IRF1 activity, with the ultimate effect of preventing luminal differentiation. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA)

Six Months of Balloon Treatment does Not Predict the Success of Gastric Banding

BACKGROUND: We studied whether weight loss by intragastric balloon would predict the outcome of subsequent gastric banding with regard to weight loss and BMI reduction. METHODS: A prospective cohort of patients with a body mass index (BMI)>40 kg/m(2) received an intragastric balloon for 6 months followed by laparoscopic adjustable gastric banding (LAGB). Successful balloon-induced weight loss was defined as > or =10% weight loss after 6 months. Successful surgical weight loss was defined as an additional 15% weight loss in the following 12 months. Patients were divided in group A, losing > or =10% of their initial weight with 6 months' balloon treatment, and group B, losing <10% of their initial weight. RESULTS: In 40 patients (32 female, 8 male; age 36.6 yr, range 26-54), the mean BMI decreased from 46.5 to 40.5 kg/m(2) (P <0.001) after 6 months of balloon treatment and to 35.2 kg/m(2) (P <0.001) 12 months after LAGB. Group A (25 patients) and group B (15 patients) had a significant difference in BMI decrease, 12.4 vs 9.0 kg/m(2) (P <0.05), after the total study duration of 18 months. However, there was no difference in BMI reduction (4.7 kg/m(2) vs 5.8 kg/m(2)) in the 12 months after LAGB. 6 patients in group A lost > or =10% of their starting weight during 6 months balloon treatment as well as > or =15% 12 months following LAGB. 6 patients in group B lost <10% of their starting weight after 6 months of BIB, but also lost > or =15% 12 months following LAGB. CONCLUSION: Intragastric balloon did not predict the success of subsequent LAG

SSR and AFLP based genetic diversity of soybean germplasm differing in photoperiod sensitivity

Forty-four soybean genotypes with different photoperiod response were selected after screening of 1000 soybean accessions under artificial condition and were profiled using 40 SSR and 5 AFLP primer pairs. The average polymorphism information content (PIC) for SSR and AFLP marker systems was 0.507 and 0.120, respectively. Clustering of genotypes was done using UPGMA method for SSR and AFLP and correlation was 0.337 and 0.504, respectively. Mantel's correlation coefficients between Jaccard's similarity coefficient and the cophenetic values were fairly high in both the marker systems (SSR = 0.924; AFLP = 0.958) indicating very good fit for the clustering pattern. UPGMA based cluster analysis classified soybean genotypes into four major groups with fairly moderate bootstrap support. These major clusters corresponded with the photoperiod response and place of origin. The results indicate that the photoperiod insensitive genotypes, 11/2/1939 (EC 325097) and MACS 330 would be better choice for broadening the genetic base of soybean for this trait