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Background--We sought to describe an optimized approach to coronary artery disease (CAD) screening and management in patients undergoing transcatheter aortic valve replacement (TAVR). Methods and Results--When invasive coronary angiography showed CAD, the treatment strategy and completeness of revascularization was determined based on coronary anatomy. TAVR was performed in the same setting if percutaneous coronary intervention (PCI) was uncomplicated; otherwise TAVR was postponed. A total of 604 patients undergoing CAD screening at the time of TAVR procedure were prospectively included in this study. Severe CAD was found in 136 patients (22.5%). Among patients with severe CAD, 53 patients (8.8%) underwent uncomplicated PCI. After PCI, TAVR was postponed in 2 patients (0.3%). In 83 patients (13.8%), coronary angiography showed severe CAD that was left untreated. After TAVR, all-cause and cardiovascular 30-day mortality rates were 2.4% and 1.4%, respectively. Disabling stroke, myocardial infarction, and life-threatening bleeding occurred in 0.5%, 0.8%, and 4.0% of patients, respectively. Acute kidney injury II or III rate was 3.3%. At 2 years, all-cause mortality rate was 14.1%. Disabling stroke and myocardial infarction occurred in 2.5% and 1.8% of patients, respectively. Patients undergoing TAVR and PCI in the same session had similar rate of the composite of death, disabling stroke, and myocardial infarction when compared with patients without CAD, and patients with severe CAD left untreated (TAVR+PCI: 10.4%; severe CAD left untreated: 15.4%; no-CAD: 14.8%; P=0.765). Conclusions--In patients undergoing TAVR, screening of CAD with invasive coronary angiography and ad hoc PCI during TAVR is feasible and was not associated with increased periprocedural risks. PCI followed by TAVR in the same session had similar outcomes than TAVR in which PCI was not performed. [ABSTRACT FROM AUTHOR]

Despite Glioblastoma (GBM) frequently expressing programmed cell death ligand-1 (PD-L1), treatment with anti-programmed cell death-1 (PD1) has not yielded brilliant results. Intratumor variability of PD-L1 can impact determination accuracy. A previous study on mouse embryonic fibroblasts (MEFs) reported a role for cyclin-D in control of PD-L1 expression. Because tumor-cell growth within a cancer is highly heterogeneous, we looked at whether PD-L1 and its cochaperone FKBP51s were influenced by cell proliferation, using U251 and SF767 GBM-cell-lines. PD-L1 was measured by Western blot, flow cytometry, confocal-microscopy, quantitative PCR (qPCR), CCND1 by qPCR, FKBP51s by Western blot and confocal-microscopy. Chromatin-Immunoprecipitation assay (xChIp) served to assess the DNA-binding of FKBP51 isoforms. In the course of cell culture, PD-L1 appeared to increase concomitantly to cyclin-D on G1/S transition, to decrease during exponential cell growth progressively. We calculated a correlation between CCND1 and PD-L1 gene expression levels. In the temporal window of PD-L1 and CCND1 peak, FKBP51s localized in ER. When cyclin-D declined, FKBP51s went nuclear. XChIp showed that FKBP51s binds CCND1 gene in a closed-chromatin configuration. Our finding suggests that the dynamism of PD-L1 expression in GBM follows cyclin-D fluctuation and raises the hypothesis that FKBP51s might participate in the events that govern cyclin-D oscillation. [ABSTRACT FROM AUTHOR]

Recent advances in tumor immunology, fostered by dramatic outcomes with cancer immunotherapy, have opened new scenarios in cancer metastasis. The cancer stemness/mesenchymal phenotype and an excess of immune suppressive signals are emerging as Intertwined aspects of human tumors. This review examines recent studies that explored the mechanistic links between cancer cell stemness and immunoevasion, and the evidence points to these key events in cancer metastasis as two sides of the same coin. This review also covers the mechanisms involved in tumor expression of programmed cell death ligand 1 (PD-L1), a major factor exploited by human neoplasias to suppress immune control. We highlight the convergence of mesenchymal traits and PD-L1 expression and examine the functions of this immune inhibitory molecule, which confers cancer cell resistance and aggressiveness. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) expression. CXCR4 is frequently overexpressed in cancer tissues, including GBM, and usually correlates with a poor prognosis. We have created a CXCR4-retargeted oncolytic herpesvirus (oHSV) by insertion of an anti-human CXCR4 nanobody in glycoprotein D of an attenuated HSV-1 (ΔICP34.5, ΔICP6, and ΔICP47), thereby describing a proof of principle for the use of nanobodies to target oHSVs toward specific cellular entities. Moreover, this virus has been armed with a transgene expressing a soluble form of TRAIL to trigger apoptosis. In vitro , this oHSV infects U87MG CXCR4 + and patient-derived GSCs in a CXCR4-dependent manner and, when armed, triggers apoptosis. In a U87MG CXCR4 + orthotopic xenograft mouse model, this oHSV slows down tumor growth and significantly improves mice survival. Customizing oHSVs with diverse nanobodies for targeting multiple proteins appears as an interesting approach for tackling the heterogeneity of GBM, especially GSCs. Altogether, our study must be considered as a proof of principle and a first step toward personalized GBM virotherapies to complement current treatments., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Aims: The aim of this study was to evaluate predictors and safety of next-day discharge (NDD) after transfemoral transcatheter aortic valve implantation (TF-TAVI) in unselected patients receiving either balloon-expandable or self-expanding devices., Methods and Results: From June 2007 to August 2018, 1,232 consecutive patients undergoing TF-TAVI were discharged alive from our institution. They had a mean age of 80.9±5.4 years and an intermediate estimated surgical mortality risk; they received either balloon-expandable (26.1%) or self-expanding prostheses (73.9%). We compared patients discharged within 24 hours from the procedure (n=160, 13.0%) with those discharged later, and accounted for confounding variables through a propensity matching adjustment. After adjustment, no differences in all-cause mortality (1.2% vs 0.0%, for NDD and no-NDD matched groups, respectively, p=0.16) or permanent pacemaker implantation (PPI) after TAVI (0.6% vs 0.6%, respectively) were encountered at 30 days. At one year, no difference in the composite endpoint of all-cause death and heart failure (HF) rehospitalisation was encountered (Kaplan-Meier [KM] estimates 91.9% vs 90.6% for NDD and no-NDD matched groups, respectively, p=0.69). After excluding patients with post-procedural major complications from the unmatched population, prior PPI (OR 2.06, 95% CI: 1.21-3.51; p<0.01) and availability of preprocedural computed tomography angiography (CTA) (OR 1.71, 95% CI: 1.15-2.54; p<0.01) were found to be predictors of NDD after TAVI., Conclusions: NDD in unselected patients after TF-TAVI using either balloon-expandable or self-expanding devices was demonstrated to be a safe strategy up to one year in the absence of procedural complications. Patients with prior PPI and undergoing preprocedural CTA had a higher chance of NDD.

The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune-inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1), the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Although a combination of multiple strategies to prevent and treat coronary artery disease (CAD) has led to a relative reduction in cardiovascular mortality over recent decades, CAD remains the greatest cause of morbidity and mortality worldwide. A variety of individual factors and circumstances other than clinical presentation and treatment type contribute to determining the outcome of CAD. It is increasingly understood that personalised medicine, by taking these factors into account, achieves better results than "one-size-fitsall" approaches. In recent years, the multiplication of risk scoring systems for CAD has generated some degree of uncertainty regarding whether, when and how predictive models should be adopted when making clinical decisions. Against this background, this article reviews the most accepted risk models for patients with evidence of CAD to provide practical guidance within the current landscape of tools developed for prognostic risk stratification., Competing Interests: Disclosure: The authors have no conflicts of interest to declare.

Background: FKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour., Methods: We used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1. FKBP51s was measured by immunoblot, flow cytometry and microscopy. In patient tumours, IHC and qPCR were used to measure protein and mRNA levels respectively. FKBP51s depletion was achieved by siRNAs, and its enzymatic function was inhibited using selective inhibitors (SAFit). We investigated protein maturation using N-glycosidase and cell fractionation approaches., Results: FKBP51s was expressed at high levels in glioma cells. Glycosylated-PD-L1 was increased and reduced by FKBP51s overexpression or silencing, respectively. Naïve PD-L1 was found in the endoplasmic reticulum (ER) of glioma cells complexed with FKBP51s, whereas the glycosylated form was measured in the Golgi apparatus. SAFit reduced PD-L1 levels (constitutively expressed and ionizing radiation-induced). SAFit reduced cell death of PBMC co-cultured with glioma., Conclusions: Here we addressed the mechanism of post-translational regulation of PD-L1 protein in glioma. FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels. These findings suggest that FKBP51s is a potential target of immunomodulatory strategies for glioblastoma treatment., Competing Interests: CONFLICTS OF INTEREST No conflicts of interest is declared.

The incidence of paediatric inflammatory bowel disease (PIBD) has dramatically increased in the last 20 years. Although first reported in mid 1970s', diagnostic laparoscopy has started to be routinely adopted in paediatric surgical practice since late 1990s'. Minimally invasive surgery was first limited to diagnostic purposes. After 2002 it was also applied to the radical treatment of PIBD, either Crohn's disease (CD) or Ulcerative colitis. During the last decade minimally invasive approaches to PIBD have gained popularity and have recently became the "gold standard" for the treatment of such invalidating and troublesome chronic diseases. The authors describe and track the historical evolution of minimally invasive surgery for PIBD and address all available opportunities, including most recent advancements such as robotic surgery, single port approaches and minimally invasive treatment of perianal fistulising CD. A systematic review of all series of PIBD treated with minimally invasive approaches published so far is provided in order to determine the incidence and type of patients' complications reported up to present days. The authors also describe their experience with minimally invasive surgery for PIBD and will report the results of 104 laparoscopic procedures performed in a series of 61 patients between January 2006 and December 2014.