V-ATPase in glioma stem cells: a novel metabolic vulnerability.

Background: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.

MIRO2 promotes cancer invasion and metastasis via MYO9B suppression of RhoA activity.

Metastasis to vital organs remains the leading cause of cancer-related deaths, emphasizing an urgent need for actionable targets in advanced-stage cancer. The role of mitochondrial Rho GTPase 2 (MIRO2) in prostate cancer growth was recently reported; however, whether MIRO2 is important for additional steps in the metastatic cascade is unknown. Here, we show that knockdown of MIRO2 ubiquitously reduces tumor cell invasion in vitro and suppresses metastatic burden in prostate and breast cancer mouse models.

Pathophysiological Markers of Acute Respiratory Distress Syndrome Severity Are Correlated With Ventilation-Perfusion Mismatch Measured by Electrical Impedance Tomography.

Objectives: Pulmonary ventilation/perfusion (V/Q) mismatch measured by electrical impedance tomography (EIT) is associated with the outcome of patients with the acute respiratory distress syndrome (ARDS), but the underlying pathophysiological mechanisms have not been fully elucidated. The present study aimed to verify the correlation between relevant pathophysiological markers of ARDS severity and V/Q mismatch.

Design: Prospective observational study.

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Unlabelled: Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring.

Biochemical properties of chromatin domains define genome compartmentalization.

Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility.

Immune checkpoint molecules in solid organ transplantation: A promising way to prevent rejection.

Immune checkpoint (IC) molecules modulate immune responses upon antigen presentation; the interaction between different IC molecules will result in the stimulation or, rather, the thwarting of such responses. Tumor cells express increased amounts of inhibitory IC molecules in an attempt to evade immune responses; therapeutic agents have been developed that bind inhibitory IC molecules, restoring tumor-directed immune responses and changing the prognosis of a number of cancers. Stimulation of inhibitory IC molecules could be beneficial in preventing rejection in the setting of solid organ transplantation (SOT), and in vivo as well as in vivo results obtained in animal models show this to indeed to be the case.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

Background: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD.

Methods: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease.

Pathophysiological profile of non-ventilated lung injury in healthy female pigs undergoing mechanical ventilation.

Background: Lung regions excluded from mechanical insufflation are traditionally assumed to be spared from ventilation-associated lung injury. However, preliminary data showed activation of potential mechanisms of injury within these non-ventilated regions (e.g.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.

Osteocalcin modulates parathyroid cell function in human parathyroid tumors.

Introduction: The bone matrix protein osteocalcin (OC), secreted by osteoblasts, displays endocrine effects. We tested the hypothesis that OC modulates parathyroid tumor cell function.

Methods: Primary cell cultures derived from parathyroid adenomas (PAds) and HEK293 cells transiently transfected with the putative OC receptor GPRC6A or the calcium sensing receptor (CASR) were used as experimental models to investigate γ-carboxylated OC (GlaOC) or uncarboxylated OC (GluOC) modulation of intracellular signaling.

Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers.

Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In this study, we analyzed differences in the epigenome of brain metastasis from the colon (n = 4) and lung (n = 14) cancer and we compared these signatures with those found in primary tumors.

PD-1 expression in transbronchial biopsies of lung transplant recipients is a possible early predictor of rejection.

Introduction: Chronic lung allograft dysfunction (CLAD) is the main cause of the reduced survival of lung transplanted (LTx) patients. The possible role of immune checkpoint molecules in establishing tolerance has been scarcely investigated in the setting of lung transplantation.

Methods: We conducted a retrospective, observational pilot study on a consecutive series of transbronchial cryobiopsies (TCB) obtained from 24 patients during LTx follow-up focusing on PD-1, one of the most investigated immune checkpoint molecules.

Mitochondrial fitness and cancer risk.

Changes in metabolism are a hallmark of cancer, but molecular signatures of altered bioenergetics to aid in clinical decision-making do not currently exist. We recently identified a group of human tumors with constitutively reduced expression of the mitochondrial structural protein, Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT). These Mic60-low tumors exhibit severe loss of mitochondrial fitness, paradoxically accompanied by increased metastatic propensity and upregulation of a unique transcriptome of Interferon (IFN) signaling and Senescence-Associated Secretory Phenotype (SASP).

Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade.

Objectives: Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up.

Methods: We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019.

Osteoclast-like stromal giant cells in breast cancer likely belong to the spectrum of immunosuppressive tumor-associated macrophages.

Breast cancer with osteoclast-like stromal giant cells (OSGC) is an exceedingly rare morphological pattern of invasive breast carcinoma. The tumor immune microenvironment (TIME) of these tumors is populated by OSGC, which resemble osteoclasts and show a histiocytic-like immunophenotype. Their role in breast cancer is unknown.

Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer.

We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92).

Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease.

Despite following a gluten-free diet, which is currently the only effective therapy for celiac disease, about 5% of patients can develop serious complications, which in the case of refractory type 2 could evolve towards intestinal lymphoma. In this study, we have identified a set of 15 microRNAs in serum discriminating between the two types of refractory disease. Upregulated miR-770-5p, miR-181b-2-3p, miR-1193, and miR-1226-3p could be useful for the better stratification of patients and the monitoring of disease development, while miR-490-3p was found to be dysregulated in patients with refractory type 1.

Inhaled CO vs. Hypercapnia Obtained by Low Tidal Volume or Instrumental Dead Space in Unilateral Pulmonary Artery Ligation: Any Difference for Lung Protection?

Background: Unilateral ligation of the pulmonary artery (UPAL) induces bilateral lung injury in pigs undergoing controlled mechanical ventilation. Possible mechanisms include redistribution of ventilation toward the non-ligated lung and hypoperfusion of the ligated lung. The addition of 5% CO to the inspiratory gas (FiCO) prevents the injury, but it is not clear whether lung protection is a direct effect of CO inhalation or it is mediated by plasmatic hypercapnia.

Rare ATG7 genetic variants predispose patients to severe fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants.

Methods: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs.

Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling.

Anti-SARS-CoV-2 immunoglobulin profile in patients with celiac disease living in a high incidence area.

Background And Aim: How symptoms and antibodies related to SARS-CoV-2 infection develop in patients with celiac disease (CD) is unclear. We aimed to investigate the impact of SARS-CoV-2 infection in CD patients.

Methods: CD patients were interviewed about the development of COVID-19 symptoms, compliance with anti-virus measures and adherence to a gluten-free diet (GFD).

Immune Checkpoints Expression in Chronic Lung Allograft Rejection.

Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD.