WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumors.

Background & Aims: WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive.

Methods: We have developed mouse models to control the specific expression of an oncogenic form of β-catenin (CTNNB1) in combination with MYC activation in Lgr5 cells of the gastric antrum.

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation.

BAP1 is mutated or deleted in many cancer types, including mesothelioma, uveal melanoma, and cholangiocarcinoma. It is the catalytic subunit of the PR-DUB complex, which removes PRC1-mediated H2AK119ub1, essential for maintaining transcriptional repression. However, the precise relationship between BAP1 and Polycombs remains elusive.

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell-like phenotype.

Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics.

PRMT1 Is Recruited via DNA-PK to Chromatin Where It Sustains the Senescence-Associated Secretory Phenotype in Response to Cisplatin.

Protein arginine methyltransferase 1 (PRMT1) is overexpressed in various human cancers and linked to poor response to chemotherapy. Various PRMT1 inhibitors are currently under development; yet, we do not fully understand the mechanisms underpinning PRMT1 involvement in tumorigenesis and chemoresistance. Using mass spectrometry-based proteomics, we identified PRMT1 as regulator of arginine methylation in ovarian cancer cells treated with cisplatin.

Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression.

Polycomb group proteins (PcGs) maintain transcriptional repression to preserve cellular identity in two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial.

Stimulation of mTORC2 by integrin αIIbβ3 is required for PI3Kβ-dependent activation of Akt but is dispensable for platelet spreading on fibrinogen.

Phosphatidylinositol 3 kinase (PI3K) is a major player in platelet activation and regulates thrombus formation and stabilization. The β isoform of PI3K is implicated in integrin αIIbβ3 outside-in signaling, is required for the phosphorylation of Akt, and controls efficient platelet spreading upon adhesion to fibrinogen. In this study we found that during integrin αIIbβ3 outside-in signaling PI3Kβ-dependent phosphorylation of Akt on Serine473 is mediated by the mammalian target of rapamycin complex 2 (mTORC2).

Loss of PRC1 activity in different stem cell compartments activates a common transcriptional program with cell type-dependent outcomes.

Polycomb repressive complexes are evolutionarily conserved complexes that maintain transcriptional repression during development and differentiation to establish and preserve cell identity. We recently described the fundamental role of PRC1 in preserving intestinal stem cell identity through the inhibition of non-lineage-specific transcription factors. To further elucidate the role of PRC1 in adult stem cell maintenance, we now investigated its role in LGR5 hair follicle stem cells during regeneration.

A new cytofluorimetric approach to evaluate the circulating microparticles in subjects with antiphospholipid antibodies.

Introduction: Growing evidence supports the idea that microparticles (MPs) could contribute to the pathogenesis of the thrombotic phenomena associated with antiphospholipid antibody syndrome (APS), inducing a hypercoagulable state. But, to date, different approaches to evaluate circulating MPs and conflicting results have been reported.

Materials And Methods: We have characterized the different circulating subpopulations of MPs in APS patients, and in asymptomatic aPL-positive subjects (carriers) by examining the correlation between the amount and phenotype of MPs and the clinical parameters.

The focal adhesion kinase Pyk2 links Ca2+ signalling to Src family kinase activation and protein tyrosine phosphorylation in thrombin-stimulated platelets.

In blood platelets, stimulation of G protein-coupled receptors (GPCRs) by thrombin triggers the activation of Src family kinases (SFKs), resulting in the tyrosine-phosphorylation of multiple substrates, but the mechanism underlying this process is still poorly understood. In the present study, we show that the time-dependent protein-tyrosine phosphorylation triggered by thrombin in human or murine platelets was totally suppressed only upon concomitant chelation of intracellular Ca(2+) and inhibition of SFKs. Thrombin-induced activation of SFKs was regulated by intracellular Ca(2+) and accordingly the Ca(2+) ionophore A23187 was sufficient to stimulate SFKs.

Activation of phosphatidylinositol 3-kinase β by the platelet collagen receptors integrin α2β1 and GPVI: The role of Pyk2 and c-Cbl.

Phosphatidylinositol 3-kinaseβ (PI3Kβ) plays a predominant role in integrin outside-in signaling and in platelet activation by GPVI engagement. We have shown that the tyrosine kinase Pyk2 mediates PI3Kβ activation downstream of integrin αIIbβ3, and promotes the phosphorylation of the PI3K-associated adaptor protein c-Cbl. In this study, we compared the functional correlation between Pyk2 and PI3Kβ upon recruitment of the two main platelet collagen receptors, integrin α2β1 and GPVI.

Detection of microparticles from human red blood cells by multiparametric flow cytometry.

Background: During storage, red blood cells (RBC) undergo chemical and biochemical changes referred to as "storage lesions". These events determine the loss of RBC integrity, resulting in lysis and release of microparticles. There is growing evidence of the clinical importance of microparticles and their role in blood transfusion-related side effects and pathogen transmission.

Amyloid β-peptide-dependent activation of human platelets: essential role for Ca2+ and ADP in aggregation and thrombus formation.

Alzheimer's disease is associated with the accumulation of Aβ (amyloid β)-peptides in the brain. Besides their cytotoxic effect on neurons, Aβ-peptides are thought to be responsible for the atherothrombotic complications associated with Alzheimer's disease, which are collectively known as cerebrovascular disease. In the present study, we investigated the effect of Aβ-peptides on human platelet signal transduction and function.

Immobilized amyloid Aβ peptides support platelet adhesion and activation.

Accumulation of amyloidogenic Aβ peptides in the brain contributes to the onset of Alzheimer disease. Aβ peptide deposits are also present in blood vessel walls, mainly deriving from circulating platelets. However, their effect on platelet function is unclear.

Phosphorylation of the guanine-nucleotide-exchange factor CalDAG-GEFI by protein kinase A regulates Ca(2+)-dependent activation of platelet Rap1b GTPase.

In blood platelets the small GTPase Rap1b is activated by cytosolic Ca2+ and promotes integrin αIIbβ3 inside-out activation and platelet aggregation. cAMP is the major inhibitor of platelet function and antagonizes Rap1b stimulation through a mechanism that remains unclear. In the present study we demonstrate that the Ca2+-dependent exchange factor for Rap1b, CalDAG-GEFI (calcium and diacylglycerol-regulated guanine-nucleotide-exchange factor I), is a novel substrate for the cAMP-activated PKA (protein kinase A).

A spontaneous decrease of blood pressure occurs in acute ischemic stroke with favourable neurological course.

Background: In the acute phase of ischemic stroke the relationship between blood pressure (BP) and clinical outcome remains not clear. The aim of our study was to evaluate the association of stroke severity and BP measurements in the acute phase of stroke, and whether early variation of neurological status affects BP profiles.

Methods: BP on admission was obtained with mercurial sphygmomanometer and 24h-ambulatory BP monitoring (ABPM) was performed on days 1(st) and 6(th).

[Survey on the ability to prescribe antibiotic therapy among Italian residents in geriatrics and internal medicine].

Antibiotic therapy is a crucial and often life-saving strategy. This study assessed the ability to prescribe antibiotic therapy among a series of Italian postgraduate students in geriatrics and internal medicine. Participants were administered an anonymous questionnaire consisting of self-assessment of their ability to prescribe antibiotics and then manage a case of community-acquired pneumonia.

Effect of intravenous tirofiban and aspirin in reducing short-term and long-term neurologic deficit in patients with ischemic stroke: a double-blind randomized trial.

Background: Thrombolysis with rt-PA is the only approved pharmacological therapy for acute ischemic stroke presently administrable in a 3-hour window (very recently extended to 4.5 h). After this time, the choice is limited to endovascular treatment and antiplatelet drugs, mainly aspirin (ASA), the efficacy of which in the acute phase of stroke has poorly been evaluated.

The hospital-based, post-acute geriatric evaluation and management unit: the experience of the acute geriatric unit in Trieste.

In 2005, the Azienda Ospedaliero-Universitaria of Trieste (AOUT) activated the hospital-based post-acute geriatric evaluation and management unit (PAGEMU). The purpose of the study is to illustrate the activities of the PAGEMU, and to evaluate the effects of personalized and multidisciplinary care on geriatric inpatients. The evaluation for admission in PAGEMU included general admitting criteria, co-morbidity, autonomy, and assessment of the patient's pre-morbid functional status.

Risk factors for vascular dementia: hypotension as a key point.

Physiologically, the cerebral autoregulation system allows maintenance of constant cerebral blood flow over a wide range of blood pressure. In old people, there is a progressive reshape of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure will result in a rapid and significant change in cerebral blood flow.

Factors influencing delay in presentation for acute stroke in an emergency department in Milan, Italy.

Background And Aims: Early treatment is critical for successful intervention in acute stroke. The aim of this study was to describe delays in presentation to hospital and in the emergency department (ED) management of patients with acute stroke and to identify factors influencing these delays in an Italian urban hospital.

Methods: The present series includes all patients presenting with acute stroke, in whom arrival delay was ascertainable.

Minor stroke and major vascular occlusion. A case report.

Occlusion of middle cerebral artery (MCA) is generally associated to severe stroke and poor prognosis; however a few patients with mild to moderate presentation and long-term reversibility of neurological deficits have been reported. A 66-year-old male presented with left-side weakness and dysarthria (NIHSS score 7), which progressively resolved within a few days; ischaemic lesion of the anterior arm of the right internal capsule was found at brain CT obtained 72 h after presentation. Transcranial Colour Doppler showed absence of flow of the right MCA.

Low-dose prolonged intermittent interleukin-2 adjuvant therapy: results of a randomized trial among human immunodeficiency virus-positive patients with advanced immune impairment.

Twenty-two patients with CD4(+)cell counts View Article and Find Full Text PDF