TRAF3 loss-of-function reveals the noncanonical NF-κB pathway as a therapeutic target in diffuse large B cell lymphoma.

Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including , a negative regulator of NF-κB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between copy number loss with accumulation of NIK, the central noncanonical (NC) NF-κB kinase, and increased NC NF-κB pathway activity.

Mature and Older Adults' Perception of Active Ageing and the Need for Supporting Services: Insights from a Qualitative Study.

The improvement in life expectancy, economic conditions, and technological and medical progress have radically changed the demographic structure of many societies. Since many countries now have an ageing population, by adopting a life-course study perspective, this paper aims to explore the needs of older adults (over 60), and the currently adult population which will become older in the coming decades (50-60 years). In detail, the study investigates the lifestyles of the target populations by focusing on two main areas concerning health (healthy diet; attitudes towards physical activity) and socio-relational-housing and living conditions (social housing, senior co-housing in rural environments, etc.

Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma.

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome.

Optical coherence tomography, intravascular ultrasound or angiography guidance for distal left main coronary stenting. The ROCK cohort II study.

Objectives: to test the safety and efficacy of intravascular imaging and specifically optical coherence tomography (OCT) as a diagnostic tool for left main angioplasty and analyze the mid-term outcome accordingly.

Background: Clinical data and international guidelines recommend the use of intravascular imaging ultrasound (IVUS) to guide left main (LM) angioplasty. Despite early experience using OCT in this setting is encouraging, the evidence supporting its use is still limited.

IntravaScular Lithotripsy for the Management of UndILatable Coronary StEnt: The SMILE Registry.

Background: Intravascular lithotripsy (IVL) showed to be effective in dilating heavily calcified de novo coronary lesions but little is known about its performance in under-expanded stents management. Aim of this study was to assess the feasibility, effectiveness and safety of IVL for the treatment of stent underexpansion refractory to balloon dilatation.

Methods: A multicentre, retrospective cohort analysis was performed in patients undergoing IVL to treat under-expanded stents following non-compliant balloon expansion failure.

TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma.

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome.

Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma.

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma-specific immune microenvironment at single-cell resolution.

Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking.

Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic mutations in 15 of 62 primary cases of PMBCL (24.

Continuous time Bayesian networks identify Prdm1 as a negative regulator of TH17 cell differentiation in humans.

T helper 17 (TH17) cells represent a pivotal adaptive cell subset involved in multiple immune disorders in mammalian species. Deciphering the molecular interactions regulating TH17 cell differentiation is particularly critical for novel drug target discovery designed to control maladaptive inflammatory conditions. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling TH17 differentiation.

Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.

Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1β. The biologically inactive IL-1β precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone.

Genome-wide analysis of the genetic regulation of gene expression in human neutrophils.

Neutrophils are an abundant immune cell type involved in both antimicrobial defence and autoimmunity. The regulation of their gene expression, however, is still largely unknown. Here we report an eQTL study on isolated neutrophils from 114 healthy individuals of Chinese ethnicity, identifying 21,210 eQTLs on 832 unique genes.

Calcium and calcineurin-NFAT signaling regulate granulocyte-monocyte progenitor cell cycle via Flt3-L.

Maintenance of myeloid progenitor cells is controlled by complex regulatory mechanisms and is orchestrated by multiple different transcription factors. Here, we report that the activation of the transcription factor nuclear factor of activated T cells (NFAT) by calcium-sensing protein calcineurin inhibits the proliferation of myeloid granulocyte-monocyte progenitors (GMPs). Myeloid progenitor subtypes exhibit variable sensitivity to induced Ca(2+) entry and consequently display differential engagement of the calcineurin-NFAT pathway.

Caspase-11: the driving factor for noncanonical inflammasomes.

Inflammasomes are large multiprotein platforms that mediate the processing of caspase-1, which in turn promotes the maturation and release of IL-1β and IL-18 in response to microbial and danger signals. While the canonical pathway of inflammasome activation has been known for some time, a novel mechanism of noncanonical inflammasome activation mediated by caspase-11 was more recently identified. This pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1β, IL-18, and IL-1α, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines.

Added value of real time three-dimensional echocardiography in the diagnosis of an apical right ventricular metastasis from malignant melanoma.

In a man presenting to the emergency room with dyspnea and atypical chest pain irradiated among the scapulae, with new-onset diffuse negative T-waves on the ECG, the first clinical and diagnostic hypothesis was pulmonary embolism (PE). However, computed tomography (CT) performed in emergency was negative for PE, showing instead a marked defect in right ventricle (RV) filling. For this reason, echocardiography was performed to better investigate the nature of the space-occupying lesion, and several echocardiographic modalities were used (two-dimensional transthoracic and transesophageal echocardiography and three-dimensional [3D] transthoracic echocardiography).