Novel imaging biomarkers: epicardial adipose tissue evaluation

Epicardial adipose tissue (EAT) is a metabolically activated beige adipose tissue, non-homogeneously surrounding the myocardium. Physiologically, EAT regulates toxic fatty acids, protects the coronary arteries against mechanical strain, regulates proinflammatory cytokines, stimulates the production of nitric oxide, reduces oxidative stress, and works as a thermogenic source against hypothermia. Conversely, EAT has pathologic paracrine interactions with the surrounded vessels, and might favour the onset of atrial fibrillation. In addition, initial atherosclerotic lesions can promote inflammation and trigger the EAT production of cytokines increasing vascular inflammation, which, in turn, may help the development of collateral vessels but also of self-stimulating, dysregulated inflammatory process, increasing coronary artery disease severity. Variations in EAT were also linked to metabolic syndrome. Echocardiography first estimated EAT measuring its thickness on the free wall of the right ventricle but does not allow accurate volumetric EAT estimates. Cardiac CT (CCT) and cardiac MR (CMR) allow for three-dimensional EAT estimates, the former showing higher spatial resolution and reproducibility but being limited by radiation exposure and long segmentation times, the latter being radiation-free but limited by lower spatial resolution and reproducibility, higher cost, and difficulties for obese patients. EAT radiodensity at CCT could to be related to underlying metabolic processes. The correlation between EAT and response to certain pharmacological therapies has also been investigated, showing promising results. In the future, semi-automatic or fully automatic techniques, machine/deep-learning methods, if validated, will facilitate research for various EAT measures and may find a place in CCT/CMR reporting

Application of imaging guidelines in patients with foreign body ingestion or inhalation: literature review

Ingestion, inhalation, and insertion of foreign bodies (FBs) are very common clinical occurrences. In any case, early diagnosis and prompt management are mandatory to avoid severe and life-threatening complications. Radiologists have an important role in revealing the presence, dimension, nature, and relationship with anatomical structures of a FB; selecting the most appropriate imaging modality; and enabling the best therapeutic choice. This review article focuses on the most frequent FBs ingested, inhaled, and inserted and presents the different tests and investigations to provide a correct radiological approach

New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs).

To gain new insights into desmoplastic small round cell tumors (DSRCTs) by means of gene expression profiling (GEP). Formalin-fixed, paraffin-embedded surgical specimens obtained from seven pretreated DSRCT patients were interrogated using GEP complemented by immunohistochemistry, a cancer stem cell array, and miRNA in situ hybridisation, including the combined chimera modules miRNA-200/ZEB1 and miRNA-34/SLUG. The chimera modules divided the cases into three classes that respectively recapitulated the traits of mesenchymal epithelial reverse transition (MErT), epithelial mesenchymal transition (EMT), and hybrid/partial EMT. This indicates a close correlation between the reprogramming governed by EMT regulators and DSRCT biology, which was further confirmed by miRNA-21 and is consistent with the broad morphological spectrum of DSRCTs. Starting from the miRNA-200/ZEB1 axis, we also found that DSRCTs carry a signature of immunological ignorance that is not responsive to PD--L1 blockade. Evidence that the up-regulation of miRNA-200 and E-cadherin, and quite a high level of miRNA-21 expression segregate with the MErT supports the idea that, in addition to the hybrid/partial state, MErT is also enriched in stemness: the androgen-positive cases, whose stemness traits were confirmed by stem cell arrays, all fell into these two classes. Our findings also confirmed that tumoral cell PDGFRA expression correlates with desmoplasia, and demonstrated the co-expression of PDGFRA and ISLR/Meflin, another marker of pluripotency. Despite the limited number of cases, these findings provide unexpectedly relevant information concerning the pathogenesis of DSRCTs, and prove the validity of miRNA-based chimera circuit modelling in the clinico-pathological setting

Extracellular matrix features discriminate aggressive HER2-positive breast cancer patients who benefit from trastuzumab treatment

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25-37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment

Circulating tumor DNA and disease recurrence in early stage breast cancer: From a case-control study to a prospective longitudinal trial

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Pharmacogenomics and analogues of the antitumor agent N6-isopentenyladenosine.

N6-isopentenyladenosine (i6A), a member of the cytokinin family of plant hormones, has potent in vitro antitumour activity in dif- ferent types of human epithelial cancer cell lines. Gene expression profile analysis of i6A-treated cells revealed induction of genes (e.g., PPP1R15A, DNAJB9, DDIT3, and HBP1) involved in the negative regulation of cell cycle progression and reportedly up- regulated during cell cycle arrest in stress conditions. Of 6 i6A analogues synthesized, only the 1 with a saturated double bond of the isopentenyl side chain had in vitro antitumour activity, although weaker than that of i6A, suggesting that i6A biological ac- tivity is highly linked to its structure. In vivo analysis of i6A and the active analogue revealed no significant inhibition of cancer cell growth in mice by either reagent. Thus, although i6A may inhibit cell proliferation by regulating the cell cycle, further studies are needed to identify active analogues potentially useful in vivo

SOCS2 controls proliferation and stemness of hematopoietic cells under stress conditions and its deregulation marks unfavorable acute leukemias

Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, replenishing bone marrow-derived circulating populations, while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK-STAT pathways, is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL3, thrombopoietin, and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil (5-FU) and, in turn, induces exhaustion of long-term HSC function along serial bone marrow transplantations. The emerging role of SOCS2 in HSC under stress conditions prompted the investigation of malignant hematopoiesis. High levels of SOCS2 characterize unfavorable subsets of acute myeloid and lymphoblastic leukemias, such as those with MLL and BCR/ABL abnormalities, and correlate with the enrichment of genes belonging to hematopoietic and leukemic stemness signatures. In this setting, SOCS2 and its correlated genes are part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two transcriptional regulators involved in normal and leukemic hematopoiesis that have never been linked to SOCS2. Accordingly, a comparison of murine wt and Socs2-/- HSC gene expression in response to 5-FU revealed a significant overlap with the molecular programs that correlate with SOCS2 expression in leukemias, particularly with the oncogenic pathways and with the IKZF1/Ikaros and MEF2C-predicted targets. Lentiviral gene transduction of murine hematopoietic precursors with Mef2c, but not with Ikzf1, induces Socs2 upregulation, unveiling a direct control exerted by Mef2c over Socs2 expression

DIAGNOSI INUSUALE DI TRICOCEFALOSI CON L'ESAME UROPARASSITOLOGICO.

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Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression