Mechanisms involved in the promoting activity of fibroblasts in HTLV-1-mediated lymphomagenesis: Insights into the plasticity of lymphomatous cells

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings

Malignant epithelial/exocrine tumors of the pancreas

Pancreatic malignant exocrine tumors represent the most important cause of cancerrelated death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided

Cognitive impairment in multiple sclerosis: An exploratory analysis of environmental and lifestyle risk factors

BACKGROUND:Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS. OBJECTIVE:The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities. METHODS:We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire. RESULTS:150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05). CONCLUSIONS:Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies

Comprehensive characterization of intraductal oncocytic papillary neoplasm (IOPN) of the pancreas: a systematic and critical review

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine the most essential features with the systematic review tool. PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathological, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) Clinicopathological Features: Male-to-female ratio was 1,5:1. Pancreatic head was the most common site (131/237, 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1/5 of cases (49/237, 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1/pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and Molecular Features: The most expressed mucins were MUC5AC (110/112, 98.2%) and MUC6 (78/84, 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (p<0.01). Moreover, fusions involving PRKACA or PRKACB genes were detected in all of 68 cases examined, with PRKACB::ATP1B1 as the most common (27/68 cases, 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (p<0.01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular features. Considering the clinical/prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management

Synthesis of an Advanced Precursor of Rivastigmine : Cinchona-derived Quaternary Ammonium Salts as Organocatalysts for Stereoselective Imine Reductions

The enantioselective reduction of ketoimines has been successfully realized, using trichlorosilane as the stoichiometric reducing agent in the presence of catalytic amounts of a Lewis base, specifically a Cinchona derivative. For the first time, a novel class of derivatives was studied, featuring a picolinamide unit bound to the alkaloid scaffold, further functionalized as quaternary ammonium salt at the quinuclidine ring. Excellent yields and from good to high enantioselectivities (up to 92% ee) were obtained in the reduction of ketoimines. The novel catalysts were successfully employed in the synthesis of an enantiomerically pure advanced precursor of the blockbuster drug Rivastigmine

Predictors of immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma: A case report

We present here a case of immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma (KS-IRIS) developed in an AIDS patient two months after initiation of antiretroviral therapy (ART). Baseline characteristics of this IRIS-KS case, within a cohort of 12 naïve AIDS-KS patients, were analyzed. No statistically significant differences in CD4 cell counts, plasma HIV RNA load, KS clinical staging, human herpesvirus 8 (HHV8) antibody titers and HHV8 load in peripheral blood mononuclear cells and saliva were evidenced. HHV8 load in plasma was found to be significantly higher in the KS-IRIS patient ( 6 log10genome equivalents/ml, p = 0.01, t-test) compared to the 11 patients with KS regression. This case highlights that measurement of HHV8 load in plasma may be useful to identify patients at risk for KS-IRIS, and that this parameter should be included in the design of larger studies to define KS-IRIS risk predictors