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Abstract Background Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusion This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.

Abstract Background Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals. Results We show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors. Conclusion These results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix.

Simple Summary: Self-sampling for HPV primary screening is recognized as a viable alternative to clinician-sampling. Its use in an Italian cervical cancer prevention program, focusing on acceptance, ease of use, and follow-up adherence, was evaluated. Self-sampling was offered to 19,327 women aged 30–64, overdue for screening due to the COVID-19 pandemic; they had never or irregularly attended. Results showed 11.5% of women chose self-sampling, more than doubling the participation rate compared to clinician-sampling alone (<5%), showing high acceptance. The return rate of self-samples was high (79.5%), with 1.1% being inadequate, indicating ease of use. HPV positivity was higher in the self-sampled group (13.1%) compared to the 2019 ordinary screening population (9.9%). Compliance with follow-up procedures exceeded 90%, and cervical cancer detection rates were higher (0.9‰) than in the routine screening population (0.4‰). Self-sampling was therefore effective in reaching non-attenders, but clinician-sampling remains important, as 6% of women opted for a clinician appointment. Background/Objectives: Self-sampling is recognized as a viable alternative to clinician-sampling for HPV primary screening. This study aimed to assess, within an Italian organized cervical cancer screening program, the acceptance and ease of use of self-sampling and the adherence to follow-up. The prevalences of HPV infection, cervical dysplasia, and cancer were contextually evaluated. Methods: Electronic records of 19,327 women, 30–64 years-old, residing within the Bologna Local Health Authority territory, who were offered self-sampling as an alternative to clinician-sampling, were retrospectively reviewed. They had never or irregularly attended and were overdue for a screening invitation due to the COVID-19 pandemic. An opt-in approach was adopted, involving local pharmacies for kit delivery and sample collection. Initially, HPV-positive results led to direct referral to colposcopy; later, cytological triage on clinician-samples was provided. Results: Self-sampling reached over twice as many women (11.5%) compared to historical clinician-sampling alone (<5%), showing high acceptance. Additionally, a high screening completion level was observed, with 79.5% of self-samples returned to pharmacies. A low percentage of self-samples resulted in inadequate results (1.1%), suggesting the method's ease of use. HPV-positivity was 13.1%, higher than the 9.9% recorded in the ordinary screening population in 2019 (p < 0.001), the last year before the pandemic. Compliance to both immediate colposcopy and cytology triage exceeded 90% (p = 0.675). The rate of cervical adenocarcinoma was twice as high as in the routinely screened population in 2019 (0.9‰ versus 0.4‰). Finally, 6% of women opted for clinician appointments. Conclusions: Self-sampling proved to be an easy-to-use and effective tool for reaching non-attenders, who are at high risk of cancer. Cytology triage on clinician-samples did not negatively impact follow-up adherence. It seems appropriate to maintain a clinician-collection option even among non-attenders. [ABSTRACT FROM AUTHOR]

Background: Inflammatory arthritis (IAs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are characterized by the presence of chronic synovitis. The Krenn's synovitis score (KSS), a simple tool detectable by haematoxylin/eosin staining of synovial biopsy samples, allows the discrimination between highgrade and low-grade synovitis. The aim of this study was to identify the clinical associations of KSS and to evaluate the relationship between high-grade synovitis and treatment response in IA patients. Methods: Clinical, laboratory and ultrasound data were retrieved from RA and PsA patients recruited in the prospective MATRIX cohort study. Inclusion criteria were age=18 years, RA or PsA diagnosis, and presence of active disease with eligibility to start/modify therapy. Patients underwent ultrasound-guided synovial biopsy of one of the most involved joints before starting/modifying treatment according to treat-to-target strategy. The samples were analysed by an expert pathologist for KSS calculation. Univariable and multivariable logistic regression analyses were performed to evaluate the relationship between KSS and baseline variables. The association between KSS and treatment response at 24 weeks of follow-up was investigated in univariable logistic regression analysis. Results: 53 patients, 34 RA and 19 PsA, completed 24 weeks of follow-up after synovial biopsy. Patients were either treatment naïve (N=6, 11%), csDMARDsexperienced (N=46, 87%) or b/tsDMARDs-experienced (N=20, 38%). Median KSS was 6.00 (Q1-Q3 4.00-7.00) in RA and 4.00 (3.00-6.00) in PsA (p=0.040), and inflammatory infiltrates score was significantly higher in RA than in PsA patients (median 3.00 vs 2.00, p=0.021). In multivariable analysis, synovial effusion in the biopsied joint (OR 9.26, 95%CI 2.12-53.91) and erythrocyte sedimentation rate (ESR) (OR 1.04, 95%CI 1.01-1.08) associated with high KSS. High-grade synovitis significantly associated with a higher probability of achieving DAS28 remission, ACR20/50 response, and Boolean2.0 remission, independently from diagnosis. Conclusion: Several markers of pro-inflammatory pathways associated with the presence of high-grade synovitis, and patients with higher KSS shared a higher probability of treatment targets achievement in the follow up. The integration of a simple and feasible tool like KSS in the clinical and prognostic stratification of patients with IA might help in intercepting patients with a disease more prone to respond to available treatment paradigms. [ABSTRACT FROM AUTHOR]

Mobile phone tracking data collected by telecommunication companies allow recording and reconstructing the practices of mobilities and the presence of users with significant spatial-temporal detail. If properly managed, analysed, and possibly combined with other sources of information, mobile phone data can represent an interesting opportunity for urban research and mobility studies as they shed light on complex socio-territorial dynamics difficult to infer from conventional data analysis. At the same time, reports of numerous experiments using these sources reveal some of the challenges that researchers face in accurately capturing the behaviours of individuals through digital data and translating them into useful research knowledge. Referring both to the direct experience of managing and analysing mobile phone data within the Department of Architecture and Urban Studies of the Politecnico di Milano and to the relevant literature, the paper proposes an overview of the potentialities and limitations of telephone data for urban research and their usability in different territorial contexts characterised by varying socio-spatial and demographic conditions. Besides positioning themselves within and enriching an already lively debate, the issues discussed here will be useful in reading the contributions of the special section that this paper introduces. [ABSTRACT FROM AUTHOR]

Liquid biopsy has advantages over tissue biopsy, but also some technical limitations that hinder its wide use in clinical applications. In this study, we aimed to evaluate the usefulness of liquid biopsy for the clinical management of patients with advanced-stage oncogene-addicted non-small-cell lung adenocarcinomas. The investigation was conducted on a series of cases—641 plasma samples from 57 patients—collected in a prospective consecutive manner, which allowed us to assess the benefits and limitations of the approach in a real-world clinical context. Thirteen samples were collected at diagnosis, and the additional samples during the periodic follow-up visits. At diagnosis, we detected mutations in ctDNA in 10 of the 13 cases (77%). During follow-up, 36 patients progressed. In this subset of patients, molecular analyses of plasma DNA/RNA at progression revealed the appearance of mutations in 29 patients (80.6%). Mutations in ctDNA/RNA were typically detected an average of 80 days earlier than disease progression assessed by RECIST or clinical evaluations. Among the cases positive for mutations, we observed 13 de novo mutations, responsible for the development of resistance to therapy. This study allowed us to highlight the advantages and disadvantages of liquid biopsy, which led to suggesting algorithms for the use of liquid biopsy analyses at diagnosis and during monitoring of therapy response. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite therapeutic advances in treatments and translational research, patient prognosis for non-small cell lung cancer (NSCLC) remains unsatisfactory. Although stage I NSCLC has a relatively favorable prognosis than more advanced stage disease, almost 40% of patients diagnosed with a localized NSCLC are predicted to have a poor prognosis after surgery. The reasons why patients diagnosed with the same NSCLC traits will experience good or bad outcomes are far from being known. Therefore, new diagnostic paradigms are needed to predict treatment response and inform clinical decision-making. The tumor microenvironment is widely orchestrated by inflammatory cells and is an essential participant in carcinogenesis, contributing to the patient's prognosis. This retrospective study explored the value use of computed tomography (CT) images as a "virtual biopsy", in assessing the biomarkers CD68 and IL-1β that we have identified on a biological scale to be related to NSCLC patients' overall survival (OS). Patient prognosis is a critical consideration in the treatment decision-making process. Conventionally, patient outcome is related to tumor characteristics, the cancer spread, and the patients' conditions. However, unexplained differences in survival time are often observed, even among patients with similar clinical and molecular tumor traits. This study investigated how inflammatory radiomic features can correlate with evidence-based biological analyses to provide translated value in assessing clinical outcomes in patients with NSCLC. We analyzed a group of 15 patients with stage I NSCLC who showed extremely different OS outcomes despite apparently harboring the same tumor characteristics. We thus analyzed the inflammatory levels in their tumor microenvironment (TME) either biologically or radiologically, focusing our attention on the NLRP3 cancer-dependent inflammasome pathway. We determined an NLRP3-dependent peritumoral inflammatory status correlated with the outcome of NSCLC patients, with markedly increased OS in those patients with a low rate of NLRP3 activation. We consistently extracted specific radiomic signatures that perfectly discriminated patients' inflammatory levels and, therefore, their clinical outcomes. We developed and validated a radiomic model unleashing quantitative inflammatory features from CT images with an excellent performance to predict the evolution pattern of NSCLC tumors for a personalized and accelerated patient management in a non-invasive way. [ABSTRACT FROM AUTHOR]

Gene mutations may affect the fate of many tumors including prostate cancer (PCa); therefore, the research of specific mutations associated with tumor outcomes might help the urologist to identify the best therapy for PCa patients such as surgical resection, adjuvant therapy or active surveillance. Genomic DNA (gDNA) was extracted from 48 paraffin‐embedded PCa samples and normal paired tissues. Next, gDNA was amplified and analyzed by next‐generation sequencing (NGS) using a specific gene panel for PCa. Raw data were refined to exclude false‐positive mutations; thus, variants with coverage and frequency lower than 100× and 5%, respectively were removed. Mutation significance was processed by Genomic Evolutionary Rate Profiling, ClinVar, and Varsome tools. Most of 3000 mutations (80%) were single nucleotide variants and the remaining 20% indels. After raw data elaboration, 312 variants were selected. Most mutated genes were KMT2D (26.45%), FOXA1 (16.13%), ATM (15.81%), ZFHX3 (9.35%), TP53 (8.06%), and APC (5.48%). Hot spot mutations in FOXA1, ATM, ZFHX3, SPOP, and MED12 were also found. Truncating mutations of ATM, lesions lying in hot spot regions of SPOP and FOXA1 as well as mutations of TP53 correlated with poor prognosis. Importantly, we have also found some germline mutations associated with hereditary cancer‐predisposing syndrome. gDNA sequencing of 48 cancer tissues by NGS allowed to detect new tumor variants as well as confirmed lesions in genes linked to prostate cancer. Overall, somatic and germline mutations linked to good/poor prognosis could represent new prognostic tools to improve the management of PCa patients. [ABSTRACT FROM AUTHOR]

Late‐onset Intrauterine growth restriction (IUGR) refers to impaired growth and development of the fetus, characterized by placental morphological abnormalities that affect the fetus's supply of nutrients. Human leukocyte antigen‐G (HLA‐G) is physiologically expressed during pregnancy, but decreased in normal placenta during the last weeks of gestation possibly inducing childbirth. Several viruses involved in congenital infection, such as herpesviruses, exploit HLA‐G expression as an immune‐escape mechanism. To date, despite different congenital herpetic infections having been associated with late IUGR, no direct implication of Human herpesvirus 6 (HHV‐6) infection has been reported. We evaluated HLA‐G expression and HHV‐6 infection in 11 placentas from late‐onset IUGR newborns and 11 placentas from uncomplicated pregnancies by histopathological and immunohistochemistry analysis. We found higher levels of HLA‐G expression and HHV‐6 presence in IUGR placenta samples compared with control placenta samples. We report HHV‐6 staining in IUGR placenta samples, characterized by high HLA‐G expression. These preliminary data suggest a possible involvement of HHV‐6 infection in HLA‐G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition. Highlights: This is a retrospective analysis describing the role of HLA‐G expression and HHV‐6 infection in late‐onset intrauterine growth restriction (IUGR) placenta samples.For the first time it has been suggested a possible involvement of HHV‐6 infection in HLA?G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition. [ABSTRACT FROM AUTHOR]