Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/ß-arr1 Axis

Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associatedMCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Herewe investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes inMCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associatedwith the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependentMAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NFkB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETB R or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC prometastatic behaviour via MMTAssociazione Italiana Ricerca sul Cancro (AIRC) to LR grant number AIRC 21372 and partially by Agencia Estatal de Investigación Project to ML-P “PID 2019-110132RBI00/AEI/10.13039/50110001103

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Axonal dysfunction in cerebral white matter in systemic sclerosis: a proton magnetic resonance spectroscopic imaging ( H-1-MRSI) study

Sem informação782442442Annual European Congress of Rheumatology (EULAR

In vitro transformation assays for non-clinical safety assessment of CRISPR/Cas9 genome-edited cells

Off-target editing is one of the main safety concerns for the use of CRISPR/Cas9 genome editing in gene therapy. Although theoretically rare, these unwanted modifications could lead to malignant transformation, which renders tumorigenicity assessment of the cell therapy product indispensable. Here, we establish two in vitro assays, the soft agar colony forming assay (SACF) and growth in low attachment plates (GILA), as valid, quick and cost-efficient methods for tumorigenicity assessment of genome-edited cells. Using a CRISPR/Cas9 based approach to transform immortalized MCF10A cells, we identified PTPN12, a known tumor suppressor, as first true positive control in GILA and SACF. Next, we assessed the limit of detection for both assays and found that SACF is more sensitive than GILA (0.8% vs. 3.2% transformed cells). We further validated SACF and GILA by identifying a set of positive and negative controls. In contrast to SACF and GILA, an in vivo tumorigenicity study failed to detect the known tumorigenic potential of PTPN12-/- demonstrating the importance of including GILA and SACF in tumorigenicity testing. In conclusion, SACF and GILA are both attractive and valuable additions to non-clinical safety assessment of genome-edited cells

A prospective cohort analysis of the prevalence and predictive factors of delayed discharge after laparoscopic cholecystectomy in Italy: the DeDiLaCo Study

Background: The concept of early discharge ≤24 hours after Laparoscopic Cholecystectomy (LC) is still doubted in Italy. This prospective multicentre study aims to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge >24 hours in an extensive Italian national database and identify potential limiting factors of early discharge after LC. Methods: This is a prospective observational multicentre study performed from January 1, 2021 to December 31, 2021 by 90 Italian surgical units. Results: A total of 4664 patients were included in the study. Clinical reasons were found only for 850 patients (37.7%) discharged >24 hours after LC. After excluding patients with nonclinical reasons for delayed discharge >24 hours, 2 groups based on the length of hospitalization were created: the Early group (≤24 h; 2414 patients, 73.9%) and the Delayed group (>24 h; 850 patients, 26.1%). At the multivariate analysis, ASA III class ( P <0.0001), Charlson's Comorbidity Index (P=0.001), history of choledocholithiasis (P=0.03), presence of peritoneal adhesions (P<0.0001), operative time >60 min (P<0.0001), drain placement (P<0.0001), pain ( P =0.001), postoperative vomiting (P=0.001) and complications (P<0.0001) were independent predictors of delayed discharge >24 hours. Conclusions: The majority of delayed discharges >24 hours after LC in our study were unrelated to the surgery itself. ASA class >II, advanced comorbidity, the presence of peritoneal adhesions, prolonged operative time, and placement of abdominal drainage were intraoperative variables independently associated with failure of early discharge