Role of Adhesion Molecules in the Mechanism of Non-MHC (Major Histocompatibility Complex) Restricted Cell-Mediated Cytotoxicity

Adhesion molecules involved in the interaction between immune system effector cells and tumor targets are surface molecules which contribute to the formation of cell-to-cell contacts and belong to the integrin family. In this paper, the role played by the adhesion molecules in the process of cell-mediated cytotoxicity is reviewed. Furthermore, the contact area between effector and target cells has been analyzed by scanning electron microscopy. This region, termed closed chamber , seems to contribute to killing efficiency by creating an intimate contact region in which cytotoxic factors can easily induce lethal hit in target cell. Thus, the extension of the closed chamber seems to be positively related to effector cell killing potential as well as to target cell sensitivity and, in this context, the adhesion molecules prove to play a pivotal role. In fact, a receptor-ligand interaction occurs between CD11a/CD18 (LFA-1) and CD2 molecules, expressed on the effector cells, and the respective counterparts on target cells, i.e., ICAM-1, ICAM-2, or LFA-3. Treatment with antibodies against such molecules strongly modifies closed chamber formation without inhibiting cell-to-cell binding. Nevertheless, in these conditions, the killing ability of different effector cells toward tumor targets appears to be strongly impaired. Hence, the adhesion molecules seem to be strongly involved in the formation of the closed chamber as well as in the activation of effector cell killing machinery

A Scanning Electron Microscopy Analysis of Human Cytotoxic Cell Subsets and of Their Mode of Conjugation with Tumor Cell Targets

In this study we describe the surface features of non-MHC (Major Histocompatibility Complex)-restricted cytotoxic cells isolated from human peripheral blood. Purified populations of CD3-, natural killer (NK) cells were allowed to interact with NK-sensitive (K562) and NK-resistant (THP-1-0) tumor cell targets. The type of effector to target cell binding was investigated by scanning electron microscope (SEM) analysis. A different interaction with the effectors is described for NK-resistant targets in comparison with NK-susceptible tumor cells. SEM was also used to investigate the relationship between interleukin 2 (IL2)-activated cytotoxic cells (lymphokine-activated killer, LAK, cells) and the tumor targets. We also describe the unique growth features of certain clones of cytotoxic T cells expressing γδ antigen receptors which support the contention that these cells may have a special ability of homing into tissues. We conclude that non-specific cytotoxic cells constitute a diverse population of effectors which differ not only for the expression of surface antigens, but also for their ability to interact with tumor cell targets and to home into the peripheral tissues where they may exert their lytic functions

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P < .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

European Atlas of Natural Radiation

Natural ionizing radiation is considered as the largest contributor to the collective effective dose received by the world population. The human population is continuously exposed to ionizing radiation from several natural sources that can be classified into two broad categories: high-energy cosmic rays incident on the Earth’s atmosphere and releasing secondary radiation (cosmic contribution); and radioactive nuclides generated during the formation of the Earth and still present in the Earth’s crust (terrestrial contribution). Terrestrial radioactivity is mostly produced by the uranium and thorium radioactive families together with potassium. In most circumstances, radon, a noble gas produced in the radioactive decay of uranium, is the most important contributor to the total dose. This Atlas aims to present the current state of knowledge of natural radioactivity, by giving general background information, and describing its various sources. This reference material is complemented by a collection of maps of Europe displaying the levels of natural radioactivity caused by different sources. It is a compilation of contributions and reviews received from more than 80 experts in their field: they come from universities, research centres, national and European authorities and international organizations. This Atlas provides reference material and makes harmonized datasets available to the scientific community and national competent authorities. In parallel, this Atlas may serve as a tool for the public to: • familiarize itself with natural radioactivity; • be informed about the levels of natural radioactivity caused by different sources; • have a more balanced view of the annual dose received by the world population, to which natural radioactivity is the largest contributor; • and make direct comparisons between doses from natural sources of ionizing radiation and those from man-made (artificial) ones, hence to better understand the latter.JRC.G.10-Knowledge for Nuclear Security and Safet

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

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

Background The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. Conclusion We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.Peer reviewe