Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer

Colorectal cancer; Personalized medicine; ResistanceCáncer colorrectal; Medicina personalizada; ResistenciaCàncer colorectal; Medicina personalitzada; ResistènciaBackground Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. Materials and methods We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. Results A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX–bevacizumab and mitomycin–capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab–second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. Conclusions Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.This Translational Research Fellowship Project was supported by the ESMO with the aid of a grant from Amgen, by the Accelerator (ACRCelerator) [grant number A26825] and Ayuda a médicos jóvenes investigadores from Fundacion Científica—Asociacion Española Contra el Cancer (FC-AECC)/Associazione Italiana per la Ricerca sul Cancro (AIRC)/Cancer Research United Kingdom (CRUK) and by Familia Armangué. Any views, opinions, findings, conclusions or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO or Amgen. We thank Regione Campania (I-Cure Research Project) [grant number: Cup 21C17000030007], ESMO Translational Research Fellowship Program

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Harnessing Big Data for Communicable Tropical and Sub-Tropical Disorders: Implications From a Systematic Review of the Literature

AimAccording to the World Health Organization (WHO), communicable tropical and sub-tropical diseases occur solely, or mainly in the tropics, thriving in hot, and humid conditions. Some of these disorders termed as neglected tropical diseases are particularly overlooked. Communicable tropical/sub-tropical diseases represent a diverse group of communicable disorders occurring in 149 countries, favored by tropical and sub-tropical conditions, affecting more than one billion people and imposing a dramatic societal and economic burden.MethodsA systematic review of the extant scholarly literature was carried out, searching in PubMed/MEDLINE and Scopus. The search string used included proper keywords, like big data, nontraditional data sources, social media, social networks, infodemiology, infoveillance, novel data streams (NDS), digital epidemiology, digital behavior, Google Trends, Twitter, Facebook, YouTube, Instagram, Pinterest, Ebola, Zika, dengue, Chikungunya, Chagas, and the other neglected tropical diseases.Results47 original, observational studies were included in the current systematic review: 1 focused on Chikungunya, 6 on dengue, 19 on Ebola, 2 on Malaria, 1 on Mayaro virus, 2 on West Nile virus, and 16 on Zika. Fifteen were dedicated on developing and validating forecasting techniques for real-time monitoring of neglected tropical diseases, while the remaining studies investigated public reaction to infectious outbreaks. Most studies explored a single nontraditional data source, with Twitter being the most exploited tool (25 studies).ConclusionEven though some studies have shown the feasibility of utilizing NDS as an effective tool for predicting epidemic outbreaks and disseminating accurate, high-quality information concerning neglected tropical diseases, some gaps should be properly underlined. Out of the 47 articles included, only 7 were focusing on neglected tropical diseases, while all the other covered communicable tropical/sub-tropical diseases, and the main determinant of this unbalanced coverage seems to be the media impact and resonance. Furthermore, efforts in integrating diverse NDS should be made. As such, taking into account these limitations, further research in the field is needed

HERPES ZOSTER: UNA MALATTIA LA CUI LUNGA STORIA NON SI \uc8 ANCORA CONCLUSA

Herpes Zoster, a disease imposing large economic and social costs, is caused by a DNA virus, human herpesvirus 3, belonging to the Herpesvirales order, Herpesviridae family. It is widespread throughout the world, with a frequency of 120-350 cases per 100,000 persons/year. Herpes Zoster is a disease with multiple names and multiple faces, which over the millennia has been mistaken for the plague, typhoid, anthrax, erysipelas, syphilis, gangrene, leprosy, and also for intoxication by rye. They are just some of the avatars, as said by Ernest Wickersheimer, that this disease has taken over time. This manuscript will investigate the cultural representation of this disease throughout history

Vaccines Meet Big Data: State-of-the-Art and Future Prospects. From the Classical 3Is (“Isolate–Inactivate–Inject”) Vaccinology 1.0 to Vaccinology 3.0, Vaccinomics, and Beyond: A Historical Overview

Vaccines are public health interventions aimed at preventing infections-related mortality, morbidity, and disability. While vaccines have been successfully designed for those infectious diseases preventable by preexisting neutralizing specific antibodies, for other communicable diseases, additional immunological mechanisms should be elicited to achieve a full protection. “New vaccines” are particularly urgent in the nowadays society, in which economic growth, globalization, and immigration are leading to the emergence/reemergence of old and new infectious agents at the animal–human interface. Conventional vaccinology (the so-called “vaccinology 1.0”) was officially born in 1796 thanks to the contribution of Edward Jenner. Entering the twenty-first century, vaccinology has shifted from a classical discipline in which serendipity and the Pasteurian principle of the three Is (isolate, inactivate, and inject) played a major role to a science, characterized by a rational design and plan (“vaccinology 3.0”). This shift has been possible thanks to Big Data, characterized by different dimensions, such as high volume, velocity, and variety of data. Big Data sources include new cutting-edge, high-throughput technologies, electronic registries, social media, and social networks, among others. The current mini-review aims at exploring the potential roles as well as pitfalls and challenges of Big Data in shaping the future vaccinology, moving toward a tailored and personalized vaccine design and administration

How often people google for vaccination: Qualitative and quantitative insights from a systematic search of the web-based activities using Google Trends

Nowadays, more and more people surf the Internet seeking health-related information. Information and communication technologies (ICTs) can represent an important opportunities in the field of Public Health and vaccinology. The aim of our current research was to investigate a) how often people search the Internet for vaccination-related information, b) if this search is spontaneous or induced by media, and c) which kind of information is in particular searched. We used Google Trends (GT) for monitoring the interest for preventable infections and related vaccines. When looking for vaccine preventable infectious diseases, vaccine was not a popular topic, with some valuable exceptions, including the vaccine against Human Papillomavirus (HPV). Vaccines-related queries represented approximately one third of the volumes regarding preventable infections, greatly differing among the vaccines. However, the interest for vaccines is increasing throughout time: in particular, users seek information about possible vaccine-related side-effects. The five most searched vaccines are those against 1) influenza; 2) meningitis; 3) diphtheria, pertussis (whooping cough), and tetanus; 4) yellow fever; and 5) chickenpox. ICTs can have a positive influence on parental vaccine-related knowledge, attitudes, beliefs and vaccination willingness. GT can be used for monitoring the interest for vaccinations and the main information searched