Search Results for: La sindrome del colon irritabile

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

Basic scienceLynch syndrome and immunotherapy—a checkpoint for tumour growth? Harrold E, Foote M, Rousseau B, et al. Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade. Nature Med 2023; 2910: 2458–2463. doi: 10.1038/s41591-023-02544-9 Lynch syndrome is caused by a germline mutation in DNA mismatch repair genes MLH1 (DNA Mismatch Repair Protein Mlh1), MSH2 (DNA mismatch repair protein Msh2), MSH6 (DNA mismatch repair protein Msh6) or PMS2 (Mismatch repair endonuclease PMS2). It confers a lifetime risk of cancer predominantly in the colon and endometrium, as well as in multiple other organs. Immune checkpoint blockade (ICB) is effective against mismatch repair deficient (dMMR) tumours. In this study, Harrold et al quantified cancer risk after ICB in patients with Lynch syndrome at a tertiary centre in New York. One hundred and seventy-two patients with Lynch-related tumours who underwent ICB over a 9-year period were identified retrospectively. Median…

Ragazza con rara sindrome cardiaca salvata all’Ospedale del Mare

Piacenza, il piccolo ha 5 anni e ha la rara sindrome Gillespie

Objective
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape.

Design
Mouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity.

Results
NOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs.

Conclusions
Our findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.

‘L’avventurosa vita di Lalà’ del prof di Unibo e chirurgo Ussia

Circulation, Volume 148, Issue Suppl_1, Page A12582-A12582, November 6, 2023. Introduction:Cardiovascular disease and cancer have previously been linked to share similar pathophysiological pathways, although these two entities are rarely studied in congruence.Method:We analyzed the 2019 National Readmission Database (NRD) and used unsupervised learning and K-means clustering for data analysis. We employed the Shapley Additive Explanation (SHAP) model to explain which features contribute the most to clustering. The final cohort was divided into four clusters guided by the Elbow method. Continuous variables were analyzed with Kruskal-Wallis test and reported as medians and interquartile ranges (IQR) after checking for normality test. We also performed sensitivity analysis on patients with cancer without applying a Boruta algorithm.Results:The final cohort includes 297,597 patients, and we randomly sampled 100,000 patients within divided into 4 clusters. The most prevalent types of cancer in clusters 1 were brain cancer (15%), prostate cancer (9.4%), non-Hodgkin’s lymphoma (8.7%), lung cancer (8.6%), and other specified and unspecified types of non-Hodgkin’s lymphoma (7.8%). Most prevalent cancers in cluster 2 were lung cancer (13.1%), prostate cancer (11.6%), breast cancer (8.5%), colon cancer (7.9%), and kidney cancer (5.5%). In cluster 3, lung cancer (15.6%), prostate cancer (9.3%), multiple myeloma (8.9%), lymphoid leukemia (7.6%), and other specified and unspecified types of non-Hodgkin’s lymphoma were more prevalent. Furthermore, in cluster 4, myeloid leukemia (27.7%), non-Hodgkin’s lymphoma (20.1%), multiple myeloma (14.8%), lymphoid leukemia (12.4%), and other specified and unspecified types of non-Hodgkin’s lymphoma (10.4%) were the most prevalent cancers. Patients grouped in Cluster 3 had higher percentages of cardiovascular risk factors and comorbidities such as hypertension, diabetes, hyperlipidemia, kidney diseases, and pulmonary hypertension. Cardiovascular outcomes were naturally more frequent in cluster 3.Conclusion:Although cardiovascular disease and cancer have previously been linked to share pathophysiology, our study emphasizes that commonality between two seemingly different diseases may all be secondary to shared underlying cardiovascular risk factors.

Circulation, Volume 148, Issue Suppl_1, Page A16391-A16391, November 6, 2023. Background:Heart diseases are associated with an increased incidence of cancer independently of shared risk factors. The mechanism beyond this link is complex, unclear and limits our ability to develop effective therapies. We aimed to test the hypothesis that small cardiac extracellular vesicles (sEVs) contribute to the link between HF and cancer.Methods & Results:We used mouse models of heterotopic and orthotopic lung cancer and post-myocardial infarction (MI) heart failure (HF). sEVs were isolated by size exclusion chromatography. To determine the role of cardiac EVs in tumor growth, we focused on sEVs from cardiac mesenchymal stromal cells (cMSCs). cMSCs after MI secreted twice more sEVs, characterized with a unique proteome, compared with cMSCs from sham-MI (Fig 1A). cMSC-sEVs from post-MI HF harbored more tumor-promoting cytokines and microRNA (miR), such as periostin, osteopontin, IL-6, TNFα, galectin-3, and miR’s 221 and 21. The pro-neoplastic effects of cMSC-sEVs on cancer cells were depended on cancer type, with a marked increase in proliferation and migration of lung and colon cancer cells but only a modest increase with more malignant triple-negative breast and melanoma cancer cells. Next, we inoculated lung cancer cells into mice and found that post-MI HF accelerated tumor growth. Furthermore, adoptive transfer of cMSC-sEVs from failing hearts accelerated tumor growth with and without systemic EV depletion (Fig 1B). Finally, we found that spironolactone mitigated the neoplastic effects of HF, attenuated tumor growth (Fig 1C), and reduced the number of cMSC-sEVs by 26%.Conclusions:We show, for the first time, that cardiac extracellular vesicles from post-MI failing heart harbor pro-neoplastic properties and promote tumor growth independently of other secreted factors. Spironolactone reduces the number of cardiac extracellular vesicles and the pro-neoplastic effects of post-MI heart failure.

Circulation, Volume 148, Issue Suppl_1, Page A14540-A14540, November 6, 2023. Introduction:Cardiovascular disease (CVD) and cancer share a common risk factor: chronic toxic stress/allostatic load (AL). Our previous research found that a 1-point increase in AL is linked to a 25-30% higher risk of major cardiac events (MACE) in prostate cancer patients.Hypothesis:Higher AL is associated with increased MACE risk in patients with breast, lung, and colon cancer.Methods:Patients ≥18 years diagnosed for the first time with the mentioned 3 cancers of interest between 2010-2019 at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11;Table 1). Adjusted Fine-Gray Cox proportional hazard regressions estimated the impact of AL pre- and 60 days post- cancer diagnosis on 2-year MACE.Results:Demographic characteristics are summarized in Table 1. Two-year mace MACE occurred in 12.3%, 23.3%, and 9.7% of breast, lung, and colon cancer patients, respectively. Heart failure was the most common MACE, observed in 7.9%, 14.4%, and 4.8% of breast, lung, and colon cancer patients, respectively. Before cancer diagnosis, a 1-point increase in AL raised MACE risk by 11% (aHR=1.11, 95% CI 1.07-1.16) in breast cancer, 18% (aHR=1.18, 95% CI 1.11-1.25) in lung cancer, and 9% (aHR=1.09, 95% CI 1.01-1.18) in colon cancer. After cancer diagnosis, a 1-point increase in AL increased MACE risk by 10% (aHR=1.10, 95% CI 1.06-1.15) in breast cancer and 19% (aHR=1.19, 95% CI 1.12-1.25) in lung cancer, but was not statistically significant in colon cancer (aHR=1.07, 95% CI 0.99-1.16).Conclusion(s):Higher AL levels prior to breast, lung, and colon cancer diagnoses are associated with increased MACE risk. Thus, effective implementation of patient-centered communication considering stress levels, stressors, and coping mechanisms is necessary during cardiovascular screening for these cancer patients. Further prospective studies are needed.

Circulation, Volume 148, Issue Suppl_1, Page A14764-A14764, November 6, 2023. Background:Sudden death accounts for approximately 10% of deaths among working age adults. The rate of sudden death among females is one third lower than males, although the burden of chronic medical conditions are similar in victims of both sexes. The reasons for this difference are unclear and may be important in addressing preventive screening underutilization, as preventive screenings have been shown to reduce morbidity and mortality.Research Questions:Does utilization of preventive services differ among sudden death victims and living controls? Do these differences vary by sex?Aims:We aim to describe receipt of preventive screenings and influenza vaccination in sudden death victims and to compare these rates to those of a living control population.Methods:Clinical records from 267 out-of-hospital sudden death victims aged 18-64 in Wake County, North Carolina from 2013-2015 and 1112 demographically matched living controls from the same county and time were compared. Victims were identified by screening Emergency Medical Service records and adjudicated to exclude expected deaths from chronic disease, trauma, suicide, and overdose. Records were systematically reviewed for evidence of influenza vaccination and receipt of colon, cervical, and breast cancer screenings within the past five years, according to USPSTF criteria. Percentage of individuals who received each preventive screening were compared using means difference tests. Binomial regression was performed to investigate the effect of insurance status on preventive care receiptResults:Rates of colonoscopy and influenza vaccination were similar between cases and controls among both sexes. Female victims had low utilization of preventive services and were less likely to have received Pap smears (24.1% vs 50.9%; p

Circulation, Volume 148, Issue Suppl_1, Page A16014-A16014, November 6, 2023. Background:People with heart failure (HF) experience impaired physical and mental health. However, health-related quality of life (HRQOL) in people with HF to those with cancer, another condition that impacts HRQOL, have not been directly compared in a contemporary population.Research Question:How does HRQOL compare in people with HF to those with lung, colon, breast, or prostate cancer?Methods:We performed a pooled analysis of Medicare Health Outcomes Survey data between 2016-2020 in participants ≥65 years with a self-reported history of HF or active treatment for lung, colon, breast, or prostate cancer using two HRQOL measures. The Veterans RAND-12 generates the physical component score (PCS) and mental component score (MCS), which range from 0-100 with a mean score of 50 (based on general US population), a standard deviation of 10, and a lower score representing worse health. We used pairwise t-tests to evaluate for differences in PCS and MCS by group. We used chi-squared to compare the distribution of days with poor physical or mental health in the past 30 days as measured by CDC Healthy Days core questions.Results:Compared to participants with lung, colon, breast, or prostate cancer, participants with HF (n=71,025; 54% female, 16% Black) had lower mean PCS and MCS (Figure; P

La sindrome di Chops, genitori hanno dato via a Fondazione

Esperta, ‘serve una strategia di prevenzione. Cruciali dieta e movimento’