CCR4‐NOT differentially controls host versus virus poly(a)‐tail length and regulates HCMV infection

Unlike most RNA and DNA viruses that broadly stimulate mRNA decay and interfere with host gene expression, human cytomegalovirus (HCMV) extensively remodels the host translatome without producing an mRNA decay enzyme. By performing a targeted loss-of-function screen in primary human fibroblasts, we here identify the host CCR4-NOT deadenylase complex members CNOT1 and CNOT3 as unexpected pro-viral host factors that selectively regulate HCMV reproduction. We find that the scaffold subunit CNOT1 is specifically required for late viral gene expression and genome-wide host responses in CCR4-NOT-disrupted cells. By profiling poly(A)-tail lengths of individual HCMV and host mRNAs using nanopore direct RNA sequencing, we reveal poly(A)-tails of viral messages to be markedly longer than those of cellular mRNAs and significantly less sensitive to CCR4-NOT disruption. Our data establish that mRNA deadenylation by host CCR4-NOT is critical for productive HCMV replication and define a new mechanism whereby herpesvirus infection subverts cellular mRNA metabolism to remodel the gene expression landscape of the infected cell. Moreover, we expose an unanticipated host factor with potential to become a therapeutic anti-HCMV target

Silver-Russell syndrome following in vitro fertilization

[No abstract available

Metabolic syndrome and C reactive protein are associated with a reduced myocardial mechano-energetic efficiency

Context: Metabolic syndrome and elevated high sensitivity C-reactive protein (CRP) levels are associated with risk of cardiovascular diseases (CVD). A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD. Objective: To evaluate the association between metabolic syndrome and hsCRP levels with impaired MEE. Methods: Myocardial MEE was assessed by a validated echocardiography-derived measure in 1975 non-diabetic and prediabetic individuals subdivided into two groups according to the presence of metabolic syndrome. Results: Individuals with metabolic syndrome exhibited increased stroke work and myocardial oxygen consumption estimated by rate pressure product, and a reduced MEE per gram of LV mass (MEEi) as compared to subjects without metabolic syndrome, after adjusting for age, and sex. Myocardial MEEi progressively decreased in parallel with the increase of the number of metabolic syndrome components. In a multivariable regression analysis, both metabolic syndrome and hsCRP contributed to reduced myocardial MEEi independently of sex, total cholesterol, HDL, triglycerides, fasting and 2-h post-load glucose levels. When the study population was divided into 4 groups by the presence or absence of metabolic syndrome and by hsCRP levels above and below 3 mg/L, hsCRP levels ≥3 mg/L were associated with reduced myocardial MEEi both in subjects with metabolic syndrome and in those without the syndrome. Conclusion: Non-diabetic and prediabetic individuals with metabolic syndrome exhibit increased stroke work and myocardial oxygen consumption, and an impaired MEEi, an established predictor of adverse cardiovascular events, and elevated hsCRP levels in combination with metabolic syndrome aggravates the myocardial MEEi impairment

Association between liver fibrosis and decreased myocardial mechano-energetic efficiency in individuals with different degree of glucose tolerance

Aim: Decreased myocardial mechano-energetic efficiency (MEEi) is associated with NAFLD and poorer prognosis in liver cirrhosis. We aim to investigate the association between liver fibrosis severity and MEEi in individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study.Methods: Myocardial MEEi, assessed by an echocardiography-derived measure, and fibrosis severity, estimated by the fibrosis-4 index (FIB-4), were evaluated in 2383 subjects with different degree of glucose tolerance. Participants were divided into four groups according to FIB-4 index values: lowest risk of fibrosis (<1.3); low risk of fibrosis (>= 1.3 to < 1.67); moderate risk of fibrosis (>= 1.67 to < 2.67); high risk of fibrosis (>= 2.67).Results: Subjects with higher risk of liver fibrosis displayed a graded decrease in myocardial MEEi compare to those with the lowest risk of liver fibrosis. In a multivariable regression analysis, FIB-4 index was independently associated with MEEi (8 = -0.080, P < 0.001), along with total cholesterol (8 = -0.067, P = 0.01), hsCRP (8 = -0.081, P < 0.001), sex (8 = -0.099, P < 0.001), glucose tolerance status (8 = -0.109, <0.001) and HOMA-IR index (8 = -0.143, P < 0.001).Conclusion: Compromised myocardial MEEi is already reported in individuals with high risk of hepatic fibrosis suggesting that its assessment may help to identify among subjects with NAFLD those with worst prognosis

The Prognostic Impact of Quitting Smoking at or around Diagnosis on the Survival of Patients with Gastrointestinal Cancers: A Systematic Literature Review

Cigarette smoking is a strong risk factor for the occurrence of gastrointestinal cancers, and a substantial proportion of newly diagnosed patients is made up of active smokers, yet the impact of smoking cessation at or around diagnosis on the clinical course of these cancers (whose prognosis is often unfavourable) has never been summarized to date. We reviewed studies published until 30 April 2022 that investigated whether smoking cessation at or around diagnosis favourably affects the clinical course of gastrointestinal cancers patients. Six studies were included for colorectal cancer patients, which provided limited yet suggestive evidence that quitters may have longer disease-specific survival compared to continued smokers. Only one study each focused on patients with gastric or HBV-positive liver cancer (both reporting a survival advantage for quitters vs. continued smokers), while we found no eligible studies for patients with cancer at other sites within the digestive system. More research is urgently needed to expand the evidence on the topic, given the potentially major clinical implications for these patients. Moreover, health professionals should provide the necessary smoking cessation support to any smoker who is undergoing diagnostic work-up or treatment for gastrointestinal cancer

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns

The clinical impact of continued smoking in patients with breast and other hormone-dependent cancer. A systematic literature review

We conducted a systematic review of studies that investigated whether quitting smoking at or around diagnosis improves survival of patients with hormone-dependent cancers (HDC). Nine studies published in 2013-2022 were included. Studies were very diverse in terms of design, definition of quitters and continued smokers, and prevalence of prognostic factors other than smoking cessation (e.g. patients' demographics, tumour characteristic, and treatments). For breast, ovarian, and endometrial cancer, all included studies found that quitters had better overall, disease specific, and disease-free survival than continued smokers. For prostate cancer, there was no evidence of an association of smoking cessation with improved survival. This literature review provided suggestive evidence that female smokers diagnosed with cancer of the breast, ovary, or endometrium may improve their chances of surviving by stopping smoking. Smoking cessation counselling should become part of standard oncological care for these patients and integrated into breast cancer screening programs