Vaccine Responses in Patients with Liver Cirrhosis: From the Immune System to the Gut Microbiota.

Vaccines prevent a significant number of deaths annually. However, certain populations do not respond adequately to vaccination due to impaired immune systems. Cirrhosis, a condition marked by a profound disruption of immunity, impairs the normal immunization process. Critical vaccines for cirrhotic patients, such as the hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcal, and coronavirus disease 19 (COVID-19), often elicit suboptimal responses in these individuals. The humoral response, essential for immunization, is less effective in cirrhosis due to a decline in B memory cells and an increase in plasma blasts, which interfere with the creation of a long-lasting response to antigen vaccination. Additionally, some T cell subtypes exhibit reduced activation in cirrhosis. Nonetheless, the persistence of memory T cell activity, while not preventing infections, may help to attenuate the severity of diseases in these patients. Alongside that, the impairment of innate immunity, particularly in dendritic cells (DCs), prevents the normal priming of adaptive immunity, interrupting the immunization process at its onset. Furthermore, cirrhosis disrupts the gut-liver axis balance, causing dysbiosis, reduced production of short-chain fatty acids (SCFAs), increased intestinal permeability, and bacterial translocation. Undermining the physiological activity of the immune system, these alterations could impact the vaccine response. Enhancing the understanding of the molecular and cellular factors contributing to impaired vaccination responses in cirrhotic patients is crucial for improving vaccine efficacy in this population and developing better prevention strategies.

Clinical Implementation of a Noninvasive, Multi-Analyte Droplet Digital PCR Test to Screen for Androgen Receptor Alterations.

Alterations of the androgen receptor (AR) are associated with resistance to AR-directed therapy in prostate cancer. Thus, it is crucial to develop robust detection methods for AR alterations as predictive biomarkers to enable applicability in clinical practice. We designed and validated five multiplex droplet digital PCR assays for reliable detection of 12 AR targets including AR amplification, AR splice variant 7, and 10 AR hotspot mutations, as well as AR and KLK3 gene expression from plasma-derived cell-free DNA and cell-free RNA. The assays demonstrated excellent analytical sensitivity and specificity ranging from 95% to 100% (95% CI, 75% to 100%). Intrarun and interrun variation analyses revealed a high level of repeatability and reproducibility. The developed assays were applied further in peripheral blood samples from 77 patients with advanced prostate cancer to assess their feasibility in a real-world scenario. Optimizing the reverse transcription of RNA increased the yield of plasma-derived cell-free RNA by 30-fold. Among 23 patients with castration-resistant prostate cancer, 6 patients (26.1%) had one or a combination of several AR alterations, whereas only 2 of 54 patients (3.7%) in the hormone-sensitive stage showed AR alterations. These findings were consistent with other studies and suggest that implementation of comprehensive AR status detection in clinical practice is feasible and can support the treatment decision-making process.

Effect of Low-Dose Alcohol Consumption on Chronic Liver Disease.

Although alcohol is one of the most important etiologic agents in the development of chronic liver disease worldwide, also recognized as a promoter of carcinogenesis, several studies have shown a beneficial effect of moderate consumption in terms of reduced cardiovascular morbidity and mortality. Whether this benefit is also present in patients with liver disease due to other causes (viral, metabolic, and others) is still debated. Although there is no clear evidence emerging from guidelines and scientific literature, total abstention from drinking is usually prescribed in clinical practice. In this review, we highlight the results of the most recent evidence on this controversial topic, in order to understand the effect of mild alcohol use in this category of individuals. The quantification of alcohol intake, the composition of the tested populations, and the discrepancy between different works in relation to the outcomes represent important limitations emerging from the scientific literature. In patients with NAFLD, a beneficial effect is demonstrated only in a few works. Even if there is limited evidence in patients affected by chronic viral hepatitis, a clear deleterious effect of drinking in determining disease progression in a dose-dependent manner emerges. Poor data are available about more uncommon pathologies such as hemochromatosis. Overall, based on available data, it is not possible to establish a safe threshold for alcohol intake in patients with liver disease.

Diagnostic Accuracy of Fecal Calprotectin in Discriminating Organic-Inflammatory Gastrointestinal Diseases and Functional Gastrointestinal Disorders in Older Patients.

Fecal calprotectin (FC) has been largely recognized as a surrogate marker of intestinal neutrophilic inflammation, very reliable in distinguishing between inflammatory bowel diseases and functional gastrointestinal (GI) disorders. Aging has been suggested to influence FC results and their diagnostic accuracy; however, no studies are specifically targeted on this focus. In a retrospective study, we evaluated the eventual age-differences of the diagnostic accuracy of FC in discriminating between organic-inflammatory GI diseases and functional GI disorders. In 573 younger and 172 older (≥65 years) subjects undergoing an FC assay, we found that the latter showed higher median FC values, 72 (25-260) µg/g vs. 47 (25-165) µg/g (p < 0.01). Younger patients were more commonly affected by IBDs, while colorectal cancer and high-risk polyps, infective colitis, and diverticular disease represented the most common findings in the older subgroup. However, the estimated optimum FC threshold in discriminating between organic-inflammatory GI diseases and functional GI disorders was quite similar between the two groups (109 µg/g for the younger subgroup and 98 µg/g for the older subgroup), maintaining a very high specificity. In conclusion, we show that FC also represents a very specific test for intestinal inflammation in older patients, at similar threshold levels to younger subjects.

The molecular landscape of breast mucoepidermoid carcinoma.

Mucoepidermoid carcinoma (MEC) of the breast is an extremely rare salivary gland-type tumor characterized by epidermoid, basaloid, intermediate, and/or mucinous cells arranged in solid and cystic patterns. Despite their triple-negative phenotype, breast MECs are generally considered low-risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor-infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death-ligand 1 (PD-L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements in MAML2 and EWSR1 were investigated by fluorescent in situ hybridization. Targeted next-generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (n = 10, 77%), with the presence of TILs (n = 9/12; 75%) and PD-L1 combined positive score ranging from 10 to 20 (n = 4/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K/AKT/mTOR and cell cycle regulation pathways, while only one case harbored TP53 mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lack TP53 mutations found in high-grade forms of triple-negative breast cancers and MAML2 or EWSR1 rearrangements pathognomonic of salivary MECs. Triple-negativity and PD-L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low-risk neoplasms.

Low-risk triple-negative breast cancers: Clinico-pathological and molecular features.

Triple-negative breast cancers (TNBC) comprise biologically and clinically heterogeneous diseases characterized by the lack of hormone receptors (HR) and HER2 expression. This subset of tumors accounts for 15-20% of all breast cancers and pursues an ominous clinical course. However, there is a spectrum of low-risk TNBCs with no/minimal metastatic potential, including the salivary gland-type tumors, those with extensive apocrine differentiation and/or high tumor-infiltrating lymphocytes, and small-sized, early-stage (pT1a/bN0M0) TNBCs. De-escalating the treatment in low-risk TNBC, however, is not trivial because of the substantial lack of dedicated randomized clinical trials and cancer registries. The development of new diagnostic and/or prognostic biomarkers based on clinical and molecular aspects of low-risk TNBCs would lead to improved clinical treatment. Here, we sought to provide a portrait of the clinicopathological and molecular features of low-risk TNBC, with a focus on the diagnostic challenges along with the most important biological characteristics underpinning their favorable clinical course.

Impact of exercise training on muscle mitochondria modifications in older adults: a systematic review of randomized controlled trials.

BACKGROUND: Previous evidence showed that cellular aging is a multifactorial process that is associated with decline in mitochondrial function. Physical exercise has been proposed as an effective and safe therapeutical intervention to improve the mitochondria network in the adult myocytes. AIMS: The aim of this systematic review of randomized controlled trials (RCTs) was to assess the exercise-induced muscle mitochondria modifications in older adults, underlining the differences related to different exercise modalities. METHODS: On November 28th, 2021, five databases (PubMed, Scopus, Web of Science, Cochrane, and PEDro) were systematically searched for RCTs to include articles with: healthy older people as participants; physical exercise (endurance training (ET), resistance training (RT), and combined training (CT)) as intervention; other different exercise modalities or physical inactivity as comparator; mitochondrial modifications (quality, density and dynamics, oxidative, and antioxidant capacity) as outcomes. The quality assessment was performed according to the PEDro scale; the bias risk was evaluated by Cochrane risk-of-bias assessment tool. RESULTS: Out of 2940 records, 6 studies were included (2 assessing ET, 2 RT, 1 CT, and 1 both ET and RT). Taken together, 164 elderly subjects were included in the present systematic review. Significant positive effects were reported in terms of mitochondrial quality, density, dynamics, oxidative and antioxidant capacity, even though with different degrees according to the exercise type. The quality assessment reported one good-quality study, whereas the other five studies had a fair quality. DISCUSSION: The overall low quality of the studies on this topic indicate that further research is needed. CONCLUSION: RT seems to be the most studied physical exercise modality improving mitochondrial density and dynamics, while ET have been related to mitochondrial antioxidant capacity improvements. However, these exercise-induced specific effects should be better explored in older people.