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Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.

Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression.

Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor epithelium. This strong desmoplasia is orchestrated by various soluble factors and signals, suggesting a critical role in shaping a tumor growth-permissive microenvironment that is responsible for CCA poor clinical outcome. Indeed stroma not only provides an abundance of factors that facilitate CCA initiation, growth and progression, but also a prejudicial impact on therapeutic outcome. This review will give an overview of tumor-stroma signaling in a microenvironment critically regulating CCA development and progression. Identification of CCA secreted factors by both the fibroblast component and immune cell subsets might provide ample opportunities for pharmacological targeting of this type of cancer.

Vitamin D plays a crucial and very well-known role in regulation of calcium homeostasis and bone metabolism and mineralization. However, a huge and more recent body of evidence supports the positive influence of vitamin D on the regulation of immune response, ranging from protection against respiratory tract infections to prevention and management of asthma. Nevertheless, vitamin D deficiency is a very common condition and there is an increasing need for suitable products for proper supplementation, allowing good compliance also in specific populations. Orally disintegrating tablets (ODT) were first developed to overcome the difficulty experienced by pediatric and geriatric patients of swallowing traditional oral dosage forms and, recently, orodispersible films (ODF) are gaining popularity as novel dosage form for assuming active pharmaceutical ingredients, vitamins, and ingredients for food supplements. This study describes a 2000 IU Vitamin D3 ODF for daily intake, consisting of hydrophilic polymers and suitable excipients, manufactured by film-casting process. Elongation-at-break (E%), Young’s modulus (Y), and tensile strength (TS) were investigated using a dynamometer. Chemical stability was evaluated assaying the vitamin D3 in the films stored at different environmental conditions. In addition, in vitro disintegration and dissolution studies were performed. Correlation existed between the mechanical properties of the film and the residual water, acting as plasticizer. The stability study showed that vitamin D3 assay was ≥90% also after 3 months at 40 °C. The film disintegrated in less than 1 min and the vitamin D3 released was ≥75% after 15 min. An ODF with suitable properties can be manufactured and used as innovative dosage form for vitamin D3 food supplements.

The assessment of well-being remains an important topic for many disciplines including medical, psychological, social, educational, and economic fields. The present study assesses the reliability and validity of a five-item instrument for evaluating physical, psychological, spiritual, relational, and general well-being. This measure uniquely utilizes a segmented numeric version of the visual analog scale in which a respondent selects a whole number that best reflects the intensity of the investigated characteristic. In study one, 939 clinical (i.e., diagnosed with cancer and liver disease with cirrhosis) and non-clinical (i.e., undergraduate students and their family and acquaintances) participants between the ages of 18 to 87 years ( M = 47.20 years, SD = 19.62, 54% males) were recruited. Results showed items have strong discriminant ability and the spread of threshold parameters attests to the appropriateness of the response categories. Moreover, convergent and discriminant validity were found with other self-report measures (e.g., depression, anxiety, optimism, well-being) and the measure showed responsiveness to two separate interventions for clinical populations. In study two, 287 Canadian (ages ranged from 18 to 30 years; M = 20.78, SD = 3.32; 23% males) and 342 Italian undergraduate psychology students (age ranged from 18 to 29 years, M = 21.21 years, SD = 1.73, 38% males) were recruited to complete self-report questionnaires. IRT-based differential item functioning analyses provided evidence that the item properties were similar for the Italian and English versions of the scale. Additionally, the validity results obtained in study one were replicated and similar relationships between criterion variables were found when comparing the Italian- and the English-speaking samples. Overall, the current study provides evidence that the Italian and English versions of the WB-NRSs offer added value in research focused on well-being and in assessing well-being changes prompted by intervention programs.

Transjugular intrahepatic portosystemic shunt (TIPS) represents a very effective treatment of complications of portal hypertension. Established indications to TIPS in cirrhotic patients include portal hypertensive bleeding and refractory ascites. Over the years additional indications have been proposed, such as the treatment of vascular disease of the liver, hepatic hydrothorax, hepatorenal syndrome and bleeding from ectopic varices. Indications under evaluation include treatment of portal hypertension prior to major abdominal surgery and treatment of portal vein thrombosis. In spite of these advances, there are still uncertainties regarding the appropriate workup for patients to be scheduled for TIPS. Moreover, prevention and management of post-TIPS complications including hepatic encephalopathy and heart failure are still suboptimal. These issues are particularly relevant considering aging in TIPS candidates in Western countries. Correct selection of patients is mandatory to prevent complications which may eventually frustrate the good hemodynamic results and worsen the patient’s quality of life or even life expectancy. The possible role of small diameter TIPS to prevent post-procedural complications is discussed.

The present study aims to develop and validate an Italian version of the Brief Self-Control Scale (BSCS). A large sample of Italian-speaking participants (N = 1139) completed the BSCS and measures of personality and individual dispositions. A clinical sample (N = 217) was administered the Italian version and an English-speaking sample (N = 274) completed the original version to test measurement invariance. Using confirmatory factor analysis, the best fit was observed for a shortened two-factor model (i.e., impulse control and self-discipline). Metric invariance across languages and partial strong invariance across genders, ages, and clinical status were demonstrated. Internal consistency and test-retest reliability for the total scale were adequate, and validity was established based on its correlations with related constructs and confirming that males and young individuals are more likely to have lower self-control. Results support the use of the shortened BSCS version to assess self-control in Italian-speaking individuals.

Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood-brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants (OCT4A, OCT4B, and OCT4B1), SOX-2 (SRY [sex determining region Y]-box 2), Nanog, and miR-145. Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A, OCT4B1, SOX-2, and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests that dendrosomal curcumin reduces the proliferation of U87MG cells through the downregulation of OCT4 (octamer binding protein 4) variants and SOX-2 (SRY [sex determining region Y]-box 2) in an miR-145-dependent manner.

Purpose Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). Methods 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Results Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months ( p  < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, ( p  = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, ( p  = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. Conclusions MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

There is a growing tendency to use noninvasive measures instead of histopathological analysis of liver tissue for the evaluation of disease progression in patients with chronic liver disease. The authors of this Review provide an overview of the proposed noninvasive diagnostic methodologies, focusing on those that are easily available to clinicians—biochemical markers and transient elastography. Although histopathological analysis of liver tissue is still the reference standard for the evaluation of disease progression in patients with chronic liver disease, a distinct change in clinical practice is occurring. The tendency to substitute histopathological analysis of liver biopsies with complex, surrogate 'noninvasive' measures of disease progression has grown to such a level that clarification and guidance on their use is needed. This Review provides an overview of the proposed noninvasive diagnostic methodologies and their possible integration with the standard invasive procedures used for the evaluation of disease progression (i.e. liver biopsy and the measurement of portal pressure). A concise analysis of what has been proposed for the differentiation of simple fatty liver from nonalcoholic steatohepatitis and its possible fibrogenic evolution is also included. In particular, the Review focuses on the methods easily available as part of daily clinical practice in hepatology—biochemical markers and transient elastography (i.e. liver stiffness measurement). Key Points Several noninvasive approaches—serum markers, transient elastography and imaging—have been proposed as a replacement for, or accompaniment to, histopathological analysis of liver biopsies for the assessment of liver fibrosis All proposed noninvasive methodologies have sufficient-to-excellent diagnostic accuracy for the detection (or exclusion) of advanced fibrosis and cirrhosis, but none allow a step-wise follow-up of the fibrogenic evolution of chronic liver disease according to the existing histopathological staging systems; in addition, none of the currently available tests has a well-defined prognostic value, such as the prediction of decompensation or death Due to 'spectrum bias' and the possible causes of discordance with the histopathological assessment, applying the different proposed cut-off values in clinical practice is currently hazardous Combining two unrelated noninvasive tests (i.e. a biochemical test and liver stiffness measurement) might be useful for the initial assessment of fibrosis evolution in patients with chronic liver disease Most noninvasive methods could be instrumental in staging advanced fibrosis from F3/F4 and beyond A noninvasive approach to NAFLD would need to differentiate NASH from bland steatosis in addition to detecting clinically relevant fibrosis and monitoring disease progression