HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl₄ or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1–3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl₄ groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl₄ treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.     

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.     

Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2

THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5′ untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson''s genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5′ UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.     

No Need for Templates in the Auditory Enhancement Effect

The audibility of a target tone in a multitone background masker is enhanced by the presentation of a precursor sound consisting of the masker alone. There is evidence that precursor-induced neural adaptation plays a role in this perceptual enhancement. However, the precursor may also be strategically used by listeners as a spectral template of the following masker to better segregate it from the target. In the present study, we tested this hypothesis by measuring the audibility of a target tone in a multitone masker after the presentation of precursors which, in some conditions, were made dissimilar to the masker by gating their components asynchronously. The precursor and the following sound were presented either to the same ear or to opposite ears. In either case, we found no significant difference in the amount of enhancement produced by synchronous and asynchronous precursors. In a second experiment, listeners had to judge whether a synchronous multitone complex contained exactly the same tones as a preceding precursor complex or had one tone less. In this experiment, listeners performed significantly better with synchronous than with asynchronous precursors, showing that asynchronous precursors were poorer perceptual templates of the synchronous multitone complexes. Overall, our findings indicate that precursor-induced auditory enhancement cannot be fully explained by the strategic use of the precursor as a template of the following masker. Our results are consistent with an explanation of enhancement based on selective neural adaptation taking place at a central locus of the auditory system.     

Reproductive isolation between oviparous and viviparous lineages of the Eurasian common lizard Zootoca vivipara in a contact zone

Contact zones between two evolutionary lineages are often useful for understanding the process of speciation because the observed genetic pattern reflects the history of differentiation. The Eurasian lacertid lizard Zootoca vivipara is a potentially interesting model for studying the role of reproductive mode in the speciation of squamate reptiles because it has both oviparous (Zootoca vivipara carniolica) and viviparous (Zootoca vivipara vivipara) populations that have recently been shown to be genetically distinct. We studied a newly‐discovered syntopic area of these two Zootoca subspecies in the central Italian Alps using genetic markers to investigate the level of introgression between them. Patterns of genetic differentiation in a fragment of the mitochondrial DNA cytb gene and a set of nuclear microsatellites show that the speciation process is complete in this area, with no evidence of recent introgression. Phylogenetic and genotypic divergence suggests that the two subspecies have experienced long independent evolutionary histories, during which genetic and phenotypic differences evolved. The possible roles of biogeography, reproductive mode, and cytogenetic differentiation in this speciation process are discussed. © 2015 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 114 , 566–573.     

Rapid MALDI-TOF-MS analysis in the study of interaction between whole bacterial cells and human target molecules: binding of Bifidobacterium to human plasminogen

MALDI-TOF (Matrix Assisted Laser Desorption Ionization-Time of Flight)—mass spectrometry has been applied, for the first time, in the investigation of whole Bifidobacterium cells-host target proteins interaction. In particular, by means of this technique, a dose dependent human plasminogen-binding activity has been shown for Bifidobacterium. The involvement of lysine binding sites on the bacterial cell surface has been proved. The obtained result was found to be consistent with that from well-established standard methodologies, thus the proposed MALDI-TOF approach has the potential to enter as a fast alternative method in the field of biorecognition studies involving in bacterial cells and proteins of human origin.     

Enhanced affinity of ketotifen toward tamarind seed polysaccharide in comparison with hydroxyethylcellulose and hyaluronic acid: a nuclear magnetic resonance investigation

Nuclear magnetic resonance (NMR) spectroscopy demonstrated that, in aqueous solution, ketotifen fumarate bound more strongly to tamarind seed polysaccharide (TSP) than to hydroxyethylcellulose or hyaluronic acid. Results were confirmed by dynamic dialysis technique.     

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review

Neurodevelopmental disorders – including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders – manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence – from two or more studies from independent research groups, with results going into the same direction – of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.     

The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials,and of some current trends aiming to de-risk trial programmes of novel agents

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.     

Impact of mental disorders on clinical outcomes of physical diseases: an umbrella review assessing population attributable fraction and generalized impact fraction

Empirical evidence indicates a significant bidirectional association between mental disorders and physical diseases, but the prospective impact of men­tal disorders on clinical outcomes of physical diseases has not been comprehensively outlined. In this PRISMA- and COSMOS-E-compliant umbrella review, we searched PubMed, PsycINFO, Embase, and Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, up to March 15, 2022, to identify systematic reviews with meta-analysis that examined the prospective association between any mental disorder and clinical outcomes of physical diseases. Primary outcomes were disease-specific mortality and all-cause mortality. Secondary outcomes were disease-specific incidence, functioning and/or disability, symptom severity, quality of life, recurrence or progression, major cardiac events, and treatment-related outcomes. Additional inclusion criteria were further applied to primary studies. Random effect models were employed, along with I² statistic, 95% prediction intervals, small-study effects test, excess significance bias test, and risk of bias (ROBIS) assessment. Associations were classified into five credibility classes of evidence (I to IV and non-significant) according to established criteria, complemented by sensitivity and subgroup analyses to examine the robustness of the main analysis. Statistical analysis was performed using a new package for conducting umbrella reviews ( https://metaumbrella.org ). Population attributable fraction (PAF) and generalized impact fraction (GIF) were then calculated for class I-III associations. Forty-seven systematic reviews with meta-analysis, encompassing 251 non-overlapping primary studies and reporting 74 associations, were included (68% were at low risk of bias at the ROBIS assessment). Altogether, 43 primary outcomes (disease-specific mortality: n=17; all-cause mortality: n=26) and 31 secondary outcomes were investigated. Although 72% of associations were statistically significant (p<0.05), only two showed convincing (class I) evidence: that between depressive disorders and all-cause mortality in patients with heart failure (hazard ratio, HR=1.44, 95% CI: 1.26-1.65), and that between schizophrenia and cardiovascular mortality in patients with cardiovascular diseases (risk ratio, RR=1.54, 95% CI: 1.36-1.75). Six associations showed highly suggestive (class II) evidence: those between depressive disorders and all-cause mortality in patients with diabetes mellitus (HR=2.84, 95% CI: 2.00-4.03) and with kidney failure (HR=1.41, 95% CI: 1.31-1.51); that between depressive disorders and major cardiac events in patients with myocardial infarction (odds ratio, OR=1.52, 95% CI: 1.36-1.70); that between depressive disorders and dementia in patients with diabetes mellitus (HR=2.11, 95% CI: 1.77-2.52); that between alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C (RR=3.15, 95% CI: 2.87-3.46); and that between schizophrenia and cancer mortality in patients with cancer (standardized mean ratio, SMR=1.74, 95% CI: 1.41-2.15). Sensitivity/subgroup analyses confirmed these results. The largest PAFs were 30.56% (95% CI: 27.67-33.49) for alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C, 26.81% (95% CI: 16.61-37.67) for depressive disorders and all-cause mortality in patients with diabetes mellitus, 13.68% (95% CI: 9.87-17.58) for depressive disorders and major cardiac events in patients with myocardial infarction, 11.99% (95% CI: 8.29-15.84) for schizophrenia and cardiovascular mortality in patients with cardiovascular diseases, and 11.59% (95% CI: 9.09-14.14) for depressive disorders and all-cause mortality in patients with kidney failure. The GIFs confirmed the preventive capacity of these associations. This umbrella review demonstrates that mental disorders increase the risk of a poor clinical outcome in several physical diseases. Prevention targeting mental disorders – particularly alcohol use disorders, depressive disorders, and schizophrenia – can reduce the incidence of adverse clinical outcomes in people with physical diseases. These findings can inform clinical practice and trans-speciality preventive approaches cutting across psychiatric and somatic medicine.