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To evaluate the effects of qualitative dietary changes and the interaction with aerobic exercise training on liver fat content independent of weight loss in patients with type 2 diabetes. With use of a factorial 2 × 2 randomized parallel-group design, 37 men and 8 women, aged 35-70 years, with type 2 diabetes in satisfactory blood glucose control on diet or diet plus metformin treatment were assigned to one of the following groups for an 8-week period: 1) high-carbohydrate/high-fiber/low-glycemic index diet (CHO/fiber group), 2) high-MUFA diet (MUFA group), 3) high-carbohydrate/high-fiber/low-glycemic index diet plus physical activity program (CHO/fiber+Ex group), and 4) high-MUFA diet plus physical activity program (MUFA+Ex group). Before and after intervention, hepatic fat content was measured by (1)H NMR. Dietary compliance was optimal and body weight remained stable in all groups. Liver fat content decreased more in MUFA (-29%) and MUFA+Ex (-25%) groups than in CHO/fiber (-4%) and CHO/fiber+Ex groups (-6%). Two-way repeated-measures ANOVA, including baseline values as covariate, showed a significant effect on liver fat content for diet (P = 0.006), with no effects for exercise training (P = 0.789) or diet-exercise interaction (P = 0.712). An isocaloric diet enriched in MUFA compared with a diet higher in carbohydrate and fiber was associated with a clinically relevant reduction of hepatic fat content in type 2 diabetic patients independent of an aerobic training program and should be considered for the nutritional management of hepatic steatosis in people with type 2 diabetes.

Adoptive transfer of engineered NK cells, one of clinical approaches to fight cancer, is gaining great interest in the last decade. However, the development of new strategies is needed to improve clinical efficacy and safety of NK cell-based immunotherapy. NK cell-mediated recognition and lysis of tumor cells are strictly dependent on the expression of ligands for NK cell-activating receptors NKG2D and DNAM-1 on tumor cells. Of note, the PVR/CD155 and Nectin-2/CD112 ligands for DNAM-1 are expressed primarily on solid tumor cells and poorly expressed in normal tissue cells. Here, we generated human NK cells expressing either the full length DNAM-1 receptor or three different DNAM-1-based chimeric receptor that provide the expression of DNAM-1 fused to a costimulatory molecule such as 2B4 and CD3ζ chain. Upon transfection into primary human NK cells isolated from healthy donors, we evaluated the surface expression of DNAM-1 and, as a functional readout, we assessed the extent of degranulation, cytotoxicity and the production of IFNγ and TNFα in response to human leukemic K562 cell line. In addition, we explored the effect of Nutlin-3a, a MDM2-targeting drug able of restoring p53 functions and known to have an immunomodulatory effect, on the degranulation of DNAM-1-engineered NK cells in response to human neuroblastoma (NB) LA-N-5 and SMS-KCNR cell lines. By comparing NK cells transfected with four different plasmid vectors and through blocking experiments, DNAM-1-CD3ζ-engineered NK cells showed the strongest response. Furthermore, both LA-N-5 and SMS-KCNR cells pretreated with Nutlin-3a were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector. Our results provide a proof-of-concept suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53.

Rabies, caused by RNA viruses in the Genus Lyssavirus, is the most fatal of all infectious diseases. This neglected zoonosis remains a major public health problem in developing countries, causing the death of an estimated 25,000-159,000 people each year, with more than half of them in children. The high incidence of human rabies in spite of effective vaccines is mainly linked to the lack of compliance with the complicated administration schedule, inadequacies of the community public health system for local administration by the parenteral route and the overall costs of the vaccine. The goal of our work was the development of a simple, affordable and effective vaccine strategy to prevent human rabies virus infection. This next generation vaccine is based on a replication-defective chimpanzee adenovirus vector belonging to group C, ChAd155-RG, which encodes the rabies glycoprotein (G). We demonstrate here that a single dose of this vaccine induces protective efficacy in a murine model of rabies challenge and elicits strong and durable neutralizing antibody responses in vaccinated non-human primates. Importantly, we demonstrate that one dose of a commercial rabies vaccine effectively boosts the neutralizing antibody responses induced by ChAd155-RG in vaccinated monkeys, showing the compatibility of the novel vectored vaccine with the current post-exposure prophylaxis in the event of rabies virus exposure. Finally, we demonstrate that antibodies induced by ChAd155-RG can also neutralize European bat lyssaviruses 1 and 2 (EBLV-1 and EBLV-2) found in bat reservoirs.

We discovered that the hepatitis C virus (HCV) envelope glycoprotein E2 binds to human hepatoma cell lines independently of the previously proposed HCV receptor CD81. Comparative binding studies using recombinant E2 from the most prevalent 1a and 1b genotypes revealed that E2 recognition by hepatoma cells is independent from the viral isolate, while E2–CD81 interaction is isolate specific. Binding of soluble E2 to human hepatoma cells was impaired by deletion of the hypervariable region 1 (HVR1), but the wild‐type phenotype was recovered by introducing a compensatory mutation reported previously to rescue infectivity of an HVR1‐deleted HCV infectious clone. We have identified the receptor responsible for E2 binding to human hepatic cells as the human scavenger receptor class B type I (SR‐BI). E2–SR‐BI interaction is very selective since neither mouse SR‐BI nor the closely related human scavenger receptor CD36, were able to bind E2. Finally, E2 recognition by SR‐BI was competed out in an isolate‐specific manner both on the hepatoma cell line and on the human SR‐BI‐transfected cell line by an anti‐HVR1 monoclonal antibody.

Here we report on the humoral and cellular immune response in eight volunteers who autonomously chose to adhere to the Italian national COVID-19 vaccination campaign more than 3 months after receiving a single-administration GRAd-COV2 vaccine candidate in the context of the phase-1 clinical trial. We observed a clear boost of both binding/neutralizing antibodies as well as T-cell responses upon receipt of the heterologous BNT162b2 or ChAdOx1-nCOV19 vaccines. These results, despite the limitation of the small sample size, support the concept that a single dose of an adenoviral vaccine may represent an ideal tool to effectively prime a balanced immune response, which can be boosted to high levels by a single dose of a different vaccine platform.

[This corrects the article DOI: 10.1371/journal.pntd.0008459.].

A 24-year-old obese Caucasian male, without relevant anamnesis, who was admitted to the ER presented with abdominal pain, nausea and vomiting, hyperglycemia, and diabetic ketoacidosis (DKA). The diagnosis of acute pancreatitis (AP) was supported by increased serum levels of triglycerides and lipase associated with abdominal CT scans. The patient was treated for five days with IV regular insulin, hydration, electrolytes replacement, and statin/fibrate therapy with clinical improvement. Some 10% hemoglobin A1c value, normal C-peptide level and negative glutamic acid decarboxylase (GAD-65), and islet cell autoantibodies suggested the diagnosis of a new-onset type 2 diabetes mellitus (DM) presenting with an uncommon triad of DKA and hypertriglyceridemia (HTG)-induced AP. Anamnestic history suggested that DKA was dependent on sugar-sweetened soft drinks abuse (soft drink ketosis), a clinical association more frequent in Asian than in Western patients.

Among approximately 1000 adenoviruses from chimpanzees and bonobos studied recently, the Pan Adenovirus type 3 (PanAd3, isolated from a bonobo, Pan paniscus) has one of the best profiles for a vaccine vector, combining potent transgene immunogenicity with minimal pre-existing immunity in the human population. In this study, we inserted into a replication defective PanAd3 a transgene expressing a fusion protein of conserved influenza antigens nucleoprotein (NP) and matrix 1 (M1). We then studied antibody and T cell responses as well as protection from challenge infection in a mouse model. A single intranasal administration of PanAd3-NPM1 vaccine induced strong antibody and T cell responses, and protected against high dose lethal influenza virus challenge. Thus PanAd3 is a promising candidate vector for vaccines, including universal influenza vaccines.

The evaluation of surgical risk is crucial in elderly patients. At present, there is little evidence of the usefulness of comprehensive geriatric assessment (CGA) as a part of the overall assessment of surgical elderly patients. We verified whether CGA associated with established surgical risk assessment tools is able to improve the prediction of postoperative morbidity and mortality in 377 elderly patients undergoing elective surgery. Overall mortality and morbidity were 2.4% and 19.9%, respectively. Multivariate analysis showed that impaired cognitive function (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.15 to 4.22; P < .02) and higher Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (OR, 1.11; 95% CI, 1.00 to 1.23; P < .04) are predictive of mortality. Higher comorbidity is predictive of morbidity (OR, 2.12; 95% CI, 1.06 to 4.22; P < .03) and higher American Society of Anesthesiologists (OR, 2.18; 95% CI, 1.31 to 3.63; P < .001) and National Confidential Enquiry into Patient Outcome of Death score (OR, 2.03; 95% CI, 1.03 to 4.00; P < .04). In elective surgical elderly patients, the morbidity and mortality are low. The use of CGA improves the identification of elderly patients at higher risk of adverse events, independent of the surgical prognostic indices. •The evaluation of surgical risk is particularly important in older patients, who have a higher risk of adverse events during and after surgery.•Comprehensive geriatric assessment is considered as a part of the overall assessment of surgical older patients.•Comprehensive geriatric assessment improves the identification of older patients at higher risk of adverse events, independent of the most used surgical prognostic indices.

Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing.