Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available ...on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD‐related HCC (NAFLD‐HCC) and to compare them to those of hepatitis C virus (HCV)‐related HCC. A total of 756 patients with either NAFLD (145) or HCV‐related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead‐time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD‐HCC patients, in contrast to the near totality of HCV‐HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD‐HCC, 25.5 months (95% confidence interval 21.9‐29.1), than in those with HCV‐HCC, 33.7 months (95% confidence interval 31.9‐35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD‐HCC and HCV‐HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD‐HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827–838)
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•The valorisation of industrial wastepaper was studied.•The glucose and xylose yields were both 95 mol% respect to glucan and xylan.•The sequential utilisation of glucose and xylose ...for lipid production was observed.•L. starkeyi converted undetoxified hydrolysate into oil with a yield of 20.2 wt%.•The lipid profile of the microbial oil was similar to those of typical vegetable oils.
Single cell oil (SCO) represents an outstanding alternative to both fossil sources and vegetable oils from food crops waste. In this work, an innovative two-step process for the conversion of cellulosic paper mill waste into SCO was proposed and optimised. Hydrolysates containing glucose and xylose were produced by enzymatic hydrolysis of the untreated waste. Under the optimised reaction conditions (Cellic® CTec2 25 FPU/g glucan, 48 h, biomass loading 20 g/L), glucose and xylose yields of 95 mol% were reached. The undetoxified hydrolysate was adopted as substrate for a batch-mode fermentation by the oleaginous yeast Lipomyces starkeyi. Lipid yield, content for single cell, production and maximum oil productivity were 20.2 wt%, 37 wt%, 3.7 g/L and 2.0 g/L/d respectively. This new generation oil, obtained from a negative value industrial waste, represents a promising platform chemical for the production of biodiesel, biosurfactants, animal feed and biobased plastics.
Production of nanotechnology-based materials is increasing worldwide: it is essential to evaluate their potential toxicity. Among these nanomaterials, carbon nanotubes (CNTs) have tremendous ...potential in many areas of research and applications. We have investigated the cyto- and genotoxic effects of single and multi-walled CNTs (SWCNTs, MWCNTs) and carbon black (CB) on the mouse macrophage cell line RAW 264.7. Specifically we have investigated inflammatory response, release of tumor necrosis factor-α (TNF-α), intracellular reactive oxygen species (ROS) production, cell death (both necrosis and apoptosis), chromosomal aberrations and cellular ultrastructural alteration caused by CB, MWCNTs and SWCNTs. Our data confirm that both CNTs and CB are cyto and geno-toxic to RAW 264.7 mouse macrophages. CNTs exposure induced ROS release, necrosis and chromosomal aberrations but did not cause an inflammatory response. In addition CNTs induce ultrastructural damage and apoptosis. CNTs penetrate the cell membrane and individual MWCNTs are seen associated with the nuclear envelope.
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•The multi-step exploitation of unpretreated giant reed was assessed.•Two undetoxified xylose-rich hydrolysates were fermented into microbial oil.•Two undetoxified glucose-rich ...hydrolysates were converted into single cell oil.•The lipid yields of L. starkeyi DSM 70,296 were in the range 15–24 wt%.•The single cell oil composition was similar to those of typical vegetable oils.
Giant reed (Arundo donax L.) is a promising source of carbohydrates that can be converted into single cell oil (SCO) by oleaginous yeasts. Microbial conversion of both hemicellulose and cellulose fractions represents the key step for increasing the economic sustainability for SCO production. Lipomyces starkeyi DSM 70,296 was cultivated in two xylose-rich hydrolysates, obtained by the microwave-assisted hydrolysis of hemicellulose catalysed by FeCl3 or Amberlyst-70, and in two glucose-rich hydrolysates obtained by the enzymatic hydrolysis of cellulose. L. starkeyi grew on both undetoxified and partially-detoxified hydrolysates, achieving the lipid content of 30 wt% and yield values in the range 15–24 wt%. For both integrated cascade processes the final production of about 8 g SCO from 100 g biomass was achieved. SCO production through integrated hydrolysis cascade processes represents a promising solution for the effective exploitation of lignocellulosic feedstock from perennial grasses towards new generation biodiesel and other valuable bio-based products.
Summary Background Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's ...antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov , number NCT01654692. Findings 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7–57·6), as did ten with brain metastases (50·0%, 27·2–72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 24% patients and neutropenia in 16 19%). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding Bristol-Myers Squibb.
Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of ...the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.
Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. ...Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 65% women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.
We provide here a first-hand description of the coseismic surface effects caused by the Mw 6.4 Petrinja earthquake that hit central Croatia on 29 December 2020. This was one of the strongest seismic ...events that occurred in Croatia in the last two centuries. Field surveys in the epicentral area allowed us to observe and map primary coseismic effects, including geometry and kinematics of surface faulting, as well as secondary effects, such as liquefaction, sinkholes and landslides. The resulting dataset consists of homogeneous georeferenced records identifying 222 observation points, each of which contains a minimum of 5 to a maximum of 14 numeric and string fields of relevant information. The earthquake caused surface faulting defining a typical 'conjugate' fault pattern characterized by Y and X shears, tension cracks (T fractures), and compression structures (P shears) within a ca. 10 km wide (across strike), NW-SE striking right-lateral strike-slip shear zone (i.e., the Petrinja Fault Zone, PFZ). We believe that the results of the field survey provide fundamental information to improve the interpretation of seismological, GPS and InSAR data of this earthquake. Moreover, the data related to the surface faulting may impact future studies focused on earthquake processes in active strike-slip settings, integrating the estimates of slip amount and distribution in assessing the hazard associated with capable transcurrent faults.
The combination of extremely high stiffness and bending flexibility with tunable electrical and optical properties makes van der Waals transition metal dichalcogenides appealing both for fundamental ...science and applied research. By taking advantage of localized H2‐bulged MoS2 membranes, an innovative approach, based on atomic force microscopy nanoindentation, is demostrated and discussed here, aiming at measuring elastic and thermodynamic properties of nanoblisters made of 2D materials. The results, interpreted in the membrane limit of the Föppl–von Karman equation, lead to the quantification of the internal pressure and mole number of the trapped H2 gas, as well as of the stretching modulus and adhesion energy of the MoS2 membrane. The latter is discussed in the limit of strong (clamped and fully bonded interlayer interface) shear, as experimentally achieved in the investigated H2‐bulged 2D blisters. Moreover, this approach allows to quantify the stress, and consequently the strain, locally imposed to the MoS2 membrane by the bulging of the domes.
A detailed study of elastic and thermodynamic properties of nanoblisters, made on purpose in MoS2 bulk flakes by means of low‐energy proton irradiation, is provided. An experimental approach, based on atomic force microscopy (AFM) nanoindentation, is used to explore the membrane response to the bulging, the resulting membrane strain, the confinement exerted on the inner gas, and the adhesion energy.
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