Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to prote...Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and migration.HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy.In line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation.In cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation.Moreover,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar hemorrhage.Of note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases.This is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis.This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its modulation.Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.展开更多
BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To inv...BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To investigate the performance of different ultrasound(US)-based techniques for the non-invasive assessment of liver fibrosis,steatosis,and inflammation in these patients.METHODS We collected data from consecutive patients who underwent liver biopsy for suspected MASLD between January 2019 and December 2021.Two-dimensional shear-wave elastography,sound speed plane-wave US,attenuation plane-wave US,viscosity plane-wave US(Vi.PLUS)using Aixplorer MACH 30 system,and transient elastography and controlled attenuation parameter from FibroScan were measured before biopsy.RESULTS A total of 120 participants were enrolled.Both transient elastography and two-dimensional shear-wave elasto-graphy showed good performance for the diagnosis of advanced fibrosis[area under the receiver operating charac-teristic curve(AUROC)=0.93 and 0.90,respectively].The diagnostic performance of Vi.PLUS for the presence of both ballooning grade≥1 and lobular inflammation≥1 was good with an AUROC of 0.72.A score based on Vi.PLUS,aspartate aminotransferase,and sound speed plane-wave US[viscosity-aspartate aminotransferase-speed of sound MASH ultrasound score(VAS-MASH-US score)]had a good accuracy for the diagnosis of MASH(AUROC=0.75).VAS-MASH-US score>0.6 showed a good sensitivity for MASH diagnosis(79.0%).According to decision curve analysis,the application of the VAS-MASH-US score would lead to a more accurate selection of patients who are candidates to undergo liver biopsy and would reduce the need for invasive procedures for patients at low risk of MASH.CONCLUSION Multiparametric US allows the non-invasive assessment of steatosis,inflammation,and fibrosis in patients with MASLD.Liver viscosity improved the capability of non-invasively identifying patients with MASH.展开更多
Grain size and formation of the Peripheral Coarse Grain(PCG)defect influence the mechanical and crash properties of extruded profiles.Controlling microstructural evolution during the extrusion of 6XXX series aluminum ...Grain size and formation of the Peripheral Coarse Grain(PCG)defect influence the mechanical and crash properties of extruded profiles.Controlling microstructural evolution during the extrusion of 6XXX series aluminum alloys is therefore essential to ensure the performance of structural components.In this work,three profiles with the same nominal geometry were extruded with a die comprising three different bearing geometries to create different extrusion conditions.Each profile was analyzed experimentally to gather data on the microstructure and mechanical properties.Bulge testing revealed that Profile 2,with the thickest PCG layer(490-1150µm),exhibited worse mechanical performance,with a hoop strain at fracture of 0.08 and a peak load of 51.5 kN,compared to Profiles 1 and 3,which had higher hoop strains(0.13 and 0.14)and peak loads(56.1 and 57.6 kN,respectively).Finite Element Method(FEM)simulations of the extrusion process were carried out using Qform Extrusion UK with a post-processing subroutine developed and implemented to calculate additional parameters such as the stored energy,percentage dynamic recrystallization,grain size,and PCG formation based on standard output parameters from the simulation including strain,temperature and strain rate.The simulation demonstrated that the highest strain rate(40-220 s^(-1))and stored energy(150,000-440,000 J m^(-3))in Profile 2 led to the thickest PCG layer.Based on these results,the proposed predictive model was validated against experimental data,demonstrating high accuracy in predicting PCG thickness and grain size while effectively capturing the influence of process parameters on microstructural evolution.展开更多
In complex geological environments,the analysis of drill cores to determine rock strength can be challenging due to the wide variability in the degree of fracturing,leading to subjectivity in the collection of represe...In complex geological environments,the analysis of drill cores to determine rock strength can be challenging due to the wide variability in the degree of fracturing,leading to subjectivity in the collection of representative samples for uniaxial compressive strength testing.This study evaluates non-destructive techniques on calcareous rocks with different tectonic deformations,including Equotip hardness,ultrasound P-wave velocity,thin section analysis,and calcimetry,integrated with photogrammetric fracture analysis.The investigated carbonate rock samples are sourced from drill cores derived from the Umbria-Marche fold and thrust belt(northern Apennines,Italy),including a gently dipping limb of an anticline,a hinge zone of an anticline,and a fault zone associated with a thrust.Fracture intensity,quantified by the P21 parameter using photogrammetric techniques on pre-loading rock samples,is assessed alongside macroscopic identification of discontinuities(such as stylolites,veins,and joints)using marker colours to monitor failures during uniaxial compression testing.Empirical correlations depicted by single and multi-linear relationships indicate a strong dependence between the mechanical and physical properties of limestones.Both Equotip and P-wave velocity are influenced by fracture intensity,but P-wave velocity varies significantly with discontinuity orientation,especially at 45°-90°.To refine uniaxial compressive strength predictions and mitigate multicollinearity,statistical approaches,including linear and multilinear regression,Principal Component Analysis and Gaussian Process Regression,were tested.Findings improve the reliability of non-destructive techniques for assessing rock strength in structurally complex settings,with implications for geotechnical applications.展开更多
Biliary lithiasis is an endemic condition in both Western and Eastern countries, in some studies affecting 20% of the general population. In up to 20% of cases, gallbladder stones are associated with common bile duct ...Biliary lithiasis is an endemic condition in both Western and Eastern countries, in some studies affecting 20% of the general population. In up to 20% of cases, gallbladder stones are associated with common bile duct stones (CBDS), which are asymptomatic in up to one half of cases. Despite the wide variety of examinations and techniques available nowadays, two main open issues remain without a clear answer: how to cost-effectively diagnose CBDS and, when they are finally found, how to deal with them. CBDS diagnosis and management has radically changed over the last 30 years, following the dramatic diffusion of imaging, including endoscopic ultrasound (EUS) and magnetic resonance cholangiography (MRC), endoscopy and laparoscopy. Since accuracy, invasiveness, potential therapeutic use and cost-effectiveness of imaging techniques used to identify CBDS increase together in a parallel way, the concept of “risk of carrying CBDS” has become pivotal to identifying the most appropriate management of a specific patient in order to avoid the risk of “under-studying” by poor diagnostic work up or “over-studying” by excessively invasive examinations. The risk of carrying CBDS is deduced by symptoms, liver/pancreas serology and ultrasound. “Low risk” patients do not require further examination before laparoscopic cholecystectomy. Two main “philosophical approaches” face each other for patients with an “intermediate to high risk” of carrying CBDS: on one hand, the “laparoscopy-first” approach, which mainly relies on intraoperative cholangiography for diagnosis and laparoscopic common bile duct exploration for treatment, and, on the other hand, the “endoscopy-first” attitude, variously referring to MRC, EUS and/or endoscopic retrograde cholangiography for diagnosis and endoscopic sphincterotomy for management. Concerning CBDS diagnosis, intraoperative cholangiography, EUS and MRC are reported to have similar results. Regarding management, the recent literature seems to show better short and long term outcome of surgery in terms of retained stones and need for further procedures. Nevertheless, open surgery is invasive, whereas the laparoscopic common bile duct clearance is time consuming, technically demanding and involves dedicated instruments. Thus, although no consensus has been achieved and CBDS management seems more conditioned by the availability of instrumentation, personnel and skills than cost-effectiveness, endoscopic treatment is largely preferred worldwide.展开更多
Non-alcoholic fatty liver disease(NAFLD)is the leading cause of diffuse liver disease.An accurate estimate of the fat in the liver is important in the diagnostic work-up of patients with NAFLD because the degree of li...Non-alcoholic fatty liver disease(NAFLD)is the leading cause of diffuse liver disease.An accurate estimate of the fat in the liver is important in the diagnostic work-up of patients with NAFLD because the degree of liver steatosis is linked to the metabolic syndrome and the cardiovascular risk.Ultrasound(US)B-mode imaging allows to subjectively estimate the fatty infiltration in the liver;however,it has a low performance for the detection of mild steatosis.Quantitative US is based on the analysis of the radiofrequency echoes detected by an US system,and it allows to calculate a backscatter coefficient or an attenuation coefficient or the sound speed.The estimation of the backscatter coefficient is rather cumbersome and requires the use of a phantom for addressing all sources of variability.Controlled attenuation parameter(CAP)available on the FibroScan system(Echosens,France)measures the attenuation of the US beam.CAP is accurate in grading fatty infiltration-even though there is an overlap between consecutive grade of liver steatosis-and the values are not influenced by liver fibrosis.Several US manufacturers are developing or have already developed software for quantifying the attenuation of the US beam.Preliminary results show that proprietary technologies implemented in US systems seem more accurate than CAP for grading liver steatosis.Another available method for quantifying liver steatosis is based on the computation of the sound speed and the initial results appear promising.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the tr...Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.展开更多
End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver tran...End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell(BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.展开更多
Two complete specimens from the Pelsonian （Middle Anisian, Middle Triassic） of Luoping, Yunnan Province, South China are referred to a new actinopterygian genus, Luopingichthys gen. nov., and ascribed to the perleid...Two complete specimens from the Pelsonian （Middle Anisian, Middle Triassic） of Luoping, Yunnan Province, South China are referred to a new actinopterygian genus, Luopingichthys gen. nov., and ascribed to the perleidiform family Polzbergidae based especially on a typical synapomorphy of a peculiar premaxillary-maxillary complex, i.e., the fusion between premaxillary and maxillary along the antero-dorsal margin of the maxillary. The new taxon differs from other deep-bodied representatives of the family, Felberia and Stoppania, in its fusiform or deep fusiform body shape; sickle-shaped preopercular with short infraorbital process; lack of modified scales at the base of the anal fin; the short-based dorsal fin; scarcely ornamented scales; and thin anterior teeth. Based on a redescription of the holotype of the taxon Ctenognathichthys hattichi from the Middle Triassic （Ladinian） Prosanto Formation, Canton Graubiinden, eastern Switzerland, the only known specimen, which shows the same fusion between premaxillary and maxillary, the systematic position of the species is clarified and the taxon is proposed to be a further representative of the family Polzbergidae, and is transferred to the new genus.展开更多
Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can imp...Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments.Repetition of liver ultrasonography(US)every 6 mo is the recommended surveillance program to detect early HCCs,and a positive US has to entrain a well-defined recall policy based on contrast-enhanced,dynamic radiological imaging or biopsy for the diagnosis of HCC.Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance,the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure.Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC.The promotion of specific educational programs for practitioners,clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.展开更多
Advanced stage hepatocellular carcinoma(HCC) is a category of disease defined by radiological, clinical and hepatic function parameters, comprehending a wide range of patients with different general conditions. The ma...Advanced stage hepatocellular carcinoma(HCC) is a category of disease defined by radiological, clinical and hepatic function parameters, comprehending a wide range of patients with different general conditions. The main therapeutic option is represented by sorafenibtreatment, a multi-kinase inhibitor with anti-proliferative and anti-angiogenic effect. Trans-arterial Radio Embolization also represents a promising new approach to intermediate/advanced HCC. Post-marketing clinical studies showed that only a portion of patients actually benefits from sorafenib treatment, and an even smaller percentage of patients treated shows partial/complete response on follow-up examinations, up against relevant costs and an incidence of drug related adverse effects. Although the treatment with sorafenib has shown a significant increase in mean overall survival in different studies, only a part of patients actually shows real benefits, while the incidence of drug related significant adverse effects and the economic costs are relatively high. Moreover, only a small percentage of patients also shows a response in terms of lesion dimensions reduction. Being able to properly differentiate patients who are responding to the therapy from non-responders as early as possible is then still difficult and could be a pivotal challenge for the future; in fact it could spare several patients a therapy often difficult to bear, directing them to other second line treatments(many of which are at the moment still under investigation). For this reason, some supplemental criteria to be added to the standard modified Response Evaluation Criteria in Solid Tumors evaluation are being searched for. In particular, finding some parameters(cellular density, perfusion grade and enhancement rate) able to predict the sensitivity of the lesions to anti-angiogenic agents could help in stratifying patients in terms of treatment responsiveness before the beginning of the therapy itself, or in the first weeks of sorafenib treatment. This would bring a strongly desirable help in clinical managements of these patients.展开更多
Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative med...Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-de- rived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events （e.g., DNA damage） or environmental cues （e.g., stressful stimuli or diseases）, which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can influence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.展开更多
Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyce...Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and/or conflicting results in animal models.展开更多
AIM： To evaluate the role of genetic factors in the pathogenesis of Crohn＇s disease （CD） and ulcerative colitis （UC）, we investigated the single nucleotide polymorphisms （SNPs） of NOD2/CARD15 （R702W, Gg08R an...AIM： To evaluate the role of genetic factors in the pathogenesis of Crohn＇s disease （CD） and ulcerative colitis （UC）, we investigated the single nucleotide polymorphisms （SNPs） of NOD2/CARD15 （R702W, Gg08R and L1007finsC）, and Toll-like receptor 4 （TLR4） genes （D299G and T399I） in a selected inflammatory bowel disease （IBD） population coming from Southern Italy. METHODS： Allele and genotype frequencies of NOD2/ CARD15 （R702W, Gg08R and L1007finsC） and TLR4 （D299G and T399I） SNPs were examined in 133 CD patients, in 45 UC patients, and in 103 healthy controls. A genotype-phenotype correlation was performed. RESULTS： NOD2/CARD15 R702W mutation was significantly more frequent in CD （9.8%） than in controls （2.4%, P = 0.001） and in UC （2.3%, P = 0.03）. No significant difference was found between UC patients and control group （P 〉 0.05）. In CD and UC patients, no significant association with G908R variant was found. L1007finsC SNP showed an association with CD （9.8%） compared with controls （2.9%, P = 0.002） and UC patients （2.3%, P = 0.01）. Moreover, in CD patients, G908R and L1007finsC mutations were significantly associated with different phenotypes compared to CD wild-type patients. No association of IBD with the TLR4 SNPs was found in either cohort （allele frequencies： D299G-controls 3.9%, CD 3.7%, UC 3.4%, P 〉 0.05; T399I-controls 2.9%, CD 3.0%, UC 3.4%, P 〉 0.05）. CONCLUSION： These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/ CARD15, but not TLR4 SNPs, are associated with increased risk of CD.展开更多
We report equilibrium sapphirine ＋ quartz assemblage in biotite-orthopyroxene-garnet granulites from a new locality in Panasapattu of Paderu region in the Eastern Ghats granulite belt, which provide new evidence for ...We report equilibrium sapphirine ＋ quartz assemblage in biotite-orthopyroxene-garnet granulites from a new locality in Panasapattu of Paderu region in the Eastern Ghats granulite belt, which provide new evidence for ultrahigh-temperature （UHT） metamorphism at 1030-1050 ℃ and 10 kbar in this region. The development of migmatitic texture, stabilization of the garnet-orthopyroxene- plagioclase-K-feldspar association, prograde biotite inclusions within garnet and sapphirine as well as sapphirine and cordierite inclusions within garnet in these granulites indicate that the observed peak assemblages probably formed during prograde dehydration melting of a Bt-Sill-Qtz assemblage, and constrain the prograde stage of the p--T path. The core domains of orthopyroxene porphyroblasts have up to w（Al203） 9.6%, which suggest that the temperatures reached up to 1150 ~C suggesting extreme crustal metamorphism. These conditions were also confirmed by the garnet-orthopyroxene thermobar- ometery, which yields a p--T range of 1012--960 ~C and 9.4 kbar. The p--T phase topologies computed using isochemical sections calculated in the model system Na20-CaO-K20--FeO-MgO-A1203-SiO2 --H2O （NCKFMASH） for metapelites, garnet-free sapphirine granulites and garnet-bearing sapphirine granulites match the melt-bearing assemblages observed in these rocks. Isochemical sections constructed in the NCKFMASH system for an average sub-aluminous metapelite bulk composition, and contoured for modal proportions of melt and garnet, as well as for the compositional isopleths of garnet, predict phase and reaction relations that are consistent with those observed in the rocks. Garnet and orthopyroxene contain Ti-rich phlogopite inclusions, suggesting formation by prograde melting reactions at the expense of phlogopite during ultrahigh-temperature conditions. These p--T results underestimate ＇peak＇ condi- tions, in part as a result of the modification of garnet compositions in the domains where some melt was retained. The post-peak evolution is constrained by a succession of melt-present reactions that occur at p 〈 10 kbar, inferred from micro-structural relations among various minerals. After high-temperature decompression from the metamorphic peak, the p--T path followed a near isobaric cooling stage to T 〈 900℃. The UHT rocks investigated in this study occur within a continental collision suture which witnessed prolonged subduction-accretion history prior to the final collision. We correlate the extreme metamorphism and the stabilization of UHT mineral assemblages to heat and volatile input from an upwelled asthenosphere during subduction--collision tectonics in a Proterozoic convergent plate margin.展开更多
Recurrence of hepatitis C virus(HCV)infection following liver transplantation(LT)is almost universal and can accelerate graft cirrhosis in up to 30%of patients.The development of effective strategies to treat or preve...Recurrence of hepatitis C virus(HCV)infection following liver transplantation(LT)is almost universal and can accelerate graft cirrhosis in up to 30%of patients.The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge,considering the shortage of donor organs and the accelerated progression of HCV in LT recipients.Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients,even though the combination is not as effective as it is in immunocompetent patients.A sustained virological response in the setting of LT improves patient and graft survival,but this is only achieved in 30%-45%of patients and the treatment is poorly tolerated.To improve the efficacy of pre-and post-transplant antiviral therapy,a new class of potent direct-acting antiviral agents (DAAs)has been developed.The aim of this review is to summarize the use of DAAs in LT HCV patients.PubMed,Cochrane Library,MEDLINE,EMBASE,Web of Science and clinical trial databases were searched for this purpose.To date,only three clinical studies on the topic have been published and most of the available data are in abstract form.Although a moderately successful early virological response has been reported,DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness.Moreover,the ongoing nature of data,the lack of randomized studies,the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable.In conclusion,large welldesigned clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.展开更多
AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, ...AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC). METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis. RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum a-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between a-FP and CgA in patients with HCC and in patients with cirrhosis. CONCLUSION: When HCC is suspected and a-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.展开更多
The Marano and Grado Lagoon is well known for being contaminated by mercury（Hg） from the Idrija mine（Slovenia） and the decommissioned chlor-alkali plant of Torviscosa（Italy）.Experimental activities were conducte...The Marano and Grado Lagoon is well known for being contaminated by mercury（Hg） from the Idrija mine（Slovenia） and the decommissioned chlor-alkali plant of Torviscosa（Italy）.Experimental activities were conducted in a local fish farm to understand Hg cycling at the sediment–water interface. Both diffusive and benthic fluxes were estimated in terms of chemical and physical features. Mercury concentration in sediments（up to 6.81 μg/g）showed a slight variability with depth, whereas the highest methylmercury（MeHg） values（up to 10 ng/g） were detected in the first centimetres. MeHg seems to be produced and stored in the 2–3 cm below the sediment–water interface, where sulphate reducing bacteria activity occurs and hypoxic–anoxic conditions become persistent for days. DMeHg in porewaters varied seasonally（from 0.1 and 17% of dissolved Hg（DHg）） with the highest concentrations in summer. DHg diffusive effluxes higher（up to 444 ng/m^2/day） than those reported in the open lagoon（~ 95 ng/m^2/day）, whereas DMeHg showed influxes in the fish farm（up to-156 ng/m^2/day）. The diurnal DHg and DMeHg benthic fluxes were found to be higher than the highest summer values previously reported for the natural lagoon environment. Bottom sediments, especially in anoxic conditions, seem to be a significant source of MeHg in the water column where it eventually accumulates. However, net fluxes considering the daily trend of DHg and DMeHg, indicated possible DMeHg degradation processes. Enhancing water dynamics in the fish farm could mitigate environmental conditions suitable for Hg methylation.展开更多
A robust voltammetric method has been developed and validated for the determination of Fe（Ⅱ） and Fe（Ⅲ） in pharmaceutical iron polysaccharidic complexes. Undesirable low molecular weight iron complexes, at concen...A robust voltammetric method has been developed and validated for the determination of Fe（Ⅱ） and Fe（Ⅲ） in pharmaceutical iron polysaccharidic complexes. Undesirable low molecular weight iron complexes, at concentration about 3% in the pharmaceutical formulation, can be easily determined with good accuracy and precision. This methodology can be proposed as a viable, environmentally sustainable substitute for the conventional Normal Pulse Polarographic method in US Pharmacopeia, with better analytical figures of merit, and reduced Hg consumption. A deeper insight in Fe（Ⅱ） and Fe（Ⅲ） composition can be gained by the combined use of a new potentiometric technique after chemical decomposition of the complex.展开更多
Non-alcoholic fatty liver disease(NAFLD) is emerging as one of the most common liver diseases,leading to the increasing interest for new therapeutic approaches for its treatment.NAFLD primarily depends on a hypercalor...Non-alcoholic fatty liver disease(NAFLD) is emerging as one of the most common liver diseases,leading to the increasing interest for new therapeutic approaches for its treatment.NAFLD primarily depends on a hypercaloric and/or unbalanced diet leading to overweight and obesity.The liver,in fact,plays a central role in lipid metabolism by importing free fatty acids from the blood and synthesizing,storing,oxidizing and exporting lipids.Furthermore,the liver is the target for the thyroid hormones,thyroxine(T4) and 3,3',5-triiodo-L-thyronine(T3),that stimulate the basal metabolic rate and lead to body weight loss.In the last decade,other iodothyronines have been shown to possess biological relevance and play some thyromimetic activities; in particular,3,5-diiodo-L-thyronine(T2) gained large interest.The global effect of iodothyronines on liver lipid metabolism results from the balance between direct and indirect actions on the hepatocyte,leading to stimulation of lipid synthesis,oxidation and autophagy.In this review,the results so far obtained on both in vivo and in vitro models of hepatosteatosis are summarized in order to obtain an updated picture of the lipid-lowering effects of iodothyronines on mammalian liver.展开更多
基金supported by:Fondazione Telethon-Italy(No.GGP19128 to AP)Fondazione Cariplo-Italy(No.2021-1544 to RC)+14 种基金Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica(AriSLA)-Italy(No.MLOpathy to APTarget-RAN to AP)Association Française contre les Myopathies-France(AFM Telethon No.23236 to AP)Kennedy’s Disease Association-USA(2018 grant to RC2020 grant to MG)Ministero dell’Universitàe della Ricerca(MIUR)-Italy(PRIN-Progetti di ricerca di interesse nazionale(No.2017F2A2C5 to APNo.2022EFLFL8 to APNo.2020PBS5MJ to VCNo.2022KSJZF5 to VC)PRIN-Progetti di ricerca di interesse nazionale-bando 2022,PNRR finanziato dall’Unione europea-Next Generation EU,componente M4C2,investimento 1.1(No.P2022B5J32 to RC and No.P20225R4Y5 to VC)CN3:RNA-Codice Proposta:CN_00000041Tematica Sviluppo di terapia genica e farmaci con tecnologia a RNA(Centro Nazionale di Ricerca-CN3 National Center for Gene Therapy and Drugs based on RNA Technology to AP)Progetto Dipartimenti di Eccellenza(to DiSFeB)Ministero della Salute,Agenzia Italiana del Farmaco(AIFA)-Italy(Co_ALS to AP)Universitàdegli Studi di Milano(piano di sviluppo della ricerca(PSR)UNIMI-linea B(to RC and BT).
文摘Heat shock protein family B(small)member 8(HSPB8)is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins.HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation,cell division,and migration.HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy.In line with this function,the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation.In cancer,HSPB8 has a dual role being capable of exerting either a pro-or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation.Moreover,HSPB8 exerts a protective function in different diseases by modulating the inflammatory response,which characterizes not only neurodegenerative diseases,but also other chronic or acute conditions affecting the nervous system,such as multiple sclerosis and intracerebellar hemorrhage.Of note,HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases.This is the case of cognitive impairment related to diabetes mellitus,in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis.This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions,focusing on the beneficial effects of its modulation.Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed,emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.
文摘BACKGROUND In metabolic dysfunction-associated steatotic liver disease(MASLD)the identi-fication of patients at high risk of evolution to metabolic dysfunction-associated steatohepatitis(MASH)is challenging.AIM To investigate the performance of different ultrasound(US)-based techniques for the non-invasive assessment of liver fibrosis,steatosis,and inflammation in these patients.METHODS We collected data from consecutive patients who underwent liver biopsy for suspected MASLD between January 2019 and December 2021.Two-dimensional shear-wave elastography,sound speed plane-wave US,attenuation plane-wave US,viscosity plane-wave US(Vi.PLUS)using Aixplorer MACH 30 system,and transient elastography and controlled attenuation parameter from FibroScan were measured before biopsy.RESULTS A total of 120 participants were enrolled.Both transient elastography and two-dimensional shear-wave elasto-graphy showed good performance for the diagnosis of advanced fibrosis[area under the receiver operating charac-teristic curve(AUROC)=0.93 and 0.90,respectively].The diagnostic performance of Vi.PLUS for the presence of both ballooning grade≥1 and lobular inflammation≥1 was good with an AUROC of 0.72.A score based on Vi.PLUS,aspartate aminotransferase,and sound speed plane-wave US[viscosity-aspartate aminotransferase-speed of sound MASH ultrasound score(VAS-MASH-US score)]had a good accuracy for the diagnosis of MASH(AUROC=0.75).VAS-MASH-US score>0.6 showed a good sensitivity for MASH diagnosis(79.0%).According to decision curve analysis,the application of the VAS-MASH-US score would lead to a more accurate selection of patients who are candidates to undergo liver biopsy and would reduce the need for invasive procedures for patients at low risk of MASH.CONCLUSION Multiparametric US allows the non-invasive assessment of steatosis,inflammation,and fibrosis in patients with MASLD.Liver viscosity improved the capability of non-invasively identifying patients with MASH.
基金supported by the European Union’s Horizon Europe research and innovation programme,Zero Emission electric Vehicles enabled by haRmonised circularity,under No.101138034.
文摘Grain size and formation of the Peripheral Coarse Grain(PCG)defect influence the mechanical and crash properties of extruded profiles.Controlling microstructural evolution during the extrusion of 6XXX series aluminum alloys is therefore essential to ensure the performance of structural components.In this work,three profiles with the same nominal geometry were extruded with a die comprising three different bearing geometries to create different extrusion conditions.Each profile was analyzed experimentally to gather data on the microstructure and mechanical properties.Bulge testing revealed that Profile 2,with the thickest PCG layer(490-1150µm),exhibited worse mechanical performance,with a hoop strain at fracture of 0.08 and a peak load of 51.5 kN,compared to Profiles 1 and 3,which had higher hoop strains(0.13 and 0.14)and peak loads(56.1 and 57.6 kN,respectively).Finite Element Method(FEM)simulations of the extrusion process were carried out using Qform Extrusion UK with a post-processing subroutine developed and implemented to calculate additional parameters such as the stored energy,percentage dynamic recrystallization,grain size,and PCG formation based on standard output parameters from the simulation including strain,temperature and strain rate.The simulation demonstrated that the highest strain rate(40-220 s^(-1))and stored energy(150,000-440,000 J m^(-3))in Profile 2 led to the thickest PCG layer.Based on these results,the proposed predictive model was validated against experimental data,demonstrating high accuracy in predicting PCG thickness and grain size while effectively capturing the influence of process parameters on microstructural evolution.
文摘In complex geological environments,the analysis of drill cores to determine rock strength can be challenging due to the wide variability in the degree of fracturing,leading to subjectivity in the collection of representative samples for uniaxial compressive strength testing.This study evaluates non-destructive techniques on calcareous rocks with different tectonic deformations,including Equotip hardness,ultrasound P-wave velocity,thin section analysis,and calcimetry,integrated with photogrammetric fracture analysis.The investigated carbonate rock samples are sourced from drill cores derived from the Umbria-Marche fold and thrust belt(northern Apennines,Italy),including a gently dipping limb of an anticline,a hinge zone of an anticline,and a fault zone associated with a thrust.Fracture intensity,quantified by the P21 parameter using photogrammetric techniques on pre-loading rock samples,is assessed alongside macroscopic identification of discontinuities(such as stylolites,veins,and joints)using marker colours to monitor failures during uniaxial compression testing.Empirical correlations depicted by single and multi-linear relationships indicate a strong dependence between the mechanical and physical properties of limestones.Both Equotip and P-wave velocity are influenced by fracture intensity,but P-wave velocity varies significantly with discontinuity orientation,especially at 45°-90°.To refine uniaxial compressive strength predictions and mitigate multicollinearity,statistical approaches,including linear and multilinear regression,Principal Component Analysis and Gaussian Process Regression,were tested.Findings improve the reliability of non-destructive techniques for assessing rock strength in structurally complex settings,with implications for geotechnical applications.
文摘Biliary lithiasis is an endemic condition in both Western and Eastern countries, in some studies affecting 20% of the general population. In up to 20% of cases, gallbladder stones are associated with common bile duct stones (CBDS), which are asymptomatic in up to one half of cases. Despite the wide variety of examinations and techniques available nowadays, two main open issues remain without a clear answer: how to cost-effectively diagnose CBDS and, when they are finally found, how to deal with them. CBDS diagnosis and management has radically changed over the last 30 years, following the dramatic diffusion of imaging, including endoscopic ultrasound (EUS) and magnetic resonance cholangiography (MRC), endoscopy and laparoscopy. Since accuracy, invasiveness, potential therapeutic use and cost-effectiveness of imaging techniques used to identify CBDS increase together in a parallel way, the concept of “risk of carrying CBDS” has become pivotal to identifying the most appropriate management of a specific patient in order to avoid the risk of “under-studying” by poor diagnostic work up or “over-studying” by excessively invasive examinations. The risk of carrying CBDS is deduced by symptoms, liver/pancreas serology and ultrasound. “Low risk” patients do not require further examination before laparoscopic cholecystectomy. Two main “philosophical approaches” face each other for patients with an “intermediate to high risk” of carrying CBDS: on one hand, the “laparoscopy-first” approach, which mainly relies on intraoperative cholangiography for diagnosis and laparoscopic common bile duct exploration for treatment, and, on the other hand, the “endoscopy-first” attitude, variously referring to MRC, EUS and/or endoscopic retrograde cholangiography for diagnosis and endoscopic sphincterotomy for management. Concerning CBDS diagnosis, intraoperative cholangiography, EUS and MRC are reported to have similar results. Regarding management, the recent literature seems to show better short and long term outcome of surgery in terms of retained stones and need for further procedures. Nevertheless, open surgery is invasive, whereas the laparoscopic common bile duct clearance is time consuming, technically demanding and involves dedicated instruments. Thus, although no consensus has been achieved and CBDS management seems more conditioned by the availability of instrumentation, personnel and skills than cost-effectiveness, endoscopic treatment is largely preferred worldwide.
文摘Non-alcoholic fatty liver disease(NAFLD)is the leading cause of diffuse liver disease.An accurate estimate of the fat in the liver is important in the diagnostic work-up of patients with NAFLD because the degree of liver steatosis is linked to the metabolic syndrome and the cardiovascular risk.Ultrasound(US)B-mode imaging allows to subjectively estimate the fatty infiltration in the liver;however,it has a low performance for the detection of mild steatosis.Quantitative US is based on the analysis of the radiofrequency echoes detected by an US system,and it allows to calculate a backscatter coefficient or an attenuation coefficient or the sound speed.The estimation of the backscatter coefficient is rather cumbersome and requires the use of a phantom for addressing all sources of variability.Controlled attenuation parameter(CAP)available on the FibroScan system(Echosens,France)measures the attenuation of the US beam.CAP is accurate in grading fatty infiltration-even though there is an overlap between consecutive grade of liver steatosis-and the values are not influenced by liver fibrosis.Several US manufacturers are developing or have already developed software for quantifying the attenuation of the US beam.Preliminary results show that proprietary technologies implemented in US systems seem more accurate than CAP for grading liver steatosis.Another available method for quantifying liver steatosis is based on the computation of the sound speed and the initial results appear promising.
文摘Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.
文摘End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell(BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.
基金supported by Peking University and NSFC(grant 40702001)by a grant from UNIMI Chancellorand FIRST funds for the Italian team
文摘Two complete specimens from the Pelsonian （Middle Anisian, Middle Triassic） of Luoping, Yunnan Province, South China are referred to a new actinopterygian genus, Luopingichthys gen. nov., and ascribed to the perleidiform family Polzbergidae based especially on a typical synapomorphy of a peculiar premaxillary-maxillary complex, i.e., the fusion between premaxillary and maxillary along the antero-dorsal margin of the maxillary. The new taxon differs from other deep-bodied representatives of the family, Felberia and Stoppania, in its fusiform or deep fusiform body shape; sickle-shaped preopercular with short infraorbital process; lack of modified scales at the base of the anal fin; the short-based dorsal fin; scarcely ornamented scales; and thin anterior teeth. Based on a redescription of the holotype of the taxon Ctenognathichthys hattichi from the Middle Triassic （Ladinian） Prosanto Formation, Canton Graubiinden, eastern Switzerland, the only known specimen, which shows the same fusion between premaxillary and maxillary, the systematic position of the species is clarified and the taxon is proposed to be a further representative of the family Polzbergidae, and is transferred to the new genus.
文摘Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments.Repetition of liver ultrasonography(US)every 6 mo is the recommended surveillance program to detect early HCCs,and a positive US has to entrain a well-defined recall policy based on contrast-enhanced,dynamic radiological imaging or biopsy for the diagnosis of HCC.Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance,the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure.Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC.The promotion of specific educational programs for practitioners,clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.
基金Supported by Protocollo TESORM by Regione Toscana,Universitàdegli Studi di Firenze and Bayer Health Care s.p.a
文摘Advanced stage hepatocellular carcinoma(HCC) is a category of disease defined by radiological, clinical and hepatic function parameters, comprehending a wide range of patients with different general conditions. The main therapeutic option is represented by sorafenibtreatment, a multi-kinase inhibitor with anti-proliferative and anti-angiogenic effect. Trans-arterial Radio Embolization also represents a promising new approach to intermediate/advanced HCC. Post-marketing clinical studies showed that only a portion of patients actually benefits from sorafenib treatment, and an even smaller percentage of patients treated shows partial/complete response on follow-up examinations, up against relevant costs and an incidence of drug related adverse effects. Although the treatment with sorafenib has shown a significant increase in mean overall survival in different studies, only a part of patients actually shows real benefits, while the incidence of drug related significant adverse effects and the economic costs are relatively high. Moreover, only a small percentage of patients also shows a response in terms of lesion dimensions reduction. Being able to properly differentiate patients who are responding to the therapy from non-responders as early as possible is then still difficult and could be a pivotal challenge for the future; in fact it could spare several patients a therapy often difficult to bear, directing them to other second line treatments(many of which are at the moment still under investigation). For this reason, some supplemental criteria to be added to the standard modified Response Evaluation Criteria in Solid Tumors evaluation are being searched for. In particular, finding some parameters(cellular density, perfusion grade and enhancement rate) able to predict the sensitivity of the lesions to anti-angiogenic agents could help in stratifying patients in terms of treatment responsiveness before the beginning of the therapy itself, or in the first weeks of sorafenib treatment. This would bring a strongly desirable help in clinical managements of these patients.
基金Fondazione Cariplo grant no. 2010- 0501 for financial support
文摘Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-de- rived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events （e.g., DNA damage） or environmental cues （e.g., stressful stimuli or diseases）, which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can influence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.
文摘Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and/or conflicting results in animal models.
文摘AIM： To evaluate the role of genetic factors in the pathogenesis of Crohn＇s disease （CD） and ulcerative colitis （UC）, we investigated the single nucleotide polymorphisms （SNPs） of NOD2/CARD15 （R702W, Gg08R and L1007finsC）, and Toll-like receptor 4 （TLR4） genes （D299G and T399I） in a selected inflammatory bowel disease （IBD） population coming from Southern Italy. METHODS： Allele and genotype frequencies of NOD2/ CARD15 （R702W, Gg08R and L1007finsC） and TLR4 （D299G and T399I） SNPs were examined in 133 CD patients, in 45 UC patients, and in 103 healthy controls. A genotype-phenotype correlation was performed. RESULTS： NOD2/CARD15 R702W mutation was significantly more frequent in CD （9.8%） than in controls （2.4%, P = 0.001） and in UC （2.3%, P = 0.03）. No significant difference was found between UC patients and control group （P 〉 0.05）. In CD and UC patients, no significant association with G908R variant was found. L1007finsC SNP showed an association with CD （9.8%） compared with controls （2.9%, P = 0.002） and UC patients （2.3%, P = 0.01）. Moreover, in CD patients, G908R and L1007finsC mutations were significantly associated with different phenotypes compared to CD wild-type patients. No association of IBD with the TLR4 SNPs was found in either cohort （allele frequencies： D299G-controls 3.9%, CD 3.7%, UC 3.4%, P 〉 0.05; T399I-controls 2.9%, CD 3.0%, UC 3.4%, P 〉 0.05）. CONCLUSION： These findings confirm that, in our IBD patients selected from Southern Italy, the NOD2/ CARD15, but not TLR4 SNPs, are associated with increased risk of CD.
文摘We report equilibrium sapphirine ＋ quartz assemblage in biotite-orthopyroxene-garnet granulites from a new locality in Panasapattu of Paderu region in the Eastern Ghats granulite belt, which provide new evidence for ultrahigh-temperature （UHT） metamorphism at 1030-1050 ℃ and 10 kbar in this region. The development of migmatitic texture, stabilization of the garnet-orthopyroxene- plagioclase-K-feldspar association, prograde biotite inclusions within garnet and sapphirine as well as sapphirine and cordierite inclusions within garnet in these granulites indicate that the observed peak assemblages probably formed during prograde dehydration melting of a Bt-Sill-Qtz assemblage, and constrain the prograde stage of the p--T path. The core domains of orthopyroxene porphyroblasts have up to w（Al203） 9.6%, which suggest that the temperatures reached up to 1150 ~C suggesting extreme crustal metamorphism. These conditions were also confirmed by the garnet-orthopyroxene thermobar- ometery, which yields a p--T range of 1012--960 ~C and 9.4 kbar. The p--T phase topologies computed using isochemical sections calculated in the model system Na20-CaO-K20--FeO-MgO-A1203-SiO2 --H2O （NCKFMASH） for metapelites, garnet-free sapphirine granulites and garnet-bearing sapphirine granulites match the melt-bearing assemblages observed in these rocks. Isochemical sections constructed in the NCKFMASH system for an average sub-aluminous metapelite bulk composition, and contoured for modal proportions of melt and garnet, as well as for the compositional isopleths of garnet, predict phase and reaction relations that are consistent with those observed in the rocks. Garnet and orthopyroxene contain Ti-rich phlogopite inclusions, suggesting formation by prograde melting reactions at the expense of phlogopite during ultrahigh-temperature conditions. These p--T results underestimate ＇peak＇ condi- tions, in part as a result of the modification of garnet compositions in the domains where some melt was retained. The post-peak evolution is constrained by a succession of melt-present reactions that occur at p 〈 10 kbar, inferred from micro-structural relations among various minerals. After high-temperature decompression from the metamorphic peak, the p--T path followed a near isobaric cooling stage to T 〈 900℃. The UHT rocks investigated in this study occur within a continental collision suture which witnessed prolonged subduction-accretion history prior to the final collision. We correlate the extreme metamorphism and the stabilization of UHT mineral assemblages to heat and volatile input from an upwelled asthenosphere during subduction--collision tectonics in a Proterozoic convergent plate margin.
文摘Recurrence of hepatitis C virus(HCV)infection following liver transplantation(LT)is almost universal and can accelerate graft cirrhosis in up to 30%of patients.The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge,considering the shortage of donor organs and the accelerated progression of HCV in LT recipients.Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients,even though the combination is not as effective as it is in immunocompetent patients.A sustained virological response in the setting of LT improves patient and graft survival,but this is only achieved in 30%-45%of patients and the treatment is poorly tolerated.To improve the efficacy of pre-and post-transplant antiviral therapy,a new class of potent direct-acting antiviral agents (DAAs)has been developed.The aim of this review is to summarize the use of DAAs in LT HCV patients.PubMed,Cochrane Library,MEDLINE,EMBASE,Web of Science and clinical trial databases were searched for this purpose.To date,only three clinical studies on the topic have been published and most of the available data are in abstract form.Although a moderately successful early virological response has been reported,DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness.Moreover,the ongoing nature of data,the lack of randomized studies,the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable.In conclusion,large welldesigned clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.
文摘AIM: The utility of serum alpha-fetoprotein (α-FP) for the detection of hepatocellular carcinoma (HCC) is questionable. High serum levels of chromogranin-A (CgA) have recently been reported in HCC. Impaired hepatic, renal, and heart functions influence circulating CgA. The aim of this study was to assess sensitivity and specificity of serum CgA as a marker of HCC in patients with liver cirrhosis (LC). METHODS: Serum CgA levels were measured by RIA in 339 patients of which 54 HCC, 132 LC, 45 chronic hepatitis (CH), 27 chronic heart failure (CHF), 36 chronic renal failure (CRF), 45 chronic inflammatory bowel disease (IBD) as disease controls and in 75 healthy controls. Patients with liver disease or IBD and concomitant renal and/or heart failure were excluded. Pearson correlation, non-parametric combination test and confidence interval analysis were used for statistical analysis. RESULTS: Serum CgA above normal values (100 ng/mL) were found in 83% of HCC patients, in 48% of LC patients, in 20% of CH patients, in 33% of IBD patients, in 92% of CRF patients, in 100% of CHF patients, and in none of the healthy controls. The mean CgA values in HCC (769±1046), in LC (249±369), in CH (87±94), in CRF (1390±1401), in CHF (577±539), in IBD (146±287) were significantly higher than those in healthy controls (48±18). HCC patients had higher CgA values (P<0.01) than LC, CH, and IBD patients but did not differ from those with CRF or CHF. The 95% CI for the mean (250-1289 ng/mL) in HCC patients was selected as a CgA range and the lower value of such range was assumed as cut-off. Sensitivity and specificity of CgA, calculated in relation to the cut-off in patients with cirrhosis and HCC, were respectively 61% (CI 48-73%) and 82% (CI 75-88%). Serum a-FP values were >200 ng/mL in 21% of the HCC patients and in none of the LC patients. No significant correlation was found between a-FP and CgA in patients with HCC and in patients with cirrhosis. CONCLUSION: When HCC is suspected and a-FP is normal or <200 ng/mL, CgA serum values represent a complementary diagnostic tool, unless kidney or heart failure is present.
基金supported by the University of Trieste (Finanziamento di Ateneo per progetti di ricerca scientifica-FRA 2014,ref.Stefano Covelli)
文摘The Marano and Grado Lagoon is well known for being contaminated by mercury（Hg） from the Idrija mine（Slovenia） and the decommissioned chlor-alkali plant of Torviscosa（Italy）.Experimental activities were conducted in a local fish farm to understand Hg cycling at the sediment–water interface. Both diffusive and benthic fluxes were estimated in terms of chemical and physical features. Mercury concentration in sediments（up to 6.81 μg/g）showed a slight variability with depth, whereas the highest methylmercury（MeHg） values（up to 10 ng/g） were detected in the first centimetres. MeHg seems to be produced and stored in the 2–3 cm below the sediment–water interface, where sulphate reducing bacteria activity occurs and hypoxic–anoxic conditions become persistent for days. DMeHg in porewaters varied seasonally（from 0.1 and 17% of dissolved Hg（DHg）） with the highest concentrations in summer. DHg diffusive effluxes higher（up to 444 ng/m^2/day） than those reported in the open lagoon（~ 95 ng/m^2/day）, whereas DMeHg showed influxes in the fish farm（up to-156 ng/m^2/day）. The diurnal DHg and DMeHg benthic fluxes were found to be higher than the highest summer values previously reported for the natural lagoon environment. Bottom sediments, especially in anoxic conditions, seem to be a significant source of MeHg in the water column where it eventually accumulates. However, net fluxes considering the daily trend of DHg and DMeHg, indicated possible DMeHg degradation processes. Enhancing water dynamics in the fish farm could mitigate environmental conditions suitable for Hg methylation.
基金supported by FAR, Fondo Ateneoper la Ricerca Universitá di Pavia,Italy
文摘A robust voltammetric method has been developed and validated for the determination of Fe（Ⅱ） and Fe（Ⅲ） in pharmaceutical iron polysaccharidic complexes. Undesirable low molecular weight iron complexes, at concentration about 3% in the pharmaceutical formulation, can be easily determined with good accuracy and precision. This methodology can be proposed as a viable, environmentally sustainable substitute for the conventional Normal Pulse Polarographic method in US Pharmacopeia, with better analytical figures of merit, and reduced Hg consumption. A deeper insight in Fe（Ⅱ） and Fe（Ⅲ） composition can be gained by the combined use of a new potentiometric technique after chemical decomposition of the complex.
文摘Non-alcoholic fatty liver disease(NAFLD) is emerging as one of the most common liver diseases,leading to the increasing interest for new therapeutic approaches for its treatment.NAFLD primarily depends on a hypercaloric and/or unbalanced diet leading to overweight and obesity.The liver,in fact,plays a central role in lipid metabolism by importing free fatty acids from the blood and synthesizing,storing,oxidizing and exporting lipids.Furthermore,the liver is the target for the thyroid hormones,thyroxine(T4) and 3,3',5-triiodo-L-thyronine(T3),that stimulate the basal metabolic rate and lead to body weight loss.In the last decade,other iodothyronines have been shown to possess biological relevance and play some thyromimetic activities; in particular,3,5-diiodo-L-thyronine(T2) gained large interest.The global effect of iodothyronines on liver lipid metabolism results from the balance between direct and indirect actions on the hepatocyte,leading to stimulation of lipid synthesis,oxidation and autophagy.In this review,the results so far obtained on both in vivo and in vitro models of hepatosteatosis are summarized in order to obtain an updated picture of the lipid-lowering effects of iodothyronines on mammalian liver.
