Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis

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Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis ( 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells

Non-fermentative gram-negative bloodstream infection in northern Italy: a multicenter cohort study

Background: The management of non-fermentative gram-negative bloodstream infection (NFGN-BSI) offers numerous challenges. In this study the aim is to analyse a large cohort of patients with NFGN-BSI recruited in the northern Italy to describe epidemiology, etiological and susceptibility pattern, therapeutic management and outcome. Methods: Multicentre retrospective cohort study of patients hospitalised at three large teaching hospitals in northern Italy in a fourth year period. Results: 355 BSI episodes were analyzed, due to P. aeruginosa (72.7%), A. baumannii (16.6%), and Stenotrophomonas maltophilia (10.7%). Overall, 21.4% of isolates were defined as DTR, highest rate among A. baumannii (64.4%). All-cause 30-day mortality rate was 17.5%. Rates of XDR or DTR A. baumannii isolation were significantly higher in non-surviving patients. Independent risk factors for 30-day mortality were: age (HR 1.03, 95%CI 1.00–1.04, p = 0.003), septic shock (HR 2.84, 95%CI 1.67–4.82, p < 0.001) and BSI due to Acinetobacter baumannii (HR 2.23, 95%CI 1.27–3.94, p = 0.005). Conclusion: The overall prevalence of DTR was high in the NFGN BSI cohort analyzied, mainly among Acinetobacter baumannii episodes (64.4%). Acinetobacter baumannii is showed to be an independent predictor of mortality. These evidences marked the urgent need of new therapeutic options against this pathogen. Trial registration number: 79/2017/O/OssN. Approved: March14th, 2017

Non-fermentative gram-negative bloodstream infection in northern Italy: a multicenter cohort study

BACKGROUND: The management of non-fermentative gram-negative bloodstream infection (NFGN-BSI) offers numerous challenges. In this study the aim is to analyse a large cohort of patients with NFGN-BSI recruited in the northern Italy to describe epidemiology, etiological and susceptibility pattern, therapeutic management and outcome. METHODS: Multicentre retrospective cohort study of patients hospitalised at three large teaching hospitals in northern Italy in a fourth year period. RESULTS: 355 BSI episodes were analyzed, due to P. aeruginosa (72.7%), A. baumannii (16.6%), and Stenotrophomonas maltophilia (10.7%). Overall, 21.4% of isolates were defined as DTR, highest rate among A. baumannii (64.4%). All-cause 30-day mortality rate was 17.5%. Rates of XDR or DTR A. baumannii isolation were significantly higher in non-surviving patients. Independent risk factors for 30-day mortality were: age (HR 1.03, 95%CI 1.00–1.04, p = 0.003), septic shock (HR 2.84, 95%CI 1.67–4.82, p < 0.001) and BSI due to Acinetobacter baumannii (HR 2.23, 95%CI 1.27–3.94, p = 0.005). CONCLUSION: The overall prevalence of DTR was high in the NFGN BSI cohort analyzied, mainly among Acinetobacter baumannii episodes (64.4%). Acinetobacter baumannii is showed to be an independent predictor of mortality. These evidences marked the urgent need of new therapeutic options against this pathogen. Trial registration number: 79/2017/O/OssN. Approved: March14th, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-021-06496-8

Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23

Background: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. Methods: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. Results: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. Conclusions: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice

Two years of flight of the Pamela experiment: results and perspectives

PAMELA is a satellite borne experiment designed to study with great accuracy cosmic rays of galactic, solar, and trapped nature in a wide energy range (protons: 80 MeV-700 GeV, electrons 50 MeV-400 GeV). Main objective is the study of the antimatter component: antiprotons (80 MeV-190 GeV), positrons (50 MeV-270 GeV) and search for antinuclei with a precision of the order of $10^{-8}$). The experiment, housed on board the Russian Resurs-DK1 satellite, was launched on June, $15^{th}$ 2006 in a $350\times 600 km$ orbit with an inclination of 70 degrees. In this work we describe the scientific objectives and the performance of PAMELA in its first two years of operation. Data on protons of trapped, secondary and galactic nature - as well as measurements of the December $13^{th}$ 2006 Solar Particle Event - are also provided.Comment: To appear on J. Phys. Soc. Jpn. as part of the proceedings of the International Workshop on Advances in Cosmic Ray Science March, 17-19, 2008 Waseda University, Shinjuku, Tokyo, Japa

Constraints on the architecture of the HD 95086 planetary system with the Gemini Planet Imager

We present astrometric monitoring of the young exoplanet HD 95086 b obtained with the Gemini Planet Imager between 2013 and 2016. A small but significant position angle change is detected at constant separation; the orbital motion is confirmed with literature measurements. Efficient Monte Carlo techniques place preliminary constraints on the orbital parameters of HD 95086 b. With 68% confidence, a semimajor axis of 61.7^{+20.7}_{-8.4} au and an inclination of 153.0^{+9.7}_{-13.5} deg are favored, with eccentricity less than 0.21. Under the assumption of a co-planar planet-disk system, the periastron of HD 95086 b is beyond 51 au with 68% confidence. Therefore HD 95086 b cannot carve the entire gap inferred from the measured infrared excess in the SED of HD 95086. We use our sensitivity to additional planets to discuss specific scenarios presented in the literature to explain the geometry of the debris belts. We suggest that either two planets on moderately eccentric orbits or three to four planets with inhomogeneous masses and orbital properties are possible. The sensitivity to additional planetary companions within the observations presented in this study can be used to help further constrain future dynamical simulations of the planet-disk system.Comment: Accepted for publication in ApJ

A new measurement of the antiproton-to-proton flux ratio up to 100 GeV in the cosmic radiation

A new measurement of the cosmic ray antiproton-to-proton flux ratio between 1 and 100 GeV is presented. The results were obtained with the PAMELA experiment, which was launched into low-earth orbit on-board the Resurs-DK1 satellite on June 15th 2006. During 500 days of data collection a total of about 1000 antiprotons have been identified, including 100 above an energy of 20 GeV. The high-energy results are a ten-fold improvement in statistics with respect to all previously published data. The data follow the trend expected from secondary production calculations and significantly constrain contributions from exotic sources, e.g. dark matter particle annihilations.Comment: 10 pages, 4 figures, 1 tabl

Mapping a Sex Hormone–Sensitive Gene Determining Female Resistance to Liver Carcinogenesis in a Congenic F344.BN-Hcs4 Rat

Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the ''resistant hepatocyte'' protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded to those of BN females. Carcinomatous nodules and HCC developed at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by B-estradiol administration, caused a decrease in Ar expression, an increase in Er-a expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance. (Cancer Res 2006; 66(21): 10384-90

aberrant inos signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease

Mounting evidence underlines the role of inducible nitric oxidesynthase (iNOS) in hepatocellular carcinoma (HCC) develop-ment, but its functional interactions with pathways involved inHCC progression remain uninvestigated. Here, we analyzed inpreneoplastic and neoplastic livers from Fisher 344 and BrownNorway rats, possessing different genetic predisposition to HCC,in transforming growth factor-a (TGF-a) and c-Myc–TGF-atransgenic mice, characterized by different susceptibility toHCC, and in human HCC: (i) iNOS function and interactionswith nuclear factor-kB (NF-kB) and Ha-RAS/extracellularsignal-regulated kinase (ERK) during hepatocarcinogenesis;(ii) influence of genetic predisposition to liver cancer on thesepathways and role of these cascades in determining a susceptibleor resistant phenotype and (iii) iNOS prognostic value in humanHCC. We found progressive iNos induction in rat and mouse liverlesions, always at higher levels in the most aggressive models rep-resented by HCC of rats genetically susceptible to hepatocarcino-genesis and c-Myc–TGF-a transgenic mice. iNOS, inhibitor of kBkinase/NF-kB and RAS/ERK upregulation was significantly higherin HCC with poorer prognosis (as defined by patients' survivallength) and positively correlated with tumor proliferation, genomicinstability and microvascularization and negatively with apoptosis.Suppression of iNOS signaling by aminoguanidine led to decreasedHCC growth and NF-kB and RAS/ERK expression and increasedapoptosis both in vivo and in vitro. Conversely, block of NF-kBsignaling by sulfasalazine or short interfering RNA (siRNA) orERK signaling by UO126 caused iNOS downregulation in HCCcell lines. These findings indicate that iNOS cross talk with NF-kB and Ha-RAS/ERK cascades influences HCC growth and prog-nosis, suggesting that key component of iNOS signaling could rep-resent important therapeutic targets for human HCC.IntroductionHepatocellular carcinoma (HCC) is one of the most frequent anddeadliest human cancers worldwide. Current therapies do not improvesignificantly the prognosis of patients with unresectable HCC (1,2).This emphasizes the need to investigate the molecular mechanismsresponsible for HCC development to identify new targets for earlydiagnosis, chemoprevention and treatment.Numerous genes regulating susceptibility to HCC and controllinggrowth, progression and redifferentiation of preneoplastic and neo-plastic lesions have been mapped in rodents (3). Decrease in growthability and/or marked redifferentiation of preneoplastic lesion char-acterizes rodent strains resistant to hepatocarcinogenesis (3,4). Con-sequently, studies on the mechanisms underlying the acquisition ofa phenotype susceptible/resistantto hepatocarcinogenesis in rodentstrains, carrying preneoplastic lesions differently prone to progressto HCC, may lead to the discovery of prognostic markers and ther-apeutic targets for the human disease. Dysplastic nodules and HCCinduced in susceptible Fisher 344 (F344) rats show upregulation ofc-Myc, Cyclin D1, E and A and E2f1 genes, increased cyclinD1–Cdk4, cyclin E–Cdk2 and E2f1–Dp1 complexes and retinoblas-toma protein (pRb) hyperphosphorylation (4–6). These changes areabsent or less pronounced in liver lesions from resistant Brown Norway(BN) rats, where a block of