Association of patient-reported outcomes and heart rate trends in heart failure. a report from the chiron project

Patient-reported outcomes (PROs) have been previously considered “soft” end-points because of the lack of association of the reported outcome to measurable biological parameters. The present study aimed to assess whether electrocardiographic measures are associated to PROs changes. We evaluated the association between heart rate (HR), QRS and QT/QTc durations and PROs, classified as “good” or “bad” according to the patients’ overall feeling of health, in patients from the Chiron project. Twenty-four chronic heart failure (HF) patients were enrolled in the study (71% male, mean age 62.9 ± 9.4 years, 42% ischemic etiology, 15 NYHA class II and 9 class III) providing 1086 days of usable physiological recordings (4 hours/day). The mean HR was significantly higher in the “bad” than in the “good” PROs class (74.0 ± 6.4 bpm vs 68.0 ± 7.2 bpm; p < 0.001). Conversely, the ratio between movement and rest activities showed significantly higher values in “good” compared to “bad” PROs. We also found significantly longer QTc and QRS durations in patients with “bad” PROs compared to patients with “good” PROs. That in patients with mild to moderate HF, higher HR, wider QRS and longer QTc, as well as a reduced HR ratio between movement and rest, were associated with “bad” PROs is clinically noteworthy because the association of worse PROs with measurable variations of biological parameters may help physicians in evaluating PROs reliability itself and in their clinical decisions. Whether a timely intervention on these biological parameters may prevent adverse outcomes is important and deserves to be investigated in further studies

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

Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans

Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease

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

Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure

Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002)

Spontaneous compartment syndrome in a patient with diabetes and statin administration: a case report

Compartment syndrome is a condition characterized by pressure increasing in the inextensible muscular compartments that leads to a decrease of capillary perfusion with consequent ischemic lesions of the logia elements. The authors report a case of an unusual compartment syndrome with spontaneous onset in a patient with type II diabetes and chronic therapy with statins (Atorvastatin). The condition was successfully treated by a fasciotomy and medical support. The importance of a correct anamnesis and a high level of suspicion is emphasized

Tumor Suppressor RASSF1A Promoter: p53 Binding and Methylation

Oncogenes and tumor suppressors work in concert to regulate cell growth or death, which is a pair of antagonist factors for regulation of tumorigenesis. Here we show promoter characteristic of tumor suppressor RASSF1A, which revealed a p53 binding site in the distal and a GC-rich region in the proximal promoter region of RASSF1A, in despite of TATA box-less. The GC-rich region, which is ∼300 bp upstream from the RASSF1A ATG, showed the strongest promoter activity in an assay of RASSF1A-driving GFP expression. Methylation analysis of the CpG island showed that 78.57% of the GC sties were methylated in testis tumor samples compared with methylation-less in normal testis. Hypermethylation of the GC-rich region is associated with RASSF1A silencing in human testis tumors. In addition, electrophoretic mobility shift assay indicated that p53 protein bound to the RASSF1A promoter. Further chromatin immunoprecipitation confirmed p53 binding to the RASSF1A. Moreover, p53 binding to the promoter down-regulated RASSF1A expression. These results suggest that p53 protein specifically binds to the RASSF1A promoter and inhibits its expression. Our results provide new insight into the mechanism of action of tumor suppressors and may be a starting point for development of new approaches to cancer treatment

Repeated exposure of the oral mucosa over 12 months with cold plasma is not carcinogenic in mice

Peri-implantitis may result in the loss of dental implants. Cold atmospheric pressure plasma (CAP) was suggested to promote re-osseointegration, decrease antimicrobial burden, and support wound healing. However, the long-term risk assessment of CAP treatment in the oral cavity has not been addressed. Treatment with two different CAP devices was compared against UV radiation, carcinogen administration, and untreated conditions over 12 months. Histological analysis of 406 animals revealed that repeated CAP exposure did not foster non-invasive lesions or squamous cell carcinoma (SCCs). Carcinogen administration promoted non-invasive lesions and SCCs. Molecular analysis by a qPCR screening of 144 transcripts revealed distinct inflammatory profiles associated with each treatment regimen. Interestingly, CAP treatment of carcinogen-challenged mucosa did not promote but instead left unchanged or reduced the proportion of non-invasive lesions and SCC formation. In conclusion, repeated CAP exposure of murine oral mucosa was well tolerated, and carcinogenic effects did not occur, motivating CAP applications in patients for dental and implant treatments in the future