QCD Critical Points and Their Associated Soft Modes

The mean-field level calculation shows that the QCD matter can have multiple critical points incorporating the color superconductivity under charge neutrality constraint due to the repulsive vector interaction; this actually implies that the QCD matter is very soft for a simultaneous formation of diquark and chiral condensates coupled with the baryonic density. Dynamical density fluctuations are analyzed as possible soft modes around the QCD critical point using dissipative relativistic fluid dynamics. It is found that the entropy fluctuation solely gets enhanced while the sound modes due to mechanical density fluctuations are strongly attenuated around the QCD CP, which may suggest a suppression or even total disappearance of Mach cone at the CP.Comment: 8 pages, 3 figures. Talk presented at Yukawa International workshop "New Frontiers in QCD 2010 --- Exotic Hadron Systems and Dense Matter ---" (NFQCD10), Jan. 18(Mon.)-Mar.19(Fri), 2010, Yukawa Institute for Theoretical Physics, Kyoto, Japa

EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma

Objectives: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance. Materials and methods: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS). Results: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner. Conclusion: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab

Successful treatment of chronic lupus myocarditis with prednisolone and mizoribine

A 36-year-old female patient who was diagnosed with chronic myocarditis as an initial manifestation of systemic lupus erythematosus (SLE) was admitted to our hospital. At her third occurrence of heart failure, we performed an endomyocardial biopsy and proved chronic myocarditis with SLE. Subsequently, she was treated with prednisolone and the immunosuppressive agent mizoribine (MZR), and her cardiac function improved. We describe for the first time treatment with MZR for chronic cardiac involvement of SLE

Comparative study of the effect of neuromuscular electrical stimulation and oral administration of branched-chain amino acid on preventing sarcopenia in patients after living-donor liver transplantation: study protocol for an open-label randomized controlled trial

Background: Liver cirrhosis is the irreversible fibrosis of the liver and causes refractory ascites and hepatic encephalopathy, which might not respond to treatment. Living donor liver transplantation (LDLT) is an effective treatment for patients with cirrhosis. However, post-LDLT patients are prone to muscle atrophy and sarcopenia. Therefore, physiotherapy of post-LDLT patients is essential for preventing the progression of sarcopenia. Recently, rehabilitation using neuromuscular electrical stimulation (NMES) has been reported to be useful for preventing the progression of sarcopenia. Similarly, nutrition therapy is essential for post-LDLT patients because these patients frequently experience malnutrition. However, the effects of combined NMES and nutrition therapy on post-LDLT patients remain unknown. Methods/design: This open-label, randomized, parallel-group study will compare the effects of combined therapy with NMES and branched-chain amino acids (BCAA) with those of NMES alone in patients with decompensated cirrhosis after LDLT. After LDLT, 50 patients with decompensated cirrhosis will be randomly assigned to receive NMES with BCAA or NMES without BCAA. The duration of the intervention will be 3 months. To analyze the change in skeletal muscle mass, InBody 770 body composition and body water analysis and ultrasonography will be performed before LDLT and 4 weeks and 12 weeks post-LDLT. The primary endpoint is changes in the skeletal muscle mass from baseline to 3 months. Important secondary endpoints are the changes in the skeletal muscle mass from baseline to 1 month and changes in the quadriceps strength from baseline to 1 month. Discussion: The results of this study are expected to provide evidence regarding the effect of NMES combined with BCAA therapy on the skeletal muscle of post-LDLT patients. Trial registration: Japan Registry of Clinical Research jRCTs071190051. Registered on February 26, 2020

Frequency components of systolic blood pressure variability reflect vasomotor and cardiac sympathetic functions in conscious rats

In this study, after confirming the suppression of autonomic nervous function by isoflurane anesthesia using autonomic antagonists, we pharmacologically investigated the involvement of vasomotor and cardiac sympathetic functions in systolic blood pressure variability (SBPV) frequency components in conscious rats at rest and during exposure to low-ambient temperature (LT-exposure, 9°C for 90 min). Under unanesthesia, phentolamine administration (α-adrenoceptor antagonist, 10 mg/kg) decreased the mid-frequency component (MF 0.33–0.73 Hz) and inversely increased the high-frequency component (HF 1.3–2.5 Hz). The increased HF was suppressed by subsequent treatment with atenolol (β-adrenoceptor antagonist, 10 mg/kg), but not with atropine (muscarinic receptor antagonist, 10 mg/kg). Moreover, phentolamine administration after atenolol decreased MF, but did not increase HF. LT-exposure increased MF and HF; however, phentolamine pretreatment suppressed the increased MF during LT-exposure, and atenolol pretreatment dose-dependently decreased the increased HF. These results suggest that MF and HF of SBPV may reflect α-adrenoceptor-mediated vasomotor function and β-adrenoceptor-mediated cardiac sympathetic function, respectively, in the conscious state

Inhibition of poly(ADP-ribose) polymerase-1 attenuates the toxicity of carbon tetrachloride

Carbon tetrachloride (CCl4) is routinely used as a model compound for eliciting centrilobular hepatotoxicity. It can be bioactivated to the trichloromethyl radical, which causes extensive lipid peroxidation and ultimately cell death by necrosis. Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) can rapidly reduce the levels of (β-nicotinamide adenine dinucleotide and adenosine triphosphate and ultimately promote necrosis. The aim of this study was to determine whether inhibition of PARP-1 could decrease CCl4-induced hepatotoxicity, as measured by degree of poly(ADP-ribosyl)ation, serum levels of lactate dehydrogenase (LDH), lipid peroxidation,and oxidative DNA damage. For this purpose, male ICR mice were administered intraperitoneally a hepatotoxic dose of CCl4 with or without 6(5H)-phenanthridinone, a potent inhibitor of PARP-1. Animals treated with CCl4 exhibited extensive poly(ADP-ribosyl)ation in centrilobular hepatocytes, elevated serum levels of LDH, and increased lipid peroxidation. In contrast, animals treated concomitantly with CCl4 and 6(5H)-phenanthridinone showed significantly lower levels of poly(ADP-ribosyl) ation, serum LDH, and lipid peroxidation. No changes were observed in the levels of oxidative DNA damage regardless of treatment. These results demonstrated that the hepatotoxicity of CCl4is dependent on the overactivation of PARP-1 and that inhibition of this enzyme attenuates the hepatotoxicity of CCl4

Real-world comparative effectiveness and safety of tofacitinib and baricitinib in patients with rheumatoid arthritis

Objective: To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting.Methods: A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks.Results: The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, −0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated.Conclusions: Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX