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We discuss a possible link between the deformation parameter \\[\\Theta ^{\\mu \\nu }\\] arising in the framework of noncommutative geometry and the parameter \\[\\beta \\] of the generalized uncertainty principle (GUP). We compute the shift of the Hawking temperature induced by the \\[\\Theta ^{\\mu \\nu }\\]-deformed Schwarzschild geometry, and then we relate it to one obtained by GUP. Results suggest a granular structure of specetime at the Planck scales. The current bounds on \\[\\beta \\] allow to constraint the noncommutative parameter \\[\\Theta ^{\\mu \\nu }\\].

BackgroundRheumatologists need to develop primary and secondary prevention strategies for cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients. We reported tofacitinib (Tofa) improved left ventricular mass index (LVMI) in patients with rheumatoid arthritis1). We have experienced RA patient with chronic heart failure (CHF). We couldn’t use some TNF blockers in RA patients with CHF2). There is no evidence that Tofa effects on left ventricular (LV) morphology and function in RA patients with CHF.ObjectivesTo study the effect of Tofa on LV morphology and function in conventional synthetic (cs) DMARDs resistant active RA patients with CHF, in a cohort study design.MethodsRA patients with CHF were eligible if they had active disease despite treatment with cs DMARDs. Consecutive 24 patients with moderate to severe active RA patients (DAS28 >3.2) despite cs DMARDs were received Tofa plus cs DMARDs. LV morphology and function was assessed with cardio-MRI at baseline and 24 weeks follow-up. Cardiovascular risk factors and clinical data were collected at regular visits.Results21 patients completed 24 weeks. New York heart association functional classification (NYHA) class 1 is 12 cases, class 2 is 7 cases, and class 3 is 2 cases respectively. Left ventricular mass index (LVMI) was attenuated significantly by Tofa (week 0 week24, −9.02±5.8 g/m2; p=0.02). Cardiac output (CO) was attenuated significantly by Tofa (week 0 week24,−0.42±1.2 l/min). DAS28 and CRP improved significantly by Tofa (week 0 week24; DAS28: −2.16±0.95; CRP: 15.1±5.7 mg/L) (p<0.05). Surprisingly, the change of disease activity (DAS 28 and CRP) is no correlation with the change of LVMI or CO in this study. Observationally, 2 cases significantly improved right ventricular mass as well as left ventricular mass (10% improved right ventricular mass index from baseline).ConclusionsTofa improved LVMI and CO in active RA despite cs DMARDs with CHF. Tofa improves LVMI and CO independently of its effects on disease activity. Tofa might be improved right ventricular mass. JAK-STAT pathway might be an important role of LV hypertrophy. Tofa, JAK-STAT pathway blocking, may prevent cardiovascular morbidity and mortality in RA with CHF.References[1] Kume K, et al. Tofacitinib improves left ventricular mass and cardiac output in patients with rheumatoid arthritis. Presentation at Annual Meeting of EULAR 2017.[2] Hochenberg MC, et al. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum2005Jun;34(6):819–36.Disclosure of InterestNone declared

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P =0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

We report the long-term results of Tokyo Children's Cancer Study Group's studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)±s.e. was 67.2±2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0±1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m 2 had no advantage over prednisolone 60 mg/m 2 in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8–22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.

The South Pacific region is characterized by a broadly elevated seafloor known as the South Pacific superswell. This region has a concentration of midplate volcanoes that experienced massive eruptions in the mid‐Cretaceous period (90–120 Ma). These characteristics suggest the presence of a large‐scale mantle plume beneath the South Pacific, called the South Pacific superplume. The geometry, origin depth, temperature, and composition of the superplume remain controversial, however, mainly due to the lack of seismological data that documents the mantle structure beneath the South Pacific. Seismic stations are sparse in the area due to its remote ocean environment. To obtain a better seismic image of the superplume, we deployed temporary broadband seismographs on oceanic islands and the seafloor in the South Pacific, which made possible the highest spatial resolution that has ever been achieved for the mantle structure beneath the region. The seismic image obtained from this new seismic data indicates that large‐scale low‐velocity anomalies (on the order of 1000 km in diameter), indicative of the superplume, are located from the bottom of the mantle to a depth of 1000 km, and small‐scale low‐velocity anomalies (on the order of 100 km in diameter) are present above it. A comparison of the seismic image with recent mantle convection studies based upon laboratory and numerical experiments suggests that the superplume may be a hot and chemically distinct mantle dome, and that the small‐scale anomalies may be narrow plumes generated from the top of the dome. This model may explain various characteristics of hot spots in the South Pacific, such as the seafloor swell, short‐lived hot spot chains, and the periodicity of massive eruptions.

The crustal and lithospheric structure of the normal oceanic plates is investigated using converted wave techniques (P and S receiver functions (RFs) and novel stacking analysis techniques without deconvolution) applied to the data from two seafloor borehole broadband seismic stations located in the central Philippine Sea and in the northwest Pacific ocean. We observe sufficient energy from at least two discontinuities within the error bounds, one from the crust‐mantle (Moho) boundary and the other from the seismic lithosphere‐asthenosphere boundary (LAB). Synthetic seismograms for seafloor stations show that the water reverberations interfere with the vertical component of seismograms but to a lesser extent with the radial part of P receiver functions. On the other hand, S receiver functions are devoid of such effects since all the multiples and converted waves are separated in time by the primary S wave in time. Waveform modeling of RFs shows that the crustal thicknesses of the western Philippine Sea plate and northwest Pacific plate are ∼7–8 km, and that depths of LAB are 76 ± 1.8 km and 82 ± 4.4 km, respectively, with an abrupt Vs drop at LAB of ∼7%–8%, as reported by Kawakatsu et al. (2009). The LAB depth for the eastern Philippine plate is found to be ∼55 km. To confirm the robustness of this observation, we further analyze vertical and radial components of the data without deconvolution for P wave backscattered reflection phases and P‐to‐S converted phases. The result indicates that the reflected/converted phases from Moho and LAB are observed at timings consistent with the receiver function results. The effect of seismic anisotropy for observed RFs is also investigated. Key Points P and S receiver functions analysis Borehole ocean bottom seismic observatories Lithosphere‐asthenosphere boundary

In the past few years, tumour budding at the invasive margin has been reported as a new risk factor for lymph node metastasis in advanced colorectal cancers, but it is sometimes difficult to detect tumour budding in submucosal colorectal cancer by haematoxylin and eosin staining. We immunohistochemically examined tumour budding at the deepest invasive margin of 56 surgically resected submucosal colorectal carcinomas using anticytokeratin antibody CAM5.2, furthermore checked by AE1/AE3, and determined the relation between tumour budding and clinicopathological factors. Moreover, we used the monoclonal antibody D2-40 for immunohistochemistry to detect lymphatic involvement. Tumour budding was detected in 42 cases (75.0%), and the budding-positive group showed a significantly higher rate of lymph node metastasis (including isolated tumour cells) (16/42 vs 0/14; P =0.004) than the budding-negative group. The sensitivity and negative predictive value of tumour budding alone for lymph node metastasis were superior to those of lymphatic invasion alone. Furthermore, the specificity and positive predictive value of the combination of either lymphatic invasion or tumour budding were superior to those of lymphatic invasion alone. Tumour budding detected immunohistochemically by using CAM5.2 is a newly found risk factor for lymph node metastasis and may help to avoid oversurgery in the future.

BackgroundPolymyalgia rheumatica (PMR) is a common inflammatory disease of the elderly, and 2012 provisional classification criteria were suggested, however it is provisional and not meant for diagnosis purpose1). Ultrasound (US), MRI and other modalities were often detected interspinous bursitis in patients with PMR2). To develop 2012 provisional classification criteria, adding interspinous bursitis evaluation by US. We reported the usefulness of interspinous bursitis evaluation by US at 2015 American college of rheumatology annual meeting.ObjectivesIn this time, we compared 2012 provisonal classification criteria to adding interspinous bursitis evaluation by US, and checked the association between US evaluation of conventional (shoulder and hip) bursitis and interspinous bursitis.MethodsThis is a prospective cohort study. Candidate criteria were evaluated 161 patients with new onset untreated PMR, and 174 patients non-PMR comparison subjects with conditions mimicking PMR. We compared the diagnosis ability of 2012 provisional classification criteria with 2012 provisional classification criteria, adding interspinous bursitis evaluation by US. US evaluation was checked cervical and lumbar spine added conventional shoulder and hip. In PMR patients, we evaluated the prevalance of interspinous bursitis without hip or shoulder bursitis, the association between interspinous bursitis and shoulder or hip bursitis.Results2012 provisional classification criteria scoring system had 66% sensitivity and 82% specificity. Adding interspinous bursitis by US had significantly increased sensitivity to 89%,and not significantly decreased specificity to 77%.(ROC anaylysis: p<0.05)PMR patients without hip or shoulder bursitis were 56 patients. Surprisingly, PMR patients without hip or shoulder bursitis had interspinous bursitis with high prevalence. (85%, 48 patients) No correlation was found between interspinous bursitis and shoulder or hip bursitis (r=0.09, P=0.36).ConclusionsInterspinous bursitis by US is important evalution in patients with PMR. Interspinous bursitis by US should be added classification criteria for PMR. If patients were suspected of PMR, interspinous bursitis by US might be performed despite hip and shoulder bursitis.ReferencesDasgupta B, et al. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2012 Apr;71(4):484–92. doi: 10.1136/annrheumdis-2011-200329.Camellino D, et al. Interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain. Arthritis Res Ther. 2014 Dec 1;16(6):492. [Epub ahead of print]Disclosure of InterestNone declared

We solve a random two-matrix model with two real asymmetric matrices whose primary purpose is to describe certain aspects of quantum chromodynamics with two colours and dynamical fermions at nonzero quark chemical potential μ . In this symmetry class the determinant of the Dirac operator is real but not necessarily positive. Despite this sign problem the unquenched matrix model remains completely solvable and provides detailed predictions for the Dirac operator spectrum in two different physical scenarios/limits: (i) the ε -regime of chiral perturbation theory at small μ , where μ 2 multiplied by the volume remains fixed in the infinite-volume limit and (ii) the high-density regime where a BCS gap is formed and μ is unscaled. We give explicit examples for the complex, real, and imaginary eigenvalue densities including N f = 2 non-degenerate flavours. Whilst the limit of two degenerate masses has no sign problem and can be tested with standard lattice techniques, we analyse the severity of the sign problem for non-degenerate masses as a function of the mass split and of μ . On the mathematical side our new results include an analytical formula for the spectral density of real Wishart eigenvalues in the limit (i) of weak non-Hermiticity, thus completing the previous solution of the corresponding quenched model of two real asymmetric Wishart matrices.

Galanin receptor 1 ( GALR1 ) maps to a common region of 18q loss in head and neck squamous cell carcinomas and is frequently inactivated by methylation. To investigate effects of GALR1 and its signaling pathways, we stably expressed hemaglutinin-tagged GALR1 in a human oral carcinoma cell line (UM-SCC-1-GALR1) that expresses no endogenous GALR1. In transfected cells, galanin induced activation of the extracellular-regulated protein kinase-1/2 (ERK1/2) and suppressed proliferation. Galanin stimulation mediated decreased expression of cyclin D1 and increased expression of the cyclin-dependent kinase inhibitors (CKI), p27 Kip1 and p57 Kip2 . Pretreatment with the ERK1/2-specific inhibitor U0126 prevented these galanin-induced effects. Phosphatidylinositol 3-kinase (PI3K) pathway activation did not differ in UM-SCC-1-GALR1 and UM-SCC-1-mock cells after galanin treatment. Pertussis toxin and LY294002 inhibition demonstrated that galanin and GALR1 induce ERK1/2 activation via G α i, not the PI3K pathway-linked to the G βγ subunit. Galanin and GALR1 also inhibit colony formation and tumor growth in vivo . Our results implicate GALR1, a Gi protein-coupled receptor, as a tumor suppressor gene that inhibits cell proliferation via ERK1/2 activation.