The positive roles of the Wnt/β-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/β-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/β-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl-CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/β-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/β-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl. Cell Death and Differentiation (2015) 22, 912-920; doi:10.1038/cdd.2014.238; published online 30 January 2015Bone is an extremely dynamic tissue at the microscopic level. A dynamic process, called bone remodeling, takes place seamlessly in the bone to repair microdamage and to replace old bone with new bone. 1 The resorption of old bone and the formation of new bone must be in balance to maintain homeostasis and a constant mass of bone. Osteoblasts have been identified as an essential factor in regulation of the bone remodeling process, which produce bone matrix and differentiate into osteocytes for bone formation, as well as regulate differentiation and activation of osteoclasts for bone resorption. 2 The Wnt/β-catenin pathway is receiving increased attention as a main regulatory pathway for osteoblast differentiation. [2][3][4] Wnt-dependent nuclear accumulation of an effector protein of the pathway, β-catenin, is a major trigger of osteoblast differentiation and bone formation. 2 Many other intracellular and extracellular components of the Wnt/β-catenin pathway are known to regulate osteoblast differentiation. 4 Especially two negative regulators of this pathway, Dickkopf 1 and sclerostin, have been highlighted as osteoblast and osteocytespecific negative regulators of bone formation. 5 CXXC finger protein 5 (CXXC5) is a member of a small protein family in which the members contain CXXC-type zincfinger domain. 6 However, unlike other members of this family, CXXC5 lacks a KFGG motif, which is essential for non-methylated CpG recognition that regulates chromatin remodeling. 7 CXXC5 localizes to the cytosol or nucleus depending on particular cell type in different tissues. Localization of CXXC5 in the nucleus was observed in promyelocytic leukemia cells. 7 CXXC5 has a role as a nuclear t...

The study was undertaken to investigate clinical characteristics of thrombotic thrombocytopenic purpura (TTP) in patients with SLE and to determine risk factors and clinical outcome of TTP in patients with SLE. Among the 1203 patients with SLE admitted to catholic medical centre of the catholic university of Korea from January 1990 to December 2006, 26 patients with SLE were found to admit with TTP. TTP was defined if microangiopathic haemolytic anaemia, thrombocytopenia and negative Coombs' test were present and when at least one of the following signs was noted: renal impairment, neurologic deficit or fever. Eighty-seven patients with SLE who admitted with other manifestations, matched for age and sex, were included as disease controls. Data were retrospectively analysed based on medical records. There were no significant demographic characteristics between SLE patients with TTP and those with other manifestations. Multivariate analysis showed that independent risk factors for the development of TTP included high SLE disease activity index score (SLEDAI > 10, P = 0.006) and coexisting nephritis (P = 0.004). Among the 26 SLE patients with TTP, 12 died during admission period (in-hospital mortality rate: 46.1%). SLE patients with infection or neurologic manifestations had higher mortality rates. Multivariate analysis showed that infection is the only independent risk factor for mortality in SLE patients with TTP (P = 0.035). Patients with SLE who are in the active stage or who have renal involvement have the increased risk for TTP. Development of TTP in patients with SLE can be fatal. Therefore, intensive therapy will be needed especially in the presence of infection. Lupus (2009) 18, 16-21.

This study was undertaken to investigate clinical characteristics of diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus (SLE) and to determine risk factors and clinical outcomes of DAH in SLE patients. Among the 1521 patients with SLE admitted between January 1993 and June 2009 to affiliated hospitals of Catholic University of Korea, 21 SLE were admitted for DAH. The inclusion criteria for DAH was defined as new infiltrates on chest radiographs, an acute hemoglobin drop of at least 1.5 g/dl in the absence of an obvious source of bleeding, and one or more of the following signs: hemoptysis, hypoxemia, bronchoscopic or biopsy evidence of DAH. Included as disease controls were 83 SLE patients, matched for age and sex, who were admitted for other manifestations. Data based on medical records were analyzed retrospectively. There were no significantly differing demographic characteristics between SLE patients with DAH and those with other manifestations. Multivariate analysis demonstrated coexisting neuropsychiatric lupus (p = 0.002) and high SLE disease activity index scores (SLEDAI > 10) as independent risk factors in the development of DAH (p = 0.029). Among the 21 SLE patients with DAH, 13 died during the admission period (in-hospital mortality rate: 61.9%). Mortality was associated with infection and requirements of mechanical ventilation. Collectively, SLE patients who have neuropsychiatric manifestations or are in the active stage of the disease have an increased risk for developing DAH. Due to the high mortality of SLE patients with DAH, early recognition of risk factors and appropriate intervention is essential.

Objectives The aim of the study was to estimate rates of linkage to HIV care and antiretroviral treatment (ART) initiation after the introduction of home‐based HIV counselling and testing (HBHCT) and telephone‐facilitated support for linkage in rural South Africa. Methods A population‐based prospective cohort study was carried out in KwaZulu Natal, South Africa. All residents aged ≥ 15 years were eligible for HBHCT. Those who tested positive and were not in care were referred for ART at one of 11 public‐sector clinics. Individuals who did not attend the clinic within 2 weeks were sent a short message service (SMS) reminder; those who had not attended after a further 2 weeks were telephoned by a nurse counsellor, to discuss concerns and encourage linkage. Kaplan–Meier methods were used to estimate the proportion of newly diagnosed individuals linking to care and initiating ART. Results Among 38 827 individuals visited, 26% accepted HBHCT. Uptake was higher in women than in men (30% versus 20%, respectively), but similar in people aged < 30 years and ≥ 30 years (28% versus 26%, respectively). A total of 784 (8%) tested HIV positive, of whom 427 (54%) were newly diagnosed. Within 6 months, 31% of women and 18% of men < 30 years old had linked to care, and 29% and 16%, respectively, had started ART. Among those ≥ 30 years, 41% of women and 38% of men had linked to care within 6 months, and 41% and 35%, respectively, had started ART. Conclusions Despite facilitated linkage, rates of timely linkage to care and ART initiation after HBHCT were very low, particularly among young men. Innovations are needed to provide effective HIV care and prevention interventions to young people, and thus maximize the benefits of universal test and treat.

Cellular senescence is an important mechanism for preventing tumor progression. The elevated expression of Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic and anti-stress protein, often correlates with poor prognosis in several cancers including glioblastoma; however, the role of BIS in the regulation of senescence has not been well defined. Here, we describe for the first time that the depletion of BIS induces G1 arrest and cellular senescence through the accumulation of p27 that is independent of p53, p21 or p16. The increase in p27 expression in BIS-depleted cells was attributable to an impairment of the ubiquitin-mediated degradation of p27, which was caused by a decrease in S-phase kinase-associated protein 2 (SKP2) at the transcriptional level. As an underlying molecular mechanism, we demonstrate that the loss of activity of signal transducer and activator of transcription 3 (STAT3) was specifically linked to the suppression of SKP2 expression. Despite a reduction in phospho-STAT3 levels, total STAT3 levels were unexpectedly increased by BIS depletion, specifically in the insoluble fraction. Our results show that 14-3-3ζ expression is decreased by BIS knockdown and that 14-3-3ζ depletion per se significantly induced senescence phenotypes. In addition, the ectopic expression of 14-3-3ζ blocked senescence caused by BIS depletion, which was paralleled with a decrease in insoluble STAT3 in A172 glioblastoma cells. These findings indicate that the impairment of the protein quality control conferred by BIS and/or 14-3-3ζ is critical for BIS depletion-induced senescence. Moreover, BIS knockdown also induced senescence along with an accumulation of total STAT3 and p27 in several different cell types as well as embryonic fibroblasts derived from Bis-knock out mice with/without variations in 14-3-3ζ levels. Therefore, our findings suggest that a downregulation of BIS expression could serve as a potential strategy for restricting tumor progression via an induction of senescence through the regulation of STAT3/SKP2/p27 pathway.

SUMMARY BackgroundDoctor visits for irritable bowel syndrome are associated with high medical costs. Predictors of medical consultation for irritable bowel syndrome remain poorly understood.

The SIR of cancer was significantly higher in SSc patients, and especially in those who were male, than in the general population. Lung cancer was the most common cancer. Active surveillance for the detection of cancer should be performed in all SSc patients.

A search for the decays of the Higgs and Z bosons to a ϕ meson and a photon is performed with a pp collision data sample corresponding to an integrated luminosity of 2.7  fb^{-1} collected at sqrt[s]=13  TeV with the ATLAS detector at the LHC. No significant excess of events is observed above the background, and 95% confidence level upper limits on the branching fractions of the Higgs and Z boson decays to ϕγ of 1.4×10^{-3} and 8.3×10^{-6}, respectively, are obtained.