DNA Damage Stress and Inhibition of Jak2-V617F Cause Its Degradation and Synergistically Induce Apoptosis through Activation of GSK3β

The cytoplasmic tyrosine kinase Jak2 plays a crucial role in cytokine receptor signaling in hematopoietic cells. The activated Jak2-V617F mutant is present in most cases of BCR/ABL-negative myeloproliferative neoplasms and constitutively activates downstream signals from homodimeric cytokine receptors, such as the erythropoietin receptor (EpoR). Here we examine the effects of DNA damage stress on Jak2 or Jak2-V617F and on induction of apoptosis in hematopoietic cells. Etoposide or doxorubicin dose-dependently decreased the expression level of Jak2 in UT7 or 32D cells expressing EpoR in the absence of Epo and that of exogenously expressed Jak2-V617F in UT7 cells when cotreated with the Jak2 inhibitor JakI-1 or AG490. Studies with pharmacological inhibitors and genetic manipulations further showed that downregulation of the PI3K/Akt pathway leading to the activation of GSK3β may be involved in downregulation of Jak2 or Jak2-V617F as well as in synergistic induction of Bax activation and apoptosis. The downregulation of Jak2 was inhibited by the proteasome inhibitor MG132 or by expression of both of loss-of-function mutants of c-Cbl and Cbl-b, E3 ubiquitin ligases which facilitated ubiquitination of Jak2-V617F when co-expressed in 293T cells. The pan-caspase inhibitor Boc-d-fmk also inhibited the Jak2 downregulation as well as appearance of a 100-kDa fragment that contained the N-terminal portion of Jak2 in response to DNA damage. Together, these data suggest that DNA damage stress with simultaneous inhibition of the kinase activity causes degradation of Jak2 or Jak2-V617F by caspase cleavage and proteasomal degradation through GSK3β activation, which is closely involved in synergistic induction of apoptosis in hematopoietic cells

Geographical Differences and the National Meeting Effect in Patients with Out-of-Hospital Cardiac Arrests: A JCS-ReSS Study Report

The "national meeting effect" refers to worse patient outcomes when medical professionals attend academic meetings and hospitals have reduced staffing. The aim of this study was to examine differences in outcomes of patients with out-of-hospital cardiac arrest (OHCA) admitted during, before, and after meeting days according to meeting location and considering regional variation of outcomes, which has not been investigated in previous studies. Using data from a nationwide, prospective, population-based, observational study in Japan, we analyzed adult OHCA patients who underwent resuscitation attempts between 2011 and 2015. Favorable one-month neurological outcomes were compared among patients admitted during the relevant annual meeting dates of three national scientific societies, those admitted on identical days the week before, and those one week after the meeting dates. We developed a multivariate logistic regression model after adjusting for confounding factors, including meeting location and regional variation (better vs. worse outcome areas), using the "during meeting days" group as the reference. A total of 40,849 patients were included in the study, with 14,490, 13,518, and 12,841 patients hospitalized during, before, and after meeting days, respectively. The rates of favorable neurological outcomes during, before, and after meeting days was 1.7, 1.6, and 1.8%, respectively. After adjusting for covariates, favorable neurological outcomes did not differ among the three groups (adjusted OR (95% CI) of the before and after meeting dates groups was 1.03 (0.83-1.28) and 1.01 (0.81-1.26), respectively. The "national meeting effect" did not exist in OHCA patients in Japan, even after comparing data during, before, and after meeting dates and considering meeting location and regional variation

Improved outcomes for out-of-hospital cardiac arrest patients treated by emergency life-saving technicians compared with basic emergency medical technicians: A JCS-ReSS study report

Background Emergency life-saving technicians (ELSTs) are specially trained prehospital medical providers believed to provide better care than basic emergency medical technicians (BEMTs). ELSTs are certified to perform techniques such as administration of advanced airways or adrenaline and are considered to have more knowledge; nevertheless, ELSTs’ effectiveness over BEMTs regarding out-of-hospital cardiac arrest (OHCA) remains unclear. We investigated whether the presence of an ELST improves OHCA patient outcomes. Methods In a retrospective study of adult OHCA patients treated in Japan from 2011 to 2015, we compared two OHCA patient groups: patients transported with at least one ELST and patients transported by only BEMTs. The primary outcome measure was one-month favorable neurological outcomes, defined as Cerebral Performance Category ≤ 2. A multivariable logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs) to evaluate the effect of ELSTs. Results Included were 552,337 OHCA patients, with 538,222 patients in the ELST group and 14,115 in the BEMT group. The ELST group had a significantly higher odds of favorable neurological outcomes (2.5% vs. 2.1%, adjusted OR 1.39, 95% CI 1.17–1.66), one-month survival (4.9% vs. 4.1%, adjusted OR 1.37, 95% CI 1.22–1.54), and return of spontaneous circulation (8.1% vs. 5.1%, adjusted OR 1.90, 95% CI 1.72–2.11) compared with the BEMT group. However, ELSTs’ limited procedure range (adrenaline administration or advanced airway management) did not promote favorable neurological outcomes. Conclusions Compared with the BEMT group, transport by the ELST group was associated with better neurological outcomes in OHCA

Hydro-bio-geomechanical properties of hydrate-bearing sediments from Nankai Trough

This paper is not subject to U.S. copyright. The definitive version was published in Marine and Petroleum Geology 66 (2015): 434-450, doi:10.1016/j.marpetgeo.2015.02.033.Natural hydrate-bearing sediments from the Nankai Trough, offshore Japan, were studied using the Pressure Core Characterization Tools (PCCTs) to obtain geomechanical, hydrological, electrical, and biological properties under in situ pressure, temperature, and restored effective stress conditions. Measurement results, combined with index-property data and analytical physics-based models, provide unique insight into hydrate-bearing sediments in situ. Tested cores contain some silty-sands, but are predominantly sandy- and clayey-silts. Hydrate saturations Sh range from 0.15 to 0.74, with significant concentrations in the silty-sands. Wave velocity and flexible-wall permeameter measurements on never-depressurized pressure-core sediments suggest hydrates in the coarser-grained zones, the silty-sands where Sh exceeds 0.4, contribute to soil-skeletal stability and are load-bearing. In the sandy- and clayey-silts, where Sh < 0.4, the state of effective stress and stress history are significant factors determining sediment stiffness. Controlled depressurization tests show that hydrate dissociation occurs too quickly to maintain thermodynamic equilibrium, and pressure–temperature conditions track the hydrate stability boundary in pure-water, rather than that in seawater, in spite of both the in situ pore water and the water used to maintain specimen pore pressure prior to dissociation being saline. Hydrate dissociation accompanied with fines migration caused up to 2.4% vertical strain contraction. The first-ever direct shear measurements on never-depressurized pressure-core specimens show hydrate-bearing sediments have higher sediment strength and peak friction angle than post-dissociation sediments, but the residual friction angle remains the same in both cases. Permeability measurements made before and after hydrate dissociation demonstrate that water permeability increases after dissociation, but the gain is limited by the transition from hydrate saturation before dissociation to gas saturation after dissociation. In a proof-of-concept study, sediment microbial communities were successfully extracted and stored under high-pressure, anoxic conditions. Depressurized samples of these extractions were incubated in air, where microbes exhibited temperature-dependent growth rates.PCCTs were developed with funding to Georgia Tech from the DOE/Chevron Joint Industry Project (JIP), with additional funds from the Joint Oceanographic Institutions, Inc. The JIP also funded the Georgia Tech participation in Sapporo. USGS participation in Sapporo was funded through a technical assistance agreement with Chevron (TAA-12-2135/CW928359). Some USGS developments on the IPTC were funded under Interagency Agreement DE-FE0002911 with the U.S. Department of Energy, with additional support from the U.S. Geological Survey. Core acquisition and Japanese participation in this study was supported by the Research Consortium for Methane Hydrate Resources in Japan (MH21 Research Consortium) to carry out Japan's Methane Hydrate R&D Program conducted by the Ministry of Economy, Trade and Industry (METI)

Utilization of automated external defibrillators installed in commonly used areas of Japanese hospitals

Objective. Since July 2004, it has become legal in Japan for laypersons to use automated external defibrillators (AEDs). We investigated the effect of AED installation in commonly used areas of Japanese Association for Acute Medicine accredited training (JAAM) hospitals. Methods. In 2008, we sent questionnaires to 419 JAAM hospitals enquiring about the systems, operations, outcome and characteristics of AED usage. Results. Valid responses were received from 271 hospitals (64.7%). A total of 251 (92.8%) hospitals installed AEDs, mostly in the outpatient departments. These AEDs could also be used by laypersons. Operational responsibility was mostly assumed by the medical emergency center staff. The Engineering Department was in charge of AED maintenance. Of the surveyed hospitals, 65.5% reported having guidelines for usage. The percentages of hospitals which kept records of AED use and outcomes were low. A total of 66.2% reported having a rapid response team and 98.1% provided a non-standardized resuscitation education program. In 68.3% of hospitals, an AED had been used. AEDs were used not only by medical doctors but also by other health professionals. Among the patients who received AED defibrillation, 42.5% survived without neurological deficit. Conclusion. The utilization of AEDs, installed in commonly used areas of JAAM hospitals, has shown beneficial and effective outcomes for improving the resuscitation and survival of patients who experience in-hospital cardiac arrest. AEDs can be used not only by doctors but also by laypersons, making them more accessible and useful. The strategic installation of AEDs can make hospitals safer

The impact of human leukocyte antigen mismatch on recipient outcomes in living‐donor liver transplantation

Donor–recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990–2020). The primary and secondary endpoints were recipient survival and the incidence of T cell–mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0–10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21–5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11–5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor–recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

金沢大学大学院医学系研究科血管分子科学The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca2+]i responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-γ-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity

Dietary fiber intake and risk of incident disabling dementia: the Circulatory Risk in Communities Study

OBJECTIVES: It has been hypothesized that dietary fiber intake has a beneficial impact on prevention of dementia, but the epidemiological evidence is scant. We sought to examine whether dietary fiber intake is inversely associated with risk of dementia requiring care under the national insurance (disabling dementia). METHODS: The study setting was the Circulatory Risk in Communities Study, involving 3739 Japanese individuals aged 40-64 years at the dietary surveys (1985-99). Dietary fiber intake was estimated using the 24-hour dietary recall method. Incident disabling dementia was followed up from 1999 through 2020. Disabling dementia was further classified into that with or without a history of stroke. Hazard ratios of disabling dementia according to quartiles of total, soluble, and insoluble fiber intake were calculated using the Cox proportional hazards model. RESULTS: During a median 19.7-year follow-up, a total of 670 cases of disabling dementia developed. Dietary fiber intake was inversely associated with risk of dementia: the multivariate hazards ratios (95% confidence intervals) were 0.83 (0.67-1.04), 0.81 (0.65-1.02), and 0.74 (0.57-0.96) for individuals with the second, third, and highest quartiles of dietary fiber intake, respectively, as compared with the lowest quartile (P for trend = 0.03). The inverse association was more evident for soluble fiber intake and was confined to dementia without a history of stroke. As for fiber-containing foods, potatoes, but not vegetables or fruits, showed a similar association. CONCLUSIONS: Dietary fiber intake, especially soluble fiber, was inversely associated with risk of disabling dementia in a general Japanese population