Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block ...hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue. This phosphorylation enhances the interaction of NF-κB and the peptidyl-prolyl cis-trans isomerase PIN1 and increases the protein stability and transcriptional activity of NF-κB. As a consequence, R-2HG enhances NF-κB-dependent expression of cytokines including IL-6, IL-8 and complement 5a to stimulate proliferation of AML cells. In addition, R-2HG also upregulates vascular endothelial adhesion molecule 1 and CXCR4 in stromal cells to enhance the contact between AML and stromal cells and attenuates chemotherapy-induced apoptosis. More importantly, we validated the R-2HG-activated gene signature in the primary bone marrow stromal cells isolated from IDH-mutated AML patients. Collectively, our results suggest that AML cell-derived R-2HG may be helpful for the establishment of a supportive bone marrow stromal niche to promote AML progression via paracrine stimulation.
Semaphorin 6A (SEMA6A), a membrane-bound protein, is downregulated in lung cancer tissue compared to its adjacent normal tissue. However, the functions of SEMA6A in lung cancer cells are still ...unclear. In the present study, full length SEMA6A and various truncations were transfected into lung cancer cells to investigate the role of the different domains of SEMA6A in cell proliferation and survival, apoptosis, and in vivo tumor growth. SEMA6A-induced cell signaling was explored using gene silencing, co-immunoprecipitation, and co-culture assays. Our results showed that overexpression of SEMA6A reduced the growth of lung cancer cells in vitro and in vivo, and silencing SEMA6A increased the proliferation of normal lung fibroblasts. Truncated SEMA6A lacking the SEMA domain or the extracellular region induced more apoptosis than full length SEMA6A, and reintroducing the SEMA domain attenuated the apoptosis. Fas-associated protein with death domain (FADD) bound to the cytosolic region of truncated SEMA6A and was involved in SEMA6A-associated cytosol-induced apoptosis. This study suggests a novel function of SEMA6A in inducing apoptosis via FADD binding in lung cancer cells.
Peripartum cardiomyopathy (PPCM) is the development of heart failure during late pregnancy to months postpartum with potential fatal outcome. However, the disease is not well-studied in Asia.We aimed ...to investigate the epidemiology and clinical outcomes of PPCM in Taiwan.Electronic medical records were retrieved from Taiwan National Health Insurance Research Database from 1997 to 2011. Patients with PPCM were separated into 3 groups based on the timing of diagnosis. Early: PPCM diagnosed first to ninth month of pregnancy. Traditional: PPCM diagnosed last month of pregnancy till fifth month post-delivery. Late: PPCM diagnosed sixth to twelfth month post-delivery. Primary outcomes defined as cardiac death, all-cause mortality, and major adverse cardiovascular events (MACE) within 1 year.A total of 3,506,081 deliveries during 1997 to 2011 were retrieved and 925 patients with PPCM were identified. Overall incidence of PPCM was 1:3,790 during the 15 years. Early, Traditional, and Late group each had 88, 742, and 95 patients. Cardiac death occurred in 31 patients, all-cause mortality in 72 patients, and MACE in 65 patients. Late group had 2- to 3-fold event rates in cardiac death, all-cause mortality, and MACE compared with Early and Traditional groups. Cumulative incidence showed significant differences for cardiac death (P = .0011), all-cause mortality (P = .0031), and MACE (P = .0014) among 3 groups. Multivariate Cox model showed Late group had significantly worse outcomes after adjusted for clinical variables compared with 2 other groups.Our study is the largest national cohort among Asian countries that showed timing of diagnosis of PPCM had different outcomes. Late diagnosis portended significantly increased morbidity and mortality, even after adjusted for clinical variables.
A directly self-crystallized graphene layer with transfer-free process on arbitrary insulator by Ni vapor-assisted growth at growth temperatures between 950 to 1100 °C via conventional chemical vapor ...deposition (CVD) system was developed and demonstrated. Domain sizes of graphene were confirmed by Raman spectra from ~12 nm at growth temperature of 1000 °C to ~32 nm at growth temperature of 1100 °C, respectively. Furthermore, the thickness of the graphene is controllable, depending on deposition time and growth temperature. By increasing growth pressure, the growth of graphite nano-balls was preferred rather than graphene growth. The detailed formation mechanisms of graphene and graphite nanoballs were proposed and investigated in detail. Optical and electrical properties of graphene layer were measured. The direct growth of the carbon-based materials with free of the transfer process provides a promising application at nanoelectronics.
Background
Visual impairment (VI) was associated with cognitive impairment. However, different visual trajectories might contribute to different risks of cognitive decline in the elderly.
Aims
This ...study aimed to evaluate the association between visual trajectories and cognitive impairment.
Methods
Four thousand two hundred eight community-dwelling elder adults were identified from Waves IV–VII (1999–2011) survey of the Taiwan Longitudinal Study on Aging (TLSA). Cognitive function was determined using the Short Portable Mental Status Questionnaire (SPMSQ) scores. Visual impairment was self-reported and visual trajectories were assessed in at least two waves of the survey. Ordinal logistic regression was performed to estimate adjusted odds ratios (adjORs) and 95% confidence intervals (CIs).
Results
Participants with visual trajectory from no VI to VI had significantly higher risk of cognitive impairment with an adjOR of 1.69 (95% CI 1.12–2.57) than participants without VI. Compared to participants without VI, participants with persistent VI (adjOR 1.32; 95% CI 0.89–1.96) and with visual trajectory from VI to no VI (adjOR 1.25; 95% CI 0.83–1.88) were not associated with cognitive impairment. A protective association between eyeglasses use and cognitive impairment (adjOR 0.69; 95% CI 0.55–0.87) was found in this study. Importantly, cataract was associated with higher risk of cognitive impairment (adjOR 1.34; 95% CI 1.10–1.62). However, nonsurgical cataract treatment did not show protective effect on cognitive impairment in patients with cataract.
Conclusions and discussion
Visual trajectory from no VI to VI is a significant risk factor for cognitive impairment that physicians should pay special attention during community screening.
The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary ...prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70–100 mg/dL in Taiwan could be cost-effective.
A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed.
Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER.
Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.
Biofunctional magnetic nanoparticles (MNPs) have been widely applied in biomedical engineering. MNPs are used as a contrast medium in magnetic imaging. Current methods of magnetic imaging, such as ...magnetic particle imaging and magnetic relaxometry, use small amounts of MNPs at target points far from the surface of the patient’s body; these methods always consume considerable power to produce magnetic fields of high uniformity or gradient excitations. Some drawbacks, such as a limited imaging region, imaging system shielding, and complex algorithms based on assumptions of MNP properties or environmental factors, also limit the application of MNP methods in clinics. Therefore, this work proposes an interdisciplinary methodology of ultrasound-induced magnetic imaging that lacks these drawbacks. In the proposed imaging method, magnet sets were designed with uniform magnetic fields to magnetize MNPs. Besides, magnetized MNPs are subjected to ultrasound vibrations; the motion of the MNPs induces weak induction voltages at the imaging pickup coils. The highly sensitive scanning superconducting quantum interference device biosusceptometry with three sets of ultrasound focus chips was developed to construct magnetic tomography at three depths. A phantom test showed favorable consistency between the visual photos and the magnetic images of alpha-fetoprotein antibody (anti-AFP) MNP distribution on gauzes. In animal tests, rats with liver tumors were imaged at the pre-injection and post-injection of anti-AFP MNPs. The consistent results of magnetic images and ultrasound images implied that the proposed method has high clinical potential.
Highlights • A major clone of Staphylococcus lugdunensis (ST6) persisted in the hospital. • High genetic similarity was confirmed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence ...typing (MLST). • All three infectious cases were nosocomial bacteraemia in the intensive care unit. • S. lugdunensis nosocomial infection surveillance and control in endemic areas is suggested.
Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured ...before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified. Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34 + cell collection of <1 × 10 6 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method. Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82–63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65–58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61–36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%. Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs.
The wrinkle-fruited leaf flower (
Phyllanthus urinaria L.) (Euphorbiaceae) is widely used as a traditional folk medicine for inflammatory relief. Geraniin, the hydrolysable tannin, was purified by a ...series of chromatographic processes from the 70% aqueous acetone extracts of
P. urinaria and identified by NMR
1H (500
MHz) and
13C NMR (126
MHz) spectra and mass spectroscopy. The scavenging activities of geraniin against DPPH radicals (half-inhibition concentration, IC
50, were 0.92 and 1.27
μM, respectively, for pH 4.5 and pH 7.9), hydroxyl radicals (IC
50 was 0.11
μM by deoxyribose method and 1.44
μM by electron spin resonance method), and superoxide radicals (IC
50 were 2.65
μM) were determined in comparison with positive controls. The inhibitory activities against xanthine oxidase (IC
50 were 30.49
μM) were measured. Geraniin also showed dose-dependent inhibitory activities against semicarbazide-sensitive amine oxidase (SSAO, IC
50 were 6.58
μM) and against angiotensin converting enzyme (ACE, IC
50 were 13.22
μM). For kinetic property determinations, geraniin showed competitive inhibitions against SSAO (the apparent inhibition constant,
K
i, was 0.70
μM) and mixed noncompetitive inhibitions against ACE. Spontaneously hypertensive rats (SHR, 10-week age) were orally administered to once (5
mg geraniin/kg SHR), and changes of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured over 24
h and compared with the positive control of captopril (2
mg/kg SHR). The geraniin showed antihypertensive activity in lowering SBP and DBP and showed a significant difference from the blank (distilled water) at 2, 4, 6, 8, and 24
h. Healthy food products could use geraniin for antioxidant protection and therapeutic effects in the future.
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