We report the effect of annealing on the crystalline ordering and physical properties in thin films of a nodal line semimetal candidate L21-type Co2FeSn. The Co–Fe–Sn films with a composition of ...Co:Fe:Sn ∼ 2:1:1 were deposited on MgO(001) substrates at a substrate temperature of 150 °C by radio-frequency magnetron sputtering. The as-deposited film showed x-ray diffraction patterns corresponding to the B2 ordering. Annealing at 600 and 700 °C after the deposition resulted in the appearance of the (111) diffraction peak, which is characteristic of the L21 ordering. Although anomalous Hall conductivity and transverse thermoelectric conductivity decreased from those of the as-deposited film with the annealing-induced L21 ordering, the low anomalous Hall conductivity of the 700 °C-annealed film was consistent with the theoretically estimated low value. These results show the significant influence of crystalline ordering on the electrical and thermoelectric transport properties. The annealing process is beneficial for studying the exotic physics arising from topological band features in the L21-ordered Co2FeSn thin films.
Background:The optimal timing of aortic valve replacement (AVR) is controversial in patients with asymptomatic severe aortic stenosis (AS) except when very severe. Prediction of progression of severe ...AS is helpful in deciding on the timing of AVR. The purpose of this study was to clarify the predictors of progression rate and clinical outcomes of severe AS.Methods and Results:We retrospectively investigated 140 consecutive patients with asymptomatic severe AS (aortic valve area AVA, 0.75–1.0 cm2). First-year progression rate and annual progression rate of AVA and of aortic jet velocity (AV-Vel) were calculated. Cardiac events were examined and the predictors of rapid progression and cardiac events were analyzed. The median follow-up period was 36 months. The median annual progression rate was −0.05 cm2/year for AVA and 0.22 m/s/year for AV-Vel. Dyslipidemia, moderate-severe calcification, and first-year AV-Vel progression ≥0.22 m/s/year were independent predictors of cardiac events. Cardiac event-free rate was lower in patients with AV-Vel first-year progression rate ≥0.22 m/s/year than in those with a lower rate. Diabetes and moderate-severe calcification were related to first-year rapid progression.Conclusions:The annual progression rate of severe AS was −0.05 cm2/year for AVA and 0.22 m/s/year for AV-Vel. Patients with first-year rapid progression or severely calcified aortic valve should be carefully observed while considering an early operation. (Circ J 2016; 80: 1863–1869)
Background:Constrictive pericarditis (CP) is characterized by impaired diastolic cardiac function leading to heart failure. Pericardiectomy is considered effective treatment for CP, but data on ...long-term clinical outcomes after pericardiectomy are limited.Methods and Results:We retrospectively investigated 45 consecutive patients (mean age, 59±14 years) who underwent pericardiectomy for CP. Preoperative clinical factors, parameters of cardiac catheterization, and cardiac events were examined. Cardiac events were defined as hospitalization owing to heart failure or cardiac death.Median follow-up was 5.7 years. CP etiology was idiopathic in 16 patients, post-cardiac surgery (CS) in 21, tuberculosis-related in 4, non-tuberculosis infection-related in 2, infarction-related in 1, and post-radiation in 1. The 5-year event-free survival was 65%. Patients with idiopathic CP and tuberculosis-related CP had favorable outcomes compared with post-CS CP (5-year event-free survival: idiopathic, 80%; tuberculosis, 100%; post-CS, 52%). Higher age (hazard ratio: 2.51), preoperative atrial fibrillation (3.25), advanced New York Heart Association class (3.92), and increased pulmonary artery pressure (1.06) were predictors of cardiac events. Patients with postoperative right-atrial pressure ≥9 mmHg had lower event-free survival than those with right-atrial pressure <9 mmHg (39% vs. 75% at 5 years, P=0.013).Conclusions:Long-term clinical outcomes after pericardiectomy among a Japanese population were related to the underlying etiology and the patient’s preoperative clinical condition. Postoperative cardiac catheterization may be helpful in the prediction of prognosis after pericardiectomy.
Cardiac-specific myosin light chain kinase (cMLCK), encoded by
, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological ...and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure.
We generated the knock-in mice (
and
3
) with a familial dilated cardiomyopathy-associated
frameshift mutation (
) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154).
Both mice (
and
3
) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_
vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3
mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_
vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the
for ventricular myosin regulatory light chain phosphorylation without affecting the
. LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3
mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower
/
messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes.
cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.
Immune cell-based therapy is a promising approach for cancer immunotherapy. Macrophages can be used for this purpose if their tumoricidal activity and viability are properly controlled. In the ...present study, we aimed to enhance these properties of macrophages by constructing uniformly sized multicellular spheroids. Mouse macrophage-like J774.1 cells were selected as model macrophages, and poly(N-isopropylacrylamide)-coated polydimethylsiloxane-based microwell plates with an approximate diameter of 750μm were used to prepare J774.1 spheroids. J774.1 spheroids were successfully generated, and the viability of cells in the spheroids was over 95%. J774.1 spheroids showed higher mRNA expression of induced nitric oxide synthase, a marker of M1-type activated macrophages, than monolayered J774.1 cells. The production of reactive oxygen species was also high in J774.1 spheroids, suggesting the existence of hypoxic regions in the spheroids. J774.1 spheroids released more tumor necrosis factor-α than monolayered cells upon stimulation with lipopolysaccharide. Moreover, J774.1 spheroids in the upper compartment of the Transwell system more efficiently inhibited the proliferation of mouse adenocarcinoma colon 26 cells in its lower compartment than monolayered J774.1 cells did. These results indicate that spheroid formation can be used to increase the tumoricidal activity of macrophages for use in cell-based cancer immunotherapy.
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Aim: Severe gastrointestinal bleeding sometimes occurs in patients with aortic stenosis (AS), known as Heyde's syndrome. This syndrome is thought to be caused by acquired von Willebrand syndrome and ...is characterized by reduced large von Willebrand factor (vWF) multimers. However, the relationship between the severity of AS and loss of large vWF multimers is unclear. Methods: We examined 31 consecutive patients with severe AS. Quantitative evaluation for loss of large vWF multimers was performed using the conventional large vWF ratio and novel large vWF multimer index. This novel index was defined as the ratio of large multimers of patients to those of controls. Results: Loss of large vWF multimers, defined as the large vWF multimer index ＜80%, was detected in 21 patients (67.7%). The large vWF multimer ratio and the large vWF multimer index were inversely correlated with the peak aortic gradient (R=-0.58, p=0.0007, and R=-0.64, p＜0.0001, respectively). Anemia defined as hemoglobin ＜9.0 g/dl was observed in 12 patients (38.7%), who were regarded as Heyde's syndrome. Aortic valve replacement was performed in 7 of these patients, resulting in the improvement of anemia in all patients from a hemoglobin concentration of 7.5±1.0g/dl preoperatively to 12.4±1.3 g/dl postoperatively (p＜0.0001). Conclusions: Acquired von Willebrand syndrome may be a differential diagnosis in patients with AS with anemia. The prevalence of AS-associated acquired von Willebrand syndrome is higher than anticipated.
We present a case of the T2-FLAIR mismatch sign in glioblastoma, isocitrate dehydrogenase (IDH)-wild type. The T2-FLAIR mismatch sign is known as a highly specific imaging finding of astrocytoma, ...IDH-mutant. Meanwhile, IDH-wildtype diffuse astrocytic gliomas with telomerase reverse transcriptase (TERT) promoter mutation in adults are defined as glioblastoma in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (2021 WHO classification), which underscores the importance of molecular information in central nervous system tumors. This indicates even glioblastoma, IDH-wild type may be masquerading as lower-grade glioma in histology. The reasons for the discrepancy between tumors with less aggressive histology and poor prognosis caused by telomerase reverse transcriptase promoter mutation of IDH-wildtype diffuse glioma remain unclear. However, glioblastoma, IDH-wildtype should be considered as a potential differential diagnosis even in patients with the T2-FLAIR mismatch sign in diffuse gliomas.
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