Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 96
Filter
1.
Stem Cell Res Ther ; 15(1): 106, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38627844

ABSTRACT

BACKGROUND: Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations. METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs. RESULTS: Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined. CONCLUSIONS: Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.


Subject(s)
Induced Pluripotent Stem Cells , Humans , Cell Differentiation/genetics , Hematopoietic Stem Cells/metabolism , Induced Pluripotent Stem Cells/metabolism , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
3.
In Vivo ; 37(5): 2197-2202, 2023.
Article in English | MEDLINE | ID: mdl-37652497

ABSTRACT

BACKGROUND/AIM: Vancomycin (VCM) is an antibiotic widely used in the treatment of resistant bacteria. In patients with methicillin-resistant Staphylococcus aureus (MRSA) infection, the clinical outcome differs according to the VCM minimum inhibitory concentration (MIC) of isolates. However, the effect of VCM MIC on the clinical outcome is unclear for bacterial species other than MRSA. This study evaluated the relationship between the VCM MIC and clinical outcomes in patients with Enterococcus faecium bacteremia. PATIENTS AND METHODS: This study included patients who had E. faecium detected in at least one set of blood cultures between April 2011 and March 2022. The study assessed the outcome according to the VCM MIC. The primary outcome was the 30-day mortality rate. Measures of interest included the initial serum concentration of VCM, MIC, the area under the curve (AUC), and the AUC over 24-48 hours (AUC24-48 h). RESULTS: A total of 26 patients were included in the study, of whom 5 died and 21 survived. The 30-day mortality was higher in patients with higher MICs and lower serum albumin levels. Patients with a serum albumin level <2.0 mg/dl and a MIC ≥1 µg/ml had significantly shorter survival than those who did not (p=0.013, log-rank test). CONCLUSION: The 30-day mortality rate of patients with E. faecium bacteremia is associated with the VCM MIC of E. faecium isolates and the patient's nutritional status. Patients with albumin <2 mg/dl and MIC ≥1 µg/ml may have a poor outcome and require careful clinical monitoring.


Subject(s)
Bacteremia , Enterococcus faecium , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Vancomycin/pharmacology , Vancomycin/therapeutic use , Staphylococcal Infections/microbiology , Retrospective Studies , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity Tests , Bacteremia/drug therapy , Bacteremia/microbiology , Serum Albumin , Treatment Outcome
4.
Cancer Sci ; 114(8): 3433-3445, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37302818

ABSTRACT

Classic Hodgkin lymphoma (cHL) is characterized by multinucleated cells called Reed-Sternberg (RS) cells and genetic complexity. Although CD30 also characterizes cHL cells, its biological roles are not fully understood. In this report, we examined the link between CD30 and these characteristics of cHL cells. CD30 stimulation increased multinucleated cells resembling RS cells. We found chromatin bridges, a cause of mitotic errors, among the nuclei of multinucleated cells. CD30 stimulation induced DNA double-strand breaks (DSBs) and chromosomal imbalances. RNA sequencing showed significant changes in the gene expression by CD30 stimulation. We found that CD30 stimulation increased intracellular reactive oxygen species (ROS), which induced DSBs and multinucleated cells with chromatin bridges. The PI3K pathway was responsible for CD30-mediated generation of multinucleated cells by ROS. These results suggest that CD30 involves generation of RS cell-like multinucleated cells and chromosomal instability through induction of DSBs by ROS, which subsequently induces chromatin bridges and mitotic error. The results link CD30 not only to the morphological features of cHL cells, but also to the genetic complexity, both of which are characteristic of cHL cells.


Subject(s)
Hodgkin Disease , Reed-Sternberg Cells , Humans , Reed-Sternberg Cells/metabolism , Reed-Sternberg Cells/pathology , Hodgkin Disease/metabolism , Reactive Oxygen Species/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Cell Line , Chromosomal Instability/genetics , Chromatin/genetics , Chromatin/metabolism , Ki-1 Antigen/genetics , Ki-1 Antigen/metabolism
5.
Sci Rep ; 13(1): 9407, 2023 Jun 09.
Article in English | MEDLINE | ID: mdl-37296148

ABSTRACT

We present an ab initio calculation to understand electronic structures and optical properties of a tungsten carbide WC being a major component of a TiCN-based cermet. The TiCN-based cermet is widely used as a cutting tool, and is discarded as usual after use. On the other hand, cermet itself is also a famous ingredient of a solar absorption film. We found that the WC has a fairly low-energy plasma excitation [Formula: see text] 0.6 eV (2 [Formula: see text]m) and therefore can be a good constituent of a solar selective absorber. The evaluated figure of merit for photothermal conversion is prominently high compared to those of the other materials included in the TiCN-based cermet. The imaginary part of the dielectric function is considerably small around the zero point of the real part of the dielectric function, corresponding to the plasma excitation energy. Therefore, a clear plasma edge appeared, ensuring the high performance of the WC as the solar absorber. This is a fascinating aspect, because the wasted TiCN-based cermet cutting tool can be recycled as the solar absorption film after proper treatments and modifications.


Subject(s)
Electronics , Motion Pictures , Cermet Cements , Pharmaceutical Vehicles
6.
J Atheroscler Thromb ; 30(10): 1364-1375, 2023 Oct 01.
Article in English | MEDLINE | ID: mdl-36775332

ABSTRACT

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p<0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.


Subject(s)
Arginine , Hypertension , Male , Humans , Female , Middle Aged , Aged , Citrulline , Prognosis , Ornithine/metabolism
7.
J Clin Med ; 12(4)2023 Feb 10.
Article in English | MEDLINE | ID: mdl-36835957

ABSTRACT

We recently reported that sub-acute myocarditis occurred following the initial two doses of messenger RNA-based vaccination against coronavirus disease 2019 (0.3 mL Comirnaty®) in elderly Japanese patients with cardiac dysfunction. The present retrospective study of 76 patients revealed that myocarditis following the initial doses persisted for 12 months, was associated with low levels of neutralizing antibodies, and was ameliorated by reducing the third vaccine dose. Low neutralizing antibody levels (<220 U/mL) after the initial doses were an independent predictor of persistent clinical events, defined as death or marked changes in brain natriuretic peptide levels. When the third dose was reduced (0.1 mL), changes in brain natriuretic peptide levels were significantly smaller (p = 0.02, n = 25), no deaths occurred due to heart failure, and neutralizing antibody levels increased 41-fold (p < 0.001) compared with the initial doses. Reduced booster doses could facilitate the worldwide distribution of messenger RNA vaccines.

8.
Transfusion ; 63(3): 463-469, 2023 03.
Article in English | MEDLINE | ID: mdl-36597800

ABSTRACT

BACKGROUND: Flow cytometry (FC) has proven its utility in scrutinizing AB antigen expression in red blood cells (RBCs), cooperating with serological tests for accurate blood group typing. However, technical difficulties may impair the characterization of weak ABO subtypes when background noises appear at non-negligible levels. STUDY DESIGN AND METHODS: We sought to establish an FC method that could prevent antibody-induced hemagglutination and an increase in cellular autofluorescence, two major issues inherent to RBC-FC analysis of AB expression. We optimized fixatives, multicolor-staining protocols, and sequential gating strategies. Blood samples from weak ABO subtype cases, Bm and Ael , were analyzed with the established protocol. RESULTS: The optimized mixture of glutaraldehyde and formaldehyde successfully generated fixed RBCs resistant to agglutination while maintaining low autofluorescence. These features allowed co-staining of leukocyte- and erythrocyte-markers, which enabled sequential gating strategies facilitating the precise AB antigen analysis in purely single RBCs with minimum background noises. By the established FC analysis, we could detect in the Bm sample a small RBC population exhibiting weak B antigen expression. The assay also proved it feasible to identify a small population (0.04%) of RBCs weakly expressing the A antigen in the Ael sample confirmed as harboring a rare c.816dupG ABO variant allele. CONCLUSION: The RBC-FC analysis described here allows the detection of AB antigens weakly expressed in RBCs while achieving minimum background noise levels in negative control samples. Overall, the modified protocol provides a quick and reliable assay valuable in transfusion medicine and is potentially applicable to the characterization of rare weak ABO variants.


Subject(s)
ABO Blood-Group System , Erythrocytes , Humans , Flow Cytometry/methods , Erythrocytes/metabolism , Antibodies/metabolism , Blood Grouping and Crossmatching , Antigens/metabolism
9.
Infect Dis Rep ; 16(1): 26-34, 2023 Dec 27.
Article in English | MEDLINE | ID: mdl-38247975

ABSTRACT

Carbapenems are antimicrobial agents commonly used to treat extended-spectrum ß-lactamase (ESBL)-producing bacteria. Although cefmetazole (CMZ) is considered effective for ESBL-producing Escherichia coli (ESBL-EC) bacteremia, previous studies showed its limitations, including the influence of the initial antimicrobial agent. Here, we examined the effects of different approaches to antimicrobial therapy with CMZ and meropenem (MEPM) on the time to defervescence in ESBL-EC bacteremia. Notably, the influence of previous antimicrobial agents was excluded. Inpatients with ESBL-EC detected in blood cultures between April 2018 and March 2023 were included and assigned to CMZ (n = 14), MEPM (n = 8), de-escalation to CMZ (dCMZ; n = 9), or escalation to MEPM (eMEPM; n = 11) groups. The median time to defervescence was 3.5, 1.0, 2.0, and 4.0 days in the CMZ, MEPM, dCMZ, and eMEPM groups, respectively, with no significant differences. Cox proportional hazards analysis showed a significant difference in the hazard ratio (95% confidence interval) of 0.378 (0.145-0.984) for the time to defervescence with CMZ versus MEPM (p = 0.046). The extent of a delayed time to defervescence is greater with early CMZ administration than with MEPM administration in patients with non-severe ESBL-EC bacteremia.

10.
Sci Rep ; 12(1): 21603, 2022 Dec 14.
Article in English | MEDLINE | ID: mdl-36517530

ABSTRACT

This report presents n-type single-walled carbon nanotubes (SWCNT) films with ultra-long air stability using a cationic surfactant and demonstrates that the n-type Seebeck coefficient can be maintained for more than two years, which is the highest stability reported thus far to the best of our knowledge. Furthermore, the SWCNT films exhibit an extremely low thermal conductivity of 0.62 ± 0.08 W/(m·K) in the in-plane direction, which is very useful for thin-film TEGs. We fabricated all-carbon-nanotube TEGs, which use p-type SWCNT films and the n-type SWCNT films developed, and their air-stability was investigated. The TEGs did not degrade for 160 days and exhibited an output voltage of 24 mV, with a maximum power of 0.4 µW at a temperature difference of 60 K. These results open a pathway to enable the widespread use of carbon nanotube TEGs as power sources in IoT sensors.

11.
Ann Hematol ; 101(11): 2433-2444, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36098792

ABSTRACT

Liver cirrhosis (LC) involves B cells that produce anti-glycoprotein (GP) IIb/IIIa antibodies, found in primary immune thrombocytopenia (ITP). The role of autoimmunity in the pathology of thrombocytopenia in LC was investigated using 25 LC patients with thrombocytopenia, 18 ITP patients, and 30 healthy controls. Anti-GPIIb/IIIa antibody-producing B cells were quantified using enzyme-linked immunospot assay. Platelet-associated and plasma anti-GPIIb/IIIa antibody, plasma B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) levels were measured using enzyme-linked immunosorbent assay. B cell subset fractions and regulatory T cells (Tregs) were quantified using flow cytometry.The number of anti-GPIIb/IIIa antibody-producing B cells was significantly higher in LC patients than in ITP patients and healthy controls (both p < 0.001). Platelet-associated anti-GPIIb/IIIa antibodies were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.002, p < 0.001, respectively). BAFF levels were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.001 and p < 0.001, respectively), and APRIL levels were significantly higher in LC patients than in healthy controls (p < 0.001). Anti-GPIIb/IIIa antibody-producing B cells and platelet-associated anti-GPIIb/IIIa antibodies were positively correlated with BAFF levels in LC patients. LC patients had more naïve B cells and plasmablasts than healthy controls (p = 0.005, p = 0.03, respectively); plasmablasts were positively correlated with BAFF levels. LC patients had similar Tregs levels as ITP patients and healthy controls. Therefore, excessive BAFF production in LC patients with thrombocytopenia is likely associated with autoimmune B cell response, inducing anti-GPIIb/IIIa antibody production.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Autoantibodies , B-Cell Activating Factor , Blood Platelets , Fibrinogen , Humans , Liver Cirrhosis/complications , Platelet Glycoprotein GPIIb-IIIa Complex
12.
Sci Rep ; 12(1): 217, 2022 Jan 07.
Article in English | MEDLINE | ID: mdl-34997126

ABSTRACT

To develop high-performance thermoelectric devices that can be created using printing technology, the interface of a composite material composed of MASnI3 and Bi2Te3, which individually show excellent thermoelectric performance, was studied based on first-principles calculations. The structural stability, electronic state, and interfacial thermal conductance of the interface between Bi2Te3 and MASnI3 were evaluated. Among the interface structure models, we found stable interface structures and revealed their specific electronic states. Around the Fermi energy, the interface structures with TeII and Bi terminations exhibited interface levels attributed to the overlapping electron densities for Bi2Te3 and MASnI3 at the interface. Calculation of the interfacial thermal conductance using the diffuse mismatch model suggested that construction of the interface between Bi2Te3 and MASnI3 could reduce the thermal conductivity. The obtained value was similar to the experimental value for the inorganic/organic interface.

13.
Circ J ; 86(2): 319-329, 2022 01 25.
Article in English | MEDLINE | ID: mdl-34544960

ABSTRACT

BACKGROUND: There is a gradual progression from paroxysmal to persistent atrial fibrillation (AF) in humans. To elucidate the mechanism involved, the creation of an artificial atrial substrate to persist AF in mice was attempted.Methods and Results:This study used wild type (WT) mice, but it is difficult to induce AF in them. A novel antegrade perfusion method from the left ventricle (LV) to enlarge both atria for artificial atrial modification was proposed in this study. Short duration AF was induced by burst pacing under this method. Optical mapping analysis revealed non-sustained focal type and meandering spiral reentrants after short duration AF. A tiny artificial substrate (~1.2 mm in diameter) was added in by laser irradiation to create a critical atrial arrhythmogenic substrate. Burst pacing was performed in a non-laser group (n=8), a circular-shape laser group (n=8), and a wedge-shaped dent laser group (n=8). We defined AF and atrial tachycardia (AT) as atrial arrhythmia (AA). Long-lasting AA was defined as lasting for ≥30 min. Long-lasting AA was observed in 0/8, 0/8, and 6/8 (75%) mice in each group. Optical mapping analysis revealed that the mechanism was AT with a stationary rotor around the irradiated margin. CONCLUSIONS: Regrettably, this study failed to reproduce persistent AF, but succeeded in creating an arrhythmic substrate that causes sustained AT in WT mice.


Subject(s)
Atrial Fibrillation , Tachycardia, Supraventricular , Animals , Atrial Fibrillation/etiology , Cardiac Pacing, Artificial/adverse effects , Disease Models, Animal , Heart Atria , Humans , Mice
14.
Ann Hematol ; 100(11): 2745-2754, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34333665

ABSTRACT

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Frail Elderly , Multiple Myeloma/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/administration & dosage , Bortezomib/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Female , Hematologic Diseases/chemically induced , Humans , Hyponatremia/chemically induced , Japan , Kaplan-Meier Estimate , Male , Peripheral Nervous System Diseases/chemically induced , Precision Medicine , Progression-Free Survival , Prospective Studies , Thalidomide/administration & dosage , Thalidomide/adverse effects , Treatment Outcome
15.
Nanomaterials (Basel) ; 11(6)2021 Jun 11.
Article in English | MEDLINE | ID: mdl-34208185

ABSTRACT

The temperature dependence thermal conductivity of the indium-gallium-zinc oxide (IGZO) thin films was investigated with the differential three-omega method for the clear demonstration of nanocrystallinity. The thin films were deposited on an alumina (α-Al2O3) substrate by direct current (DC) magnetron sputtering at different oxygen partial pressures ([PO2] = 0%, 10%, and 65%). Their thermal conductivities at room temperature were measured to be 1.65, 1.76, and 2.58 Wm-1K-1, respectively. The thermal conductivities decreased with an increase in the ambient measurement temperature. This thermal property is similar to that of crystalline materials. Electron microscopy observations revealed the presence of nanocrystals embedded in the amorphous matrix of the IGZO films. The typical size of the nanocrystals was approximately 2-5 nm with the lattice distance of about 0.24-0.26 nm. These experimental results indicate that the nanocrystalline microstructure controls the heat conduction in the IGZO films.

16.
Diagn Interv Radiol ; 27(2): 269-271, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33599204

ABSTRACT

A 79-year-old man was admitted to our hospital with C6-C7 pyogenic spondylodiscitis with an epidural abscess. Since the cervical intervertebral space is narrower than the thoracolumbar intervertebral space, drain insertion into the cervical intervertebral space requires a more accurate procedure. Moreover, the specific anatomy of cervical vertebrae, which includes the transverse foramen through which the vertebral artery passes and the uncinate process on the side edges of the top surface of the bodies, makes it impossible to perform computed tomography (CT)-guided percutaneous intervertebral drain insertion through the posterolateral approach. Therefore, CT fluoroscopy-guided percutaneous cervical intervertebral drain insertion using a lateral approach, in which the needle is advanced between the carotid sheath and scalene muscle, and simultaneous intravenous contrast enhancement might be a safe and useful technique. There have been no papers on CT fluoroscopy-guided percutaneous intervertebral drain insertion for cervical pyogenic spondylodiscitis, while successful CT fluoroscopy-guided percutaneous intervertebral drain insertion for thoracolumbar pyogenic spondylodiscitis has been reported. Here, we successfully performed CT fluoroscopy-guided percutaneous intervertebral drain insertion for cervical pyogenic spondylodiscitis.


Subject(s)
Discitis , Aged , Cervical Vertebrae , Discitis/diagnostic imaging , Discitis/surgery , Drainage , Fluoroscopy , Humans , Male , Tomography, X-Ray Computed
17.
Dig Dis ; 39(3): 234-242, 2021.
Article in English | MEDLINE | ID: mdl-32759604

ABSTRACT

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.


Subject(s)
Autoantibodies/biosynthesis , B-Lymphocytes/immunology , Cinnamates/therapeutic use , Liver Diseases/complications , Platelet Glycoprotein GPIIb-IIIa Complex/immunology , Thiazoles/therapeutic use , Thrombocytopenia/drug therapy , Thrombocytopenia/immunology , Aged , Aged, 80 and over , Autoantibodies/immunology , Blood Platelets/pathology , Cinnamates/administration & dosage , Female , Humans , Liver Diseases/blood , Male , Middle Aged , Multivariate Analysis , Organ Size , Platelet Count , Prospective Studies , Spleen/pathology , Thiazoles/administration & dosage , Thrombocytopenia/blood , Thrombocytopenia/complications
18.
Br J Haematol ; 192(1): 190-199, 2021 01.
Article in English | MEDLINE | ID: mdl-33152120

ABSTRACT

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.


Subject(s)
Anemia, Aplastic/drug therapy , Anemia, Refractory/drug therapy , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/therapeutic use , Adult , Aged , Anemia, Aplastic/blood , Anemia, Refractory/blood , Blood Cell Count , Female , Headache/chemically induced , Hematopoiesis/drug effects , Humans , Male , Middle Aged , Receptors, Fc/administration & dosage , Receptors, Fc/blood , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/blood , Spasm/chemically induced , Thrombopoietin/administration & dosage , Thrombopoietin/adverse effects , Thrombopoietin/blood , Treatment Outcome , Young Adult
19.
Rinsho Ketsueki ; 61(8): 865-869, 2020.
Article in Japanese | MEDLINE | ID: mdl-32908047

ABSTRACT

Acute leukemia (AL) during pregnancy poses a substantial risk to both mothers and fetuses. Treatment for leukemia should be initiated promptly; however, the management of AL in pregnant women and fetuses is usually challenging, especially during the second trimester. Here, we report two cases of AL that developed during the second trimester of pregnancy. In one case, chemotherapy was initiated while continuing the pregnancy; in the second case, a cesarean section was performed prior to chemotherapy initiation. As per current medical records, both infants are thriving without any medical problems. The optimal strategy for the treatment of AL during pregnancy typically includes chemotherapy after delivery. However, if fetal development is not sufficient for ex utero survival, the only alternatives available are the initiation of treatment while continuing the pregnancy or treatment after therapeutic abortion (if it is legally allowed). According to previous studies and as per the results from our first case, the initiation of chemotherapy while sustaining the pregnancy may be an acceptable option if it is conducted with appropriate informed consent. The treatment of AL in the second trimester of pregnancy should be carefully decided, while taking into account the medical, legal, and social aspects, such as gestational weeks, maternal and fetal status, and wishes of the patients and their families.


Subject(s)
Leukemia, Myeloid, Acute , Pregnancy Complications, Neoplastic , Acute Disease , Cesarean Section , Female , Humans , Pregnancy , Pregnancy Trimester, Second
20.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 76(Pt 2): 259-266, 2020 Apr 01.
Article in English | MEDLINE | ID: mdl-32831228

ABSTRACT

Electrical and thermal transport controlled by growth mode can be used to optimize thermoelectric properties of ZnO:Al films, which was adjusted by the re-evaporation of Zn and Al via substrate temperatures. The growth modes include equiaxed crystal, columnar crystal and coexistence of both crystals. In the ZnO:Al film, equiaxed crystals improve the carrier mobility and reduce the lattice thermal conductivity. Thus, the carrier mobility and thermal conductivity are tuned by the ratio of equiaxed crystals to columnar crystals. The carrier mobility is dependent on the growth-mode-related defects of oxygen vacancies, zinc interstitials and the substitutional dopant of Al. Improved thermoelectric properties with a power factor of 198.45 µW m-1 K-2 at 510 K were achieved. This study presents a film with the structure of an equiaxed-crystal buffer layer to enhance its thermoelectric properties.

SELECTION OF CITATIONS
SEARCH DETAIL