RESUMEN
The objective of the study is to investigate the safety, feasibility, and degradation profile of a novel Mg alloy-based bioresorbable coronary scaffold (JFK-PRODUCT BRS) with thin struts (110 µm). Polymer- or Mg alloy-based BRSs have not replaced nondegradable metal stents because of the higher prevalence of scaffold thrombosis and restenosis in clinical practice; these poor clinical outcomes were due to inadequate scaffold designs, including thick struts (more than 150 µm) and their inappropriate degradation processes. Fourteen healthy pigs received 17 JFK-PRODUCT BRSs in the coronary arteries and were sacrificed at 1, 6, 12, 18, and 26 months after implantation. Angiography, optical coherence tomography, microfocus X-ray computed tomography (µCT), scanning electron microscopy with energy-dispersive X-ray spectrometry (SEM-EDX), and histopathological evaluation were performed. The JFK-PRODUCT had a median percent late recoil of 11.28% at 1 month. The µCT observation confirmed that scaffold discontinuity reached 64.8% at 12 months with increased scaffold inner area thereafter, suggesting artery positive remodeling. The inflammation was mild, peaked at 18 months, and decreased thereafter. The SEM-EDX analysis demonstrated gradual degradation of the scaffold with formation of inorganic deposits, presumed to be calcium phosphates. It also revealed the disappearance of calcium phosphates at 26 months, achieving almost complete replacement of the scaffold by biocomponents. The current study demonstrated the safety and feasibility of JFK-PRODUCT with a lower acute recoil rate despite its thin struts. The scaffolds were almost completely disappeared at 26 months after implantation.
RESUMEN
Background: Constipation causes substantial morbidity worldwide. Methods: This survey assessed constipation-related factors in Japan using the Japanese version of the Irritable Bowel Syndrome Quality of Life (IBS-QOL-J) instrument. We also examined the relationship among laxative type, Bristol Stool Form Scale (BSFS) scores, and treatment cost. Finally, we examined differences in satisfaction scores according to laxative type, treatment type, treatment cost, and BSFS score. Results: IBS-QOL-J was higher among those taking salt and/or irritation laxatives. Those paying >JPY 5000 (USD 50.00) had the lowest IBS-QOL-J. IBS-QOL-J was significantly lower among those with a BSFS score of 1 or 2 (severe constipation). Conclusions: This study's findings suggest that a variety of factors, including treatment type and cost, are associated with defecation satisfaction. Those who had hard stools, used multiple laxatives, or spent more on treatment were less satisfied. Future strategies should target therapies that do not require multiple laxatives with lower treatment costs. Adequate defecation with a small number of appropriate laxatives at minimal cost appears to improve defecation satisfaction. It is desirable to identify appropriate laxatives and improve dietary habits and exercise routines. It is also necessary to stop blindly increasing laxative usage and properly diagnose constipation disorders such as anatomical abnormalities other than functional constipation.
RESUMEN
PURPOSE: Target positions should be acquired during beam delivery for accurate lung stereotactic body radiotherapy. We aimed to perform kilovoltage (kV) imaging during beam irradiation (intra-irradiation imaging) under phase-gated conditions and evaluate its performance. METHODS: Catphan 504 and QUASAR respiratory motion phantoms were used to evaluate image quality and target detectability, respectively. TrueBeam STx linac and the Developer Mode was used. The imaging parameters were 125 kVp and 1.2 mAs/projection. Flattened megavoltage (MV) X-ray beam energies 6, 10 and 15 MV and un-flattened beam energies 6 and 10 MV were used with field sizes of 5 × 5 and 15 × 15 cm2 and various frame rates for intra-irradiation imaging. In addition, using a QUASAR phantom, intra-irradiation imaging was performed during intensity-modulated plan delivery. The root-mean-square error (RMSE) of the CT-number for the inserted rods, image noise, visual assessment, and contrast-to-noise ratio (CNR) were evaluated. RESULTS: The RMSEs of intra-irradiation cone-beam computed tomography (CBCT) images under gated conditions were 50-230 Hounsfield Unit (HU) (static < 30 HU). The noise of the intra-irradiation CBCT images under gated conditions was 15-35 HU, whereas that of the standard CBCT images was 8.8-27.2 HU. Lower frame rates exhibited large RMSEs and noise; however, the iterative reconstruction algorithm (IR) was effective at improving these values. Approximately 7 fps with the IR showed an equivalent CNR of 15 fps without the IR. The target was visible on all the gated intra-irradiation CBCT images. CONCLUSION: Several image quality improvements are required; however, intra-irradiated CBCT images showed good visual target detection.
Asunto(s)
Tomografía Computarizada de Haz Cónico , Fantasmas de Imagen , Tomografía Computarizada de Haz Cónico/métodos , Humanos , Radioterapia de Intensidad Modulada/métodos , Relación Señal-Ruido , Procesamiento de Imagen Asistido por Computador/métodos , Respiración , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
Purpose: In concurrent chemoradiotherapy for advanced esophageal cancer, a 2-phase method consisting of initial irradiation of a wide elective nodal region and boost irradiation of the primary lesion is commonly employed. Although dose escalation to the primary lesion may be required to achieve higher local control rates, the radiation dose to critical organs must not exceed dose constraints. To achieve an optimum balance of dose prescription and dose reduction to surrounding organs, such as the lungs and heart, we compared hybrid dose distributions and investigated the best combination of the following recent irradiation techniques: volumetric modulation arc therapy (VMAT), proton broad-beam irradiation, and intensity-modulated proton beam therapy (IMPT). Materials and Methods: Forty-five patients with advanced esophageal cancer whose primary lesions were located in the middle- or lower-thoracic region were studied. Radiotherapy plans for the initial and boost irradiation in the 2-phase method were calculated using VMAT, proton broad-beam irradiation, and IMPT calculation codes, and the dose-volume histogram indices of the lungs and heart for the accumulated plans were compared. Results: In plans using boost proton irradiation with a prescribed dose of 60 Gy(RBE), all dose-volume histogram indices were significantly below the tolerance limits. Initial and boost irradiation with VMAT resulted in the median dose of V30 Gy(RBE)(heart) of 27.4% and an achievement rate below the tolerance limit of 57.8% (26 cases). In simulations of dose escalation up to 70 Gy(RBE), initial and boost IMPT resulted in the highest achievement rate, satisfying all dose constraints in 95.6% (43 cases). Conclusion: Applying VMAT to both initial and boost irradiation is not recommended because of the increased risk of the cardiac dose exceeding the tolerance limit. IMPT may allow dose escalation of up to 70 Gy(RBE) without radiation risks to the lungs and heart in the treatment of advanced esophageal cancer.
RESUMEN
BACKGROUND AND AIMS: High density lipoprotein (HDL) exerts an anti-atherosclerotic effect via reverse cholesterol transport (RCT). Several phases of RCT are transcriptionally controlled by Liver X receptors (Lxrs). Although macrophage Lxrs reportedly promote RCT, it is still uncertain whether hepatic Lxrs affect RCT in vivo. METHODS: To inhibit Lxr-dependent pathways in mouse livers, we performed hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) using adenoviral vector (Ad-Sult2b1). Ad-Sult2b1 or the control virus was intravenously injected into wild type mice and Lxrα/ß double knockout mice, under a normal or high-cholesterol diet. A macrophage RCT assay and an HDL kinetic study were performed. RESULTS: Hepatic Sult2b1 overexpression resulted in reduced expression of Lxr-target genes - ATP-binding cassette transporter G5/G8, cholesterol 7α hydroxylase and Lxrα itself - respectively reducing or increasing cholesterol levels in HDL and apolipoprotein B-containing lipoproteins (apoB-L). A macrophage RCT assay revealed that Sult2b1 overexpression inhibited fecal excretion of macrophage-derived 3H-cholesterol only under a high-cholesterol diet. In an HDL kinetic study, Ad-Sult2b1 promoted catabolism/hepatic uptake of HDL-derived cholesterol, thereby reducing fecal excretion. Finally, in Lxrα/ß double knockout mice, hepatic Sult2b1 overexpression increased apoB-L levels, but there were no differences in HDL levels or RCT compared to the control, indicating that Sult2b1-mediated effects on HDL/RCT and apoB-L were distinct: the former was Lxr-dependent, but not the latter. CONCLUSIONS: Hepatic Lxr inhibition negatively regulates circulating HDL levels and RCT by reducing Lxr-target gene expression.
RESUMEN
BACKGROUND AND PURPOSE: Quantitative susceptibility mapping (QSM) has been proposed to assess intraplaque hemorrhage (IPH) in the carotid artery. The purpose of this study was to compare the diagnostic accuracy of preoperative QSM with that of the conventional T1-weighed (T1W) three-dimensional (3D)-FSE sequence for detecting IPH in cervical ICA stenosis in patients undergoing carotid endarterectomy (CEA) using histology as the reference standard. MATERIALS AND METHODS: Carotid T1W 3D-FSE and QSM images were obtained from 16 patients with cervical ICA stenosis before CEA. Relative signal intensity (RSI) and susceptibility of the ICA were measured on three axial images including the location of most severe stenosis on T1W 3D-FSE and QSM images, respectively. Three transverse sections of carotid plaques excised by CEA, which corresponded with images on MRI, were stained with H&E, antibody against glycophorin A and Prussian blue, and the relative area (RA) of histologic IPH was calculated. RESULTS: The correlation coefficient was significantly greater between susceptibility and RA-histologic IPH (ρ = 0.691) than between RSI and RA-histologic IPH (ρ = 0.413; P = .0259). The areas under the receiver operating characteristic curves for detecting histologic sections consisting primarily of IPH (RA-histologic IPH > 40.7%) tended to be greater for susceptibility (0.964) than for T1WI FSE-RSI (0.811). Marginal homogeneity was observed between susceptibility and histologic sections consisting primarily of IPH (P = .0412) but not between T1W FSE-RSI and histologic sections consisting primarily of IPH (P = .1824). CONCLUSIONS: Pre-CEA QSM detects histologic IPH in cervical ICA stenosis more accurately than preoperative T1W 3D-FSE imaging. ABBREVIATIONS: QSM = quantitative susceptibility mapping; IPH = intraplaque hemorrhage; T1W = T1-weighed; 3D = three-dimensional; CEA = carotid endarterectomy; RSI = relative signal intensity; RA = relative area.
RESUMEN
BACKGROUND AND IMPORTANCE: A double-layer micromesh stent is designed for the treatment of carotid artery stenosis that has been reported to potentially provide a flow diversion effect. However, the actual flow diversion effect of stents remains unclear. Here, we present a case of a growing saphenous vein graft (SVG) aneurysm treated with the placement of the double-layer micromesh stent using its flow diversion effect. CLINICAL PRESENTATION: A 66-year-old woman, who underwent high-flow bypass using a SVG for a blister-like internal carotid artery aneurysm 13 years earlier at our institute, was referred to our hospital with a pulsatile cervical mass. Magnetic resonance angiography showed a 9-mm aneurysm on the left SVG, although the aneurysm was a small pouch 4 years earlier. Digital subtracted angiography demonstrated a 9.4 × 8.3-mm aneurysm from the SVG at the auricular level. Because the diameter of the graft was larger than that of the available flow diverter stents in Japan, we decided to place the double-layer micromesh stent (CASPER RX, 7 × 25 mm MicroVention) using its flow diversion effect. Computational fluid dynamics analysis before and after stent deployment showed a significant reduction in the average flow velocity and wall shear stress in the aneurysm, indicating actual flow diversion. An angiogram 2 months postoperatively showed complete obliteration of the aneurysm. CONCLUSION: Obliteration of the saphenous vein aneurysm was achieved because of the flow diversion effect of the double-layer micromesh stent. The stents might be a feasible alternative for treating cervical carotid aneurysms.
RESUMEN
The total synthesis of marine macrolide glycoside (-)-irijimaside A is described. Key to the synthesis is the convergent fragment assembly enabled by nickel/zirconocene-mediated one-pot reductive ketone coupling. At the last stage of the synthesis, Stille coupling and glycosylation led to the first total synthesis of (-)-irijimaside A.
RESUMEN
This study aimed to evaluate the dose reduction using gonad shielding (GS) during pelvic imaging. Three types of pelvic images (radiography, magnetic resonance and computed tomography) were fused to elucidate the three-dimensional relationship between the position of ovaries and GS. To estimate the dose received by the ovaries, the off-axis dose at any given depth was measured under two different imaging conditions using thermoluminescence dosemeters and a polymethyl methacrylate phantom. The mean ovarian depth was 8.4 cm. The mean estimated ovarian dose without an additional filter was 0.36 mGy without GS and 0.14 mGy with GS. The mean estimated ovarian dose with an additional filter was 0.24 mGy without GS and 0.10 mGy with GS. The efficacy of ovarian dose reduction should be evaluated based on the achieved ovarian dose, considering the ovarian depth and use of additional filtration, rather than the ovarian protection rate of GS.
Asunto(s)
Ovario , Pelvis , Fantasmas de Imagen , Dosis de Radiación , Protección Radiológica , Femenino , Humanos , Protección Radiológica/métodos , Ovario/efectos de la radiación , Ovario/diagnóstico por imagen , Pelvis/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Dosimetría Termoluminiscente/instrumentación , Gónadas/efectos de la radiaciónRESUMEN
OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma , Mieloma Múltiple , Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/epidemiología , Estudios Retrospectivos , Japón/epidemiología , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/diagnóstico , Linfoma/epidemiología , Linfoma/etiología , Linfoma/terapiaRESUMEN
BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.
RESUMEN
Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.
Asunto(s)
Hiperlipoproteinemia Tipo II , Intención , Niño , Humanos , Pruebas Genéticas , Asesoramiento Genético , Hiperlipoproteinemia Tipo II/genética , GenómicaRESUMEN
BACKGROUND: Centrally located lung tumours present a challenge because of their tendency to exhibit symptoms such as airway obstruction, atelectasis, and bleeding. Surgical resection of these tumours often requires sacrificing the lungs, making definitive radiotherapy the preferred alternative to avoid pneumonectomy. However, the proximity of these tumours to mediastinal organs at risk increases the potential for severe adverse events. To mitigate this risk, we propose a dual-method approach: deep inspiration breath-hold (DIBH) radiotherapy combined with adaptive radiotherapy. The aim of this single-centre, single-arm phase II study is to investigate the efficacy and safety of DIBH daily online adaptive radiotherapy. METHODS: Patients diagnosed with centrally located lung tumours according to the International Association for the Study of Lung Cancer recommendations, are enrolled and subjected to DIBH daily online adaptive radiotherapy. The primary endpoint is the one-year cumulative incidence of grade 3 or more severe adverse events, as classified by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). DISCUSSION: Delivering definitive radiotherapy for centrally located lung tumours presents a dilemma between ensuring optimal dose coverage for the planning target volume and the associated increased risk of adverse events. DIBH provides measurable dosimetric benefits by increasing the normal lung volume and distancing the tumour from critical mediastinal organs at risk, leading to reduced toxicity. DIBH adaptive radiotherapy has been proposed as an adjunct treatment option for abdominal and pelvic cancers. If the application of DIBH adaptive radiotherapy to centrally located lung tumours proves successful, this approach could shape future phase III trials and offer novel perspectives in lung tumour radiotherapy. TRIAL REGISTRATION: Registered at the Japan Registry of Clinical Trials (jRCT; https://jrct.niph.go.jp/ ); registration number: jRCT1052230085 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1052230085 ).
Asunto(s)
Corazón , Neoplasias Pulmonares , Humanos , Contencion de la Respiración , Órganos en Riesgo , Neoplasias Pulmonares/radioterapia , Pulmón , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Ensayos Clínicos Fase II como AsuntoRESUMEN
INTRODUCTION: While patients who experience improved cognition following carotid endarterectomy (CEA) typically demonstrate restored brain perfusion after the procedure, it is worth noting that less than 50% of patients in whom postoperative cerebral blood flow (CBF) restoration is achieved actually show improved cognition after postoperatively. This suggests that factors beyond the mere restoration of CBF may play a role in postoperative cognitive improvement. Increased iron deposition in the cerebral cortex may cause neural damage, and quantitative susceptibility mapping (QSM) obtained using magnetic resonance imaging (MRI) quantifies magnetic susceptibility in the cerebral cortex, allowing for the assessment of iron deposition in vivo. The purpose of the present study was to determine whether preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA. METHODS: Brain MRI with a three-dimensional gradient echo sequence was preoperatively performed in 53 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≥70%), and QSM with brain surface correction and vein removal was obtained. Cortical magnetic susceptibility was measured in the cerebral hemisphere ipsilateral to surgery on QSM. Preoperatively and at two months after the surgery, brain perfusion single-photon emission computed tomography (SPECT) and neuropsychological assessments were conducted. Using these collected data, we evaluated alterations in CBF within the affected hemisphere and assessed cognitive improvements following the operation. RESULTS: A logistic regression analysis showed that a postoperative greater increase in CBF (95% confidence interval [CI], 1.06-1.90; p = 0.0186) and preoperative lower cortical magnetic susceptibility (95% CI, 0.03-0.74; p = 0.0201) were significantly associated with postoperatively improved cognition. Although sensitivity, specificity, and positive- and negative-predictive values with the cutoff value lying closest to the upper left corner of a receiver operating characteristic curve for the prediction of postoperatively improved cognition did not differ between postoperative changes in CBF and preoperative cortical magnetic susceptibility, the specificity and the positive-predictive value were significantly greater for the combination of postoperative changes in CBF and preoperative cortical magnetic susceptibility (specificity, 95% CI, 93-100%; positive-predictive value 95% CI, 68-100%) than for the former parameter alone (specificity, 95% CI, 63-88%; positive-predictive value 95% CI, 20-64%). CONCLUSION: Preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA.
RESUMEN
Although cognitive decline after carotid endarterectomy (CEA) is mainly related to postoperative cerebral hyperperfusion, approximately 30% of patients with cognitive decline do not have postoperative cerebral hyperperfusion. In patients with acute ischemic events, the development of cognitive decline after such events is associated with the presence of chronic cerebral white matter hyperintensities (WMHs). The present prospective observational study aimed to determine whether preoperative WMHs and postoperative new ischemic lesions (PNILs) are associated with cognitive decline after CEA in patients without cerebral hyperperfusion after CEA. Brain magnetic resonance imaging (MRI) was performed preoperatively, and WMHs were graded according to the Fazekas scale in patients undergoing CEA for severe stenosis of the ipsilateral internal carotid. Diffusion-weighted MRI was performed before and after CEA to determine the development of PNILs. Neuropsychological testing was performed preoperatively and at 2 months postoperatively to determine the development of postoperative cognitive decline (PCD). In 142 patients without postoperative cerebral hyperperfusion, logistic regression analysis revealed that preoperative Fazekas scale of periventricular WMHs (PVWMHs) (95% confidence interval [CI]: 1.78-28.10; P = 0.0055) and PNILs in the eloquent areas (95% CI: 7.42-571.89; P = 0.0002) were significantly associated with PCD. The specificity and positive-predictive value for the prediction of PCD were significantly greater for the combination of preoperative Fazekas scale 2 or 3 of PVWMHs and PNILs in the eloquent areas than for each individually. Preoperative PVWMHs, PNILs in the eloquent areas, and the combination of both were associated with PCD in patients without cerebral hyperperfusion after CEA.
Asunto(s)
Estenosis Carotídea , Disfunción Cognitiva , Endarterectomía Carotidea , Sustancia Blanca , Humanos , Endarterectomía Carotidea/efectos adversos , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Estenosis Carotídea/etiología , Sustancia Blanca/diagnóstico por imagen , Imagen por Resonancia Magnética , Disfunción Cognitiva/etiología , Circulación CerebrovascularRESUMEN
An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.
Asunto(s)
Pueblos del Este de Asia , Neoplasias Esofágicas , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Consumo de Bebidas Alcohólicas/genética , Genotipo , Aldehído Deshidrogenasa Mitocondrial/genética , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/genética , Predisposición Genética a la EnfermedadRESUMEN
Bone fractures represent a common health problem, particularly in an increasingly aging population. Bioresorbable magnesium (Mg) alloy-based implants offer promising alternatives to traditional metallic implants for the treatment of bone fractures because they eliminate the need for implant removal after healing. The Mg-Y-rare-earth (RE)-Zr alloy WE43, designed for orthopedic implants, has received European Conformity mark approval. However, currently, WE43 is not clinically used in certain countries possibly because of concerns related to RE metals. In this study, we investigated the use of a RE-free alloy, namely, Mg-Zn-Zr alloy (ZK30), as an implant for bone fractures. Hydrofluoric acid (HF) treatment was performed to improve the corrosion resistance of ZK30. HF-treated ZK30 (HF-ZK30) exhibited lower corrosion rate and higher biocompatibility than those of WE43 in in vitro experiments. After implanting a rod of HF-ZK30 into the fractured femoral bones of mice, HF-ZK30 held the bones and healed the fracture without deformation. Treatment results of HF-ZK30 were comparable to those of WE43, indicating the potential of HF-ZK30 as a bioresorbable and safe implant for bone repair.
Asunto(s)
Implantes Absorbibles , Aleaciones , Magnesio , Animales , Magnesio/química , Magnesio/farmacología , Aleaciones/química , Ratones , Fluoruros/química , Corrosión , Ensayo de Materiales , Fracturas Óseas/terapia , Masculino , Materiales Biocompatibles/químicaRESUMEN
BACKGROUND: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.MethodsâandâResults: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis. CONCLUSIONS: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Embólico , Accidente Cerebrovascular , Humanos , Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/efectos adversos , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/efectos adversos , Resultado del TratamientoRESUMEN
Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.
Asunto(s)
Proteínas de Punto de Control Inmunitario , Leucemia Mieloide Aguda , Humanos , Nectinas , Proteínas de Punto de Control Inmunitario/metabolismo , Células Asesinas Naturales , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/metabolismo , Receptores Inmunológicos , Tratamiento Basado en Trasplante de Células y Tejidos , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/metabolismoRESUMEN
PURPOSE: Chemotherapy for the hemodialysis (HD) patient is a challenging situation because it requires special considerations including dose modifications and timing of drug administration in relation with HD sessions. Polaltuzumab vedotin (PV), an antibody-drug conjugate in which monomethyl auristatin E (MMAE) is linked to an anti-CD79b monoclonal antibody, is an extremely promising therapeutic for treating diffuse large B cell lymphoma (DLBCL), but the pharmacokinetics are unknown in HD patients. METHODS: We carried out pharmacokinetic studies of PV when administered at 1.2 mg/kg to a DLBCL patient on HD, and compared the results with that of non-HD patients. PV was administered in conjunction with bendamustine and rituximab. RESULTS: Serum concentration-time curves of both antibodyconjugated and unconjugated MMAE in the presented HD patient were similar compared to that of non-HD patients. We also demonstrate that elimination of both antibody-conjugated and unconjugated MMAE through HD is limited. PV administration at 1.2 mg/kg to an HD patient was also clinically feasible, and no signs of peripheral neuropathy were observed. CONCLUSIONS: PV therapy may be a relatively safe treatment method for DLBCL patients on HD.