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1.
ACS Omega ; 9(17): 19560-19565, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38708218

RESUMEN

The excellent emulsifying capacity of nanocellulose allows for the preparation of porous nanocellulose/polymer composites through the emulsion templating process. However, the effects of the polymer chemical structure and porosity on the material properties have not been extensively explored. Here, we discuss the effects of these two factors on the thermal and mechanical properties of the composites. Two types of porous nanocellulose/polymer composites were fabricated with styrene-divinylbenzene (poly(St-co-DVB)) or styrene-poly(ethylene glycol) dimethacrylate (poly(St-co-EGDMA)) copolymers as the polymer phases. The porosity of the composite was changed up to ∼50% v/v by varying the aqueous phase volume fraction in the original nanocellulose-stabilized w/o emulsions. As the porosity increased, the thermal conductivity of the composite decreased. The mechanical properties were strongly influenced by the polymer type; the nanocellulose/poly(St-co-DVB) composite showed stiff but brittle behavior, whereas the nanocellulose/poly(St-co-EGDMA) composite showed higher strength and toughness. In both types of composites, the nanocelluloses served as reinforcing agents, contributing to the improvement of the mechanical properties.

3.
Kyobu Geka ; 76(9): 714-718, 2023 Sep.
Artículo en Japonés | MEDLINE | ID: mdl-37735732

RESUMEN

A 53-year-old man presented to the emergency department with chest and back pain. Contrast-enhanced computed tomography( CT) revealed a Stanford type A acute aortic dissection with a pseudo-lumen occlusion. On the same day, the patient underwent emergent aortic arch replacement with frozen elephant trunk. When introducing cardiopulmonary bypass, arterial cannula was inserted into the right femoral artery. The day after surgery, swelling of the right lower leg appeared with CK and intramuscular compartment pressure elevation. Thus, the patient was diagnosed with compartment syndrome and decompressive fasciotomy was performed. Although there was no preoperative blood flow disturbance in the lower extremities on preoperative CT, lower limbs ischemia happened. Necrotic muscles in his right leg required debridement, but amputation was not needed. The patient was discharged unaided utilising orthotics on the day 120. In muscular, young male patients, care should be taken in the method of blood delivery.


Asunto(s)
Disección Aórtica , Síndromes Compartimentales , Humanos , Masculino , Persona de Mediana Edad , Síndromes Compartimentales/diagnóstico por imagen , Síndromes Compartimentales/etiología , Síndromes Compartimentales/cirugía , Pierna , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/cirugía , Puente Cardiopulmonar , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/cirugía
4.
Ann Rehabil Med ; 47(4): 300-306, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37644719

RESUMEN

OBJECTIVE: To evaluate the reliability and validity of this new measure, called the caregivers' fear of falling index (CFFI). METHODS: The study surveyed home-based rehabilitation patients with fall-related fracture, and their primary caregivers. The characteristics of these patients were evaluated, and the caregivers were surveyed using the CFFI and Falls Efficacy Scale-International (FES-I). The reliability of the CFFI was assessed using item-total correlation, while the validity of the CFFI was evaluated through correlation coefficients calculated between the CFFI and the FES-I. RESULTS: The participants were 51 patient-caregiver pairs. The internal consistency of the CFFI showed an alpha coefficient of 0.904. No items were excluded in the corrected item-total correlations. The CFFI showed a moderate correlation with FES-I (r=0.432, p=0.002). CONCLUSION: This study found the CFFI to be a reliable and valid tool for measuring the primary caregivers' fear. The CFFI may be a useful tool for healthcare professionals to identify and supporting these primary caregivers.

5.
Cell Transplant ; 32: 9636897231194497, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37646153

RESUMEN

Haploidentical-related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) and cord blood transplantation (CBT) are valid alternatives for patients with hematological malignancies when HLA-matched donor transplantation (MDT) is unavailable. However, the effects of graft-versus-host disease (GVHD) on outcomes after these transplants have not been fully elucidated. Therefore, we evaluated the effects of acute and chronic GVHD on transplant outcomes after PTCy-haplo transplants and compared them with CBT and MDT. We included a total of 914 adult patients with hematological malignancies in the Kyoto Stem Cell Transplantation Group registry who received PTCy-haplo (N = 120), CBT (N = 402), and MDT (N = 392), and achieved neutrophil engraftment. A multivariate analysis revealed that grade I-II acute GVHD improved of overall survival (OS) after PTCy-haplo [hazard ratio (HR) = 0.39, P = 0.018] and CBT (HR = 0.48, P < 0.001), but not after MDT (HR = 0.80, P = 0.267) compared with patients without acute GVHD. Grade I-II acute GVHD had a trend toward reducing the risk of nonrelapse mortality (NRM) after PTCy-haplo (HR = 0.13, P = 0.060) and this positive effect was significant after CBT (HR = 0.39, P = 0.003). A negative impact of grade III-IV acute GVHD on NRM was observed after CBT and MDT, but not after PTCy-haplo. Limited chronic GVHD had a positive impact on OS after CBT and MDT, but not after PTCy-haplo. In conclusion, mild acute GVHD improved outcomes after PTCy-haplo and CBT, and limited chronic GVHD improved outcomes after CBT and MDT. These data indicated that the effects of GVHD on transplant outcomes depended on transplant platforms.


Asunto(s)
Síndrome de Bronquiolitis Obliterante , Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Ciclofosfamida/uso terapéutico , Ciclofosfamida/farmacología , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/terapia , Acondicionamiento Pretrasplante , Estudios Retrospectivos
6.
Gastric Cancer ; 26(1): 44-54, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36094595

RESUMEN

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated. METHODS: We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes. RESULTS: Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P < 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells. CONCLUSIONS: Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.


Asunto(s)
Adenocarcinoma , Neoplasias Gástricas , Humanos , Factor Nuclear Tiroideo 1/genética , Genes Homeobox , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Perfilación de la Expresión Génica
7.
Prog Rehabil Med ; 8: 20230046, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38162288

RESUMEN

Objectives: To evaluate caregivers' fear of post-fracture patients falling, we previously developed the Caregivers' Fear of Falling Index (CFFI). In this study, we investigated the relationship between patient performance in activities of daily living (ADLs) and CFFI. Methods: We surveyed 55 patients receiving home-visit rehabilitation after fall-related fracture and their primary caregivers. Participants (patient and caregiver pair) were divided into two groups based on patient performance in basic ADLs (BADLs) and instrumental ADLs (IADLs). ROC analysis was conducted to assess the usefulness of CFFI and Falls Efficacy Scale-International (FES-I) in determining declines in performance in BADLs and IADLs. Multivariate logistic regression analysis was performed to examine the association between CFFI and declining performance in BADLs and IADLs. Results: ROC analysis showed that CFFI exhibited a higher accuracy than FES-I (AUC: 0.73 in BADLs, 0.77 in IADLs) as an indicator of reduced ADL performance. Multivariate logistic analysis adjusted for age, sex, and physical function showed that CFFI was associated with a decline in patients' performance in IADLs (odds ratio, 0.92; 95% confidence interval, 0.85-0.99). Conclusions: Caregivers' fear of post-fracture patients falling was associated with a decline in patients' performance in IADLs. These findings may serve as a guide for supporting caregivers of post-fracture patients.

8.
Digestion ; 103(6): 411-420, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36075194

RESUMEN

INTRODUCTION: Helicobacter pylori eradication is expected to significantly change the prevalence of Barrett's esophagus (BE). However, few reports on this relationship exist. We analyzed the risk factors of BE using the current consensus on length of BE considering H. pylori infection status. METHODS: We analyzed 10,122 individuals (5,962 men; mean age = 52.9 ± 9.9 years) who had undergone esophagogastroduodenoscopy as part of a medical checkup. Correlations among factors including H. pylori infectious status, endoscopic findings, and BE ≥1 cm were analyzed. RESULTS: Prevalence of BE, long-segment BE, and esophageal adenocarcinoma was 22.5%, 0.014%, and 0%, respectively. Logistic regression analysis showed that the risk factors for BE were hiatal hernia (odds ratio [OR]: 2.89 [2.59-3.24]), female sex (OR: 0.52 [0.46-0.59]), social drinking (OR:0.77 [0.68-0.87]), H. pylori eradication therapy (OR: 1.34 [1.19-1.51]), proton pump inhibitor (PPI) use (OR: 1.52 [1.18-1.96]), bile reflux (OR: 1.18 [1.04-1.33]), age ≥50 years (OR: 1.13 [1.02-1.26]), and nonsteroidal anti-inflammatory drug (NSAID) use (OR: 1.29 [1.02-1.62]). Although reflux esophagitis (RE) was more common in H. pylori-negative patients (17.2%) than in those after H. pylori eradication therapy (11.8%, p < 0.00001), the latter was correlated with BE, disputing RE as a strong risk factor for BE. Therefore, we conducted a subgroup analysis; most of the risk factors except for PPI use (p = 0.75), H2-receptor antagonist use (p = 0.078), and atrophic gastritis absence (p = 0.72) were positively correlated with BE after H. pylori eradication therapy compared with H. pylori-negative status. CONCLUSIONS: H. pylori eradication, bile reflux, PPI use, and NSAID use were risk factors for BE along with hiatal hernia, male sex, and older age.


Asunto(s)
Esófago de Barrett , Reflujo Biliar , Esofagitis Péptica , Infecciones por Helicobacter , Helicobacter pylori , Hernia Hiatal , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Esófago de Barrett/diagnóstico , Esófago de Barrett/epidemiología , Estudios Transversales , Hernia Hiatal/epidemiología , Reflujo Biliar/complicaciones , Reflujo Biliar/tratamiento farmacológico , Japón/epidemiología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Esofagitis Péptica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Factores de Riesgo
9.
Int J Rehabil Res ; 45(4): 366-369, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-35942635

RESUMEN

This study aimed to identify evaluation items that can be used to create an index to evaluate caregivers' fear of care recipient falls. A three-round Delphi method was conducted with medical professionals engaged in discharge support for patients with fall-related fractures. In the first round, a working group brainstormed evaluation items. In the second and third rounds, opinions of medical professionals were quantified and evaluation items were refined. The Delphi method showed convergence of opinion with Kendall's W of 0.561 in the third round. Of the 109 evaluation items pooled in the first round, the consensus was reached on the importance of 19 items and one more item was additionally included. The 20 items may be useful for creating an index that sensitively measures caregivers' fear of care recipient falls.


Asunto(s)
Cuidadores , Miedo , Humanos , Técnica Delphi , Encuestas y Cuestionarios
10.
Sci Rep ; 12(1): 8349, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35589745

RESUMEN

This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or < 20 mm), shape (depression or non-depression), and color (red or non-red) were extracted. Fourteen endoscopists diagnosed adenoma or cancer in the 100 cases with conventional white light imaging (C-WLI), then did the same with C-WLI + M-NBI.The cancer diagnostic sensitivity, specificity, and accuracy were assessed. The sensitivity of C-WLI + M-NBI for cancer diagnosis was 79.9% compared to 71.6% with C-WLI (p < 0.001). There were no significant differences in specificity (40.1% vs. 36.3%, p = 0.296) and accuracy (55.9% vs. 58.1%, p = 0.163). High-grade cytological or architectural atypia was diagnosed more often with irregular microvascular pattern (IMVP) or microsurface pattern (IMSP), respectively, than the low-grade forms. In conclusion, IMVP and IMSP correlate with high-grade cytological and architectural atypia. M-NBI is useful in differentiating intramucosal carcinoma from adenoma and can reduce underdiagnosis of cancer.


Asunto(s)
Adenocarcinoma , Adenoma , Neoplasias Gástricas , Adenocarcinoma/diagnóstico por imagen , Adenoma/diagnóstico por imagen , Adenoma/patología , Endoscopía Gastrointestinal/métodos , Humanos , Imagen de Banda Estrecha/métodos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología
11.
Surg Endosc ; 36(9): 6387-6395, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-34997343

RESUMEN

BACKGROUND: Endoscopic submucosal dissection (ESD) is one of the main methods of treatments for early gastric cancer. Sarcopenia is a known risk factor for postoperative adverse events; however, the effect of sarcopenia on gastric ESD is unclear. We investigated the impact of sarcopenia on short-term prognosis after gastric ESD. METHODS: This was a retrospective cohort study. We reviewed 832 patients who underwent gastric ESD between January 2015 and December 2019 and classified them into two groups: sarcopenia and non-sarcopenia groups. The curative resection rate, adverse events, and lengths of hospital stay were evaluated. We also evaluated risk factors associated with adverse events. RESULTS: 700 patients were analyzed (239 in the sarcopenia group and 461 in the non-sarcopenia group). The curative resection rates were similar in both groups. Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 (17% vs. 10%) were significantly more common, and the length of hospital stay was longer (8 vs. 7 days) in the sarcopenia group. Univariate analysis identified age ≥ 75 years, antithrombotic medication, history of gastric surgery, submucosal (SM) invasion, and sarcopenia as risk factors for CTCAE grade ≥ 2. Multivariate analysis showed that sarcopenia [odds ratio (OR) 1.79, 95% confidence interval (CI) 1.11-2.89, p = 0.016], history of gastric surgery (OR 9.32, 95% CI 1.97-44.05, p = 0.005), and SM invasion (OR 2.14, 95% CI 1.24-3.70, p = 0.006) were significant independent risk factors. CONCLUSIONS: Sarcopenia significantly affected short-term prognosis and is a novel risk factor for gastric ESD.


Asunto(s)
Resección Endoscópica de la Mucosa , Sarcopenia , Neoplasias Gástricas , Anciano , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Humanos , Estudios Retrospectivos , Sarcopenia/complicaciones , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/cirugía , Resultado del Tratamiento
12.
Mol Cell Biol ; 42(1): e0002421, 2022 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-34748402

RESUMEN

A germ line copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP, was identified in families with myeloproliferative neoplasm (MPN). Here, we show that mice lacking both Atg2b and Gskip, but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP, the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double-knockout fetal livers was significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Proteínas Represoras/genética , Proteínas de Transporte Vesicular/genética , Animales , Autofagia/fisiología , Proteínas Relacionadas con la Autofagia/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Cromosomas/genética , Hematopoyesis/fisiología , Ratones , Proteínas Represoras/metabolismo , Proteínas de Transporte Vesicular/metabolismo
13.
Medicine (Baltimore) ; 101(49): e32115, 2022 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-36626416

RESUMEN

The objective of this study was to evaluate the long-term prognosis of T1a-MM/T1b-SM 1 esophageal squamous cell carcinoma (ESCC) after endoscopic resection (ER) and to validate the follow-up policy for pT1a-MM lymphovascular invasion (LVI)-negative ESCC. In this retrospective single-center analysis, patients who underwent ER for superficial ESCC between April 2002 and June 2021 were identified. The overall survival (OS), metastatic recurrence, and recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method. Cox proportional hazards models for OS, metastatic recurrence, and RFS were used. A total of 104 ESCC patients were eligible for the analysis. Of 104 patients, 81 had pT1a-MM, and 23 had pT1b-SM1. The 5-year OS, RFS, and metastatic recurrence rates of the 56 cases of pT1a-MM LVI-negative ESCC without additional treatment were 0.848 (95% confidence interval [CI]: 0.687-0.931), 0.817 (95% CI: 0.647-0.911), and 0.061 (95% CI: 0.014-0.240), respectively. Cox regression analysis for OS, RFS, and metastatic recurrence showed that only lymphatic invasion was strongly associated with metastatic recurrence (adjusted hazard ratio, 10.3; 95% CI: 2.01-53.3; P = .005). The proportion of deaths from other diseases was considerably higher (17/104, 16.3%) than that from ESCC (2/104, 1.9%). This may be related to the high complication rate of malignant tumors in other organs (43.3%, 45/104). The prognosis of ER for pT1a-MM and LVI-negative ESCC is good, and the follow-up policy is valid. Malignant tumors in other organs may be a major prognostic factor for superficial ESCC after ER.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/patología , Estudios Retrospectivos , Estadificación de Neoplasias , Pronóstico , Esofagectomía/métodos
14.
Nat Commun ; 12(1): 16, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397898

RESUMEN

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.


Asunto(s)
Autofagosomas/metabolismo , Estrés Oxidativo , Proteína Sequestosoma-1/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagosomas/ultraestructura , Autofagia , Línea Celular , Geles , Hepatocitos/metabolismo , Hepatocitos/ultraestructura , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Hígado/lesiones , Hígado/patología , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Unión Proteica , Liposomas Unilamelares
15.
DEN Open ; 1(1): e9, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35310152

RESUMEN

Objectives: The natural history of sporadic non-ampullary duodenal epithelial tumors (SNADETs) is poorly documented. The aim of this study was to evaluate the history of SNADETs in patients where immediate resection could not be performed. Methods: This is a single-center retrospective study of 86 consecutive cases of SNADETs who did not undergo immediate resection and were followed-up with upper gastrointestinal endoscopy for more than 6 months. Results: During a follow-up period of 36.8 (6.0-613.0) months, macroscopic progression was admitted in eight (9.3%). Of these, the final histology in four was adenocarcinoma, and three cases demonstrated submucosal invasion. Rates of macroscopic progression at 150 months after detection were 11.1%, 16.7%, and 30.0% for SNADETs <5 mm, <10 mm, and ≥10 mm, respectively. Conclusion: The overall risk of SNADETs progressing to invasive cancer is low. However, changes in macroscopic size or shape of SNADETs signify a high risk of progression to invasive cancer.

16.
Front Cell Dev Biol ; 8: 577342, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33102484

RESUMEN

Membrane tethering is a crucial step to determine the spatiotemporal specificity of secretory and endocytic trafficking pathways in all eukaryotic endomembrane systems. Recent biochemical studies by a chemically-defined reconstitution approach reveal that, in addition to the structurally-diverse classic tethering factors such as coiled-coil tethering proteins and multisubunit tethering complexes, Rab-family small GTPases also retain the inherent membrane tethering functions to directly and physically bridge two distinct lipid bilayers by themselves. Although Rab-mediated membrane tethering reactions are fairly efficient and specific in the physiological context, its mechanistic basis is yet to be understood. Here, to explore whether and how the intrinsic tethering potency of Rab GTPases is controlled by their C-terminal hypervariable region (HVR) domains that link the conserved small GTPase domains (G-domains) to membrane anchors at the C-terminus, we quantitatively compared tethering activities of two representative Rab isoforms in humans (Rab5a, Rab4a) and their HVR-deleted mutant forms. Strikingly, deletion of the HVR linker domains enabled both Rab5a and Rab4a isoforms to enhance their intrinsic tethering potency, exhibiting 5- to 50-fold higher initial velocities of tethering for the HVR-deleted mutants than those for the full-length, wild-type Rabs. Furthermore, we revealed that the tethering activity of full-length Rab5a was significantly reduced by the omission of anionic lipids and cholesterol from membrane lipids and, however, membrane tethering driven by HVR-deleted Rab5a mutant was completely insensitive to the headgroup composition of lipids. Reconstituted membrane tethering assays with the C-terminally-truncated mutants of Rab4a further uncovered that the N-terminal residues in the HVR linker, located adjacent to the G-domain, are critical for regulating the intrinsic tethering activity. In conclusion, our current findings establish that the non-conserved, flexible C-terminal HVR linker domains define membrane tethering potency of Rab-family small GTPases through controlling the close attachment of the globular G-domains to membrane surfaces, which confers the active tethering-competent state of the G-domains on lipid bilayers.

17.
Blood Adv ; 4(13): 3169-3179, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32658984

RESUMEN

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, so far, no large cohort study determined the risk factors and the most effective therapeutic strategies for TA-TMA. Thus, the present study aimed to clarify these clinical aspects based on a large multicenter cohort. This retrospective cohort study was performed by the Kyoto Stem Cell Transplantation Group (KSCTG). A total of 2425 patients were enrolled from 14 institutions. All patients were aged ≥16 years, presented with hematological diseases, and received allo-HSCT after the year 2000. TA-TMA was observed in 121 patients (5.0%) on day 35 (median) and was clearly correlated with inferior overall survival (OS) (hazard ratio [HR], 4.93). Pre- and post-HSCT statistically significant risk factors identified by multivariate analyses included poorer performance status (HR, 1.69), HLA mismatch (HR, 2.17), acute graft-versus-host disease (aGVHD; grades 3-4) (HR, 4.02), Aspergillus infection (HR, 2.29), and veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS; HR, 4.47). The response rate and OS significantly better with the continuation or careful reduction of calcineurin inhibitors (CNI) than the conventional treatment strategy of switching from CNI to corticosteroids (response rate, 64.7% vs 20.0%). In summary, we identified the risk factors and the most appropriate therapeutic strategies for TA-TMA. The described treatment strategy could improve the outcomes of patients with TA-TMA in the future.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Microangiopatías Trombóticas , Anciano , Estudios de Cohortes , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Retrospectivos , Factores de Riesgo , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/terapia
18.
Int J Hematol ; 112(2): 265, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32596795

RESUMEN

M. Nishikori receives honoraria from Eisai and funding from Eisai and Sumitomo Dainippon Pharmaceutical.

19.
Fukushima J Med Sci ; 66(1): 17-24, 2020 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-32281584

RESUMEN

Autophagy is an essential intracellular self-degradation system, and is known to maintain the homeostatic balance between the synthesis, degradation, and recycling of cellular proteins and organelles. Recent studies have suggested a possible role of autophagy in systemic sclerosis (SSc);however, differences in autophagy among pathological phases of SSc have not yet been examined. Therefore, in the current study we investigated the expression pattern of an autophagosome marker protein, microtubule-associated protein 1 light chain 3 (LC3) in the lesional skin of a murine model and human SSc. In bleomycin-induced mouse scleroderma skin, the number of LC3-positive puncta was significantly higher than that in phosphate buffered salts-injected control skin after 4 weeks of treatment. Such an increase, however, was not observed in the skin after 2 weeks of bleomycin treatment, in which few myofibroblasts were detected. In the sclerotic phase of SSc patients, the number of LC3-positive puncta in the lower dermis was significantly higher than in the upper dermis. It was also significantly higher than in the lower dermis of the control patients. No increase in LC3-positive puncta was observed in the skin from SSc patients in edematous phase, in which myofibroblasts were hardly detected. These results suggest that changes in the autophagic degradation system reflect a skin remodeling process that leads to fibrosis.


Asunto(s)
Autofagia/fisiología , Esclerodermia Sistémica/patología , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/análisis , Persona de Mediana Edad , Esclerodermia Sistémica/metabolismo , Esclerosis , Piel/química
20.
Int J Hematol ; 111(5): 724-732, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31894535

RESUMEN

Mucosa-associated lymphoid tissue (MALT) lymphoma with t(11;18)(q21;q21), resulting in an API2-MALT1 fusion transcript, is reported to rarely transform into aggressive lymphoma. Here, we report the clinical course of a patient who experienced histologic transformation after 20 years' disease history of t(11;18)-positive MALT lymphoma. The patient suddenly developed a large intrapelvic mass and ascites with a rapid increase in lactate dehydrogenase. Cytology of the ascites detected large abnormal cells, and flow cytometric analysis revealed that the cells were positive for cytoplasmic CD3, CD4, and CD38, and partially positive for CD7, but negative for CD19 and CD20. Antigen receptor gene rearrangement analysis and in situ hybridization of the immunoglobulin light chains confirmed that the tumor cells were of B-cell lineage. Chromosomal analysis showed complex karyotypes with intraclonal variation, and in addition to t(11;18), t(8;14) and heterozygous loss of the TP53 were demonstrated. Although histological and phenotypic features were significantly altered from the original MALT lymphoma, the presence of t(11;18) led us to the diagnosis of histologic transformation of MALT lymphoma. Although transformation of t(11;18)-positive MALT lymphoma into aggressive lymphoma is extremely rare, it may occur, probably with additional genetic abnormalities such as cMYC rearrangement and/or the loss of TP53.


Asunto(s)
Antígenos CD , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 11/genética , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Translocación Genética , Humanos , Linfoma de Células B de la Zona Marginal/inmunología , Linfocitos T/inmunología , Proteína p53 Supresora de Tumor/genética
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