Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 78
Filtrar
1.
Kidney Int ; 105(3): 608-617, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38110152

RESUMO

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.


Assuntos
Glomerulosclerose Segmentar e Focal , Transplante de Rim , Humanos , Criança , Glomerulosclerose Segmentar e Focal/patologia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Proteínas de Membrana/genética , Imunoglobulina G , Recidiva
2.
Int J Clin Oncol ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833113

RESUMO

BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001). CONCLUSION: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

3.
Int J Urol ; 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822642

RESUMO

OBJECTIVES: To identify risk factors for the long-term persistent genitourinary toxicity (GUT) after stereotactic body radiation therapy (SBRT) for localized prostate cancer (PCa). METHODS: A total of 306 patients who underwent SBRT at our institution between March 2017 and April 2022 were retrospectively evaluated. SBRT was performed at 35 Gy in five fractions over 5 or 10 days. Factors related to the long-term persistence of acute GUT after SBRT were analyzed. RESULTS: During the median follow-up period of 39.1 months, 203 (66%) patients experienced any grade of acute GUT, which remained in 78 (26%) patients 6 months after SBRT. Multivariate analysis revealed that age ≥75 years was consistently a significant independent risk factor for any grade of acute GUT 6, 12, and 24 months after SBRT (hazard ratio [HR] 2.31, p = 0.010; HR 2.84, p = 0001; and HR 3.05, p = 0.009, respectively). Older age was not a significant risk factor for the development of grade ≥2 acute GUT. The duration of acute GUT was significantly longer in the older group than in the nonolder group (median duration = 234 vs. 61 days, p < 0.001), and the incidence of persistent GUT was significantly more frequent in the older group beyond 6 months after SBRT. CONCLUSIONS: Older age is a significant independent risk factor for the long-term persistent GUT after SBRT for localized PCa.

4.
Int J Urol ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39010666

RESUMO

OBJECTIVES: To evaluate the clinical characteristics of oligometastatic disease (OMD) in metastatic urothelial carcinoma (mUC) with visceral metastases when classified into synchronous and metachronous metastases. METHODS: Of 957 cases of de novo mUC treated between 2008 and 2023, 374 with visceral metastases were analyzed. Cases were classified into OMD with up to three metastatic lesions and polymetastatic disease (PMD), and into synchronous and metachronous metastases. The clinical characteristics and overall survival (OS) for each group were analyzed. RESULTS: Overall, 196 (52.4%) had synchronous metastasis and 178 (47.6%) had metachronous metastasis. Median OS for synchronous metastases was significantly shorter than for metachronous metastases (12.1 months vs. 15.3 months, p = 0.011). Among the synchronous metastases, 48 (24.5%) were OMD and 148 (75.6%) were PMD. There was no significant difference in OS between the OMDs and PMDs (median 14.9 months vs. 11.7 months, p = 0.32), and only decreased albumin level was identified as a significant predictor of poor OS. Among the metachronous metastases, 64 (36.0%) were OMD and 114 (64.0%) were PMD. There was no significant difference in OS between the OMD and PMD (median 21.2 months vs. 15.0 months, p = 0.35), and no significant predictors of poor OS were identified. CONCLUSIONS: For mUC with visceral metastases, the timing of metastasis appearance was associated with prognosis, with synchronous metastases being a poorer prognostic factor compared to metachronous metastases. There was no prognostic difference between OMD and PMD with visceral metastases when classified into synchronous or metachronous metastases.

5.
BMC Cancer ; 23(1): 940, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37798659

RESUMO

BACKGROUND: This study aimed to identify patients with upper urinary tract urothelial carcinoma (UTUC) having potential Lynch syndrome (pLS) by immunohistochemistry (IHC) of DNA mismatch repair gene-related proteins (MMRPs) and Amsterdam criteria II and explore their clinical characteristics. METHODS: We retrospectively collected the clinical data of 150 consecutive patients with UTUC who underwent surgical resection at our institution between February 2012 and December 2020, and immunohistochemistry (IHC) of four MMRPs (MLH1, MSH2, MSH6, and PMS2) on all UTUC specimens was performed. Patients who tested positive for Amsterdam criteria (AMS) II and/or IHC screening were classified as having pLS and others as non-pLS, and their characteristics were explored. RESULTS: In this study, 5 (3%) and 6 (4%) patients were positive for AMS II and IHC screening, respectively. Two patient were positive for both AMS II and IHC screening, resulting in 9 (6%) patients with pLS. The pLS group was predominantly female (67% vs. 36%; p = 0.0093) and had more right-sided tumors (100% vs. 43%; p = 0.0009) than the non-pLS group. Of the 6 patients who were positive for IHC screening, 4 showed a combined loss of MSH2/MSH6 (n = 3) and MLH1/PMS2 (n = 1). Other two patients showed single loss of MSH6 and PSM2. CONCLUSIONS: AMS II and IHC screening identified pLS in 6% of patients with UTUC. The IHC screening-positive group tends to have relatively high rate of combined loss, but some patients have single loss. AMS II may overlook patients with LS, and a universal screening may be required for patients with UTUC as well as those with colorectal and endometrial cancer.


Assuntos
Carcinoma de Células de Transição , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Renais , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Sistema Urinário , Humanos , Feminino , Masculino , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/epidemiologia , Carcinoma de Células de Transição/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Estudos Retrospectivos , Prevalência , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Neoplasias Ureterais/diagnóstico , Neoplasias Ureterais/epidemiologia , Sistema Urinário/metabolismo , Sistema Urinário/patologia , Reparo de Erro de Pareamento de DNA
6.
BMC Urol ; 22(1): 145, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071427

RESUMO

BACKGROUND: We assess whether short-term recovery of urinary incontinence following robot-assisted laparoscopic radical prostatectomy (RARP) is associated with postoperative membranous urethral length (MUL) and position of vesico-urethral anastomosis (PVUA). METHODS: Clinical variables including PVUA and pre-and postoperative MUL were evaluated in 251 patients who underwent RARP from August 2019 to February 2021. Continence recovery was defined as no pad or one security liner per day assessed by patient interview at least 6 months follow-up. Univariate and multivariate logistic regression analyses were used to assess variables associated with continence recovery at 3 months after the operation. RESULTS: Continence recovery rates at 3 and 6 months were 75% and 84%, respectively. Lower BMI (< 25 kg/m2) (p = 0.040), longer preoperative MUL (≥ 9.5 mm) (p = 0.013), longer postoperative MUL (≥ 9 mm) (p < 0.001), higher PVUA (< 14.5 mm) (p = 0.019) and shorter operating time (< 170 min) (p = 0.013) were significantly associated with continence recovery at 3 months in univariate analysis. Multivariate analysis revealed that postoperative MUL (OR 3.75, 95% CI 1.90-7.40, p < 0.001) and higher PVUA (OR 2.02, 95% CI 1.07-3.82, p = 0.032) were independent factors for continence recovery. Patients were divided into 3 groups based on the multivariate analysis, with urinary continence recovery rates found to have increased in turn with rates of 43.7% versus 68.2% versus 85.0% (p < 0.001) at 3 months. CONCLUSIONS: PVUA and postoperative MUL were significant factors for short-term continence recovery. Preservation of urethral length might contribute to continence recovery after RARP.


Assuntos
Laparoscopia , Robótica , Anastomose Cirúrgica , Humanos , Masculino , Prostatectomia/efeitos adversos , Recuperação de Função Fisiológica
7.
Pediatr Surg Int ; 39(1): 21, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36449115

RESUMO

PURPOSE: Total parenteral nutrition causes liver damage in patients with short bowel syndrome (SBS), in whom intestinal failure-associated liver disease (IFALD) is the strongest risk factor for mortality. We previously demonstrated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4-Is) for nutritional absorption and intestinal barrier function enhancement. Herein, we investigated the efficacy of DPP4-Is in preventing liver damage in SBS rat models. METHODS: Rats were allocated to one of five groups: normal saline (NS) + sham, DPP4-I + sham, NS + SBS, DPP4-I + SBS, and GLP-2 + SBS. DPP4-I or NS was administered orally once daily. Serum aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, and total bile acid levels were measured to assess liver function. Moreover, we evaluated liver damage using the SAF (steatosis activity fibrosis) score, which is also used to assess nonalcoholic steatohepatitis. RESULTS: ALT levels and SAF scores were significantly lower in the DPP4-I + SBS group than in the NS + SBS group. Jejunal and ileal villus heights were significantly higher in the DPP4-I + SBS group than in the GLP-2 + SBS group. CONCLUSIONS: The downregulation of ALT levels and SAF scores triggered by DPP4-I use may be correlated with DPP4-I-induced adiposis inhibition in SBS and NASH models. Therefore, DPP4-I may be used to reduce IFALD in patients with SBS.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Falência Hepática , Hepatopatia Gordurosa não Alcoólica , Síndrome do Intestino Curto , Ratos , Animais , Síndrome do Intestino Curto/complicações , Síndrome do Intestino Curto/tratamento farmacológico , Dipeptidil Peptidase 4 , Peptídeo 2 Semelhante ao Glucagon , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico
8.
Traffic ; 20(1): 82-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30426618

RESUMO

Phosphatidylinositol 4-phophate (PtdIns(4)P) is an essential signaling molecule in the Golgi body, endosomal system, and plasma membrane and functions in the regulation of membrane trafficking, cytoskeletal organization, lipid metabolism and signal transduction pathways, all mediated by direct interaction with PtdIns(4)P-binding proteins. PtdIns(4)P was recently reported to have functional roles in autophagosome biogenesis. LC3 and GABARAP subfamilies and a small GTP-binding protein, Rab7, are localized on autophagosomal membranes and participate at each stage of autophagosome formation and maturation. To better understand autophagosome biogenesis, it is essential to determine the localization of PtdIns(4)P and to examine its relationship with LC3 and GABARAP subfamilies and Rab7. To analyze PtdIns(4)P distribution, we used an electron microscopy technique that labels PtdIns(4)P on the freeze-fracture replica of intracellular biological membranes, which minimizes the possibility of artificial perturbation because molecules in the membrane are physically immobilized in situ. Using this technique, we found that PtdIns(4)P is localized on the cytoplasmic, but not the luminal (exoplasmic), leaflet of the inner and outer membranes of autophagosomes. Double labeling revealed that PtdIns(4)P mostly colocalizes with Rab7, but not with LC3B, GABARAP, GABARAPL1 and GABARAPL2. Rab7 plays essential roles in autophagosome maturation and in autophagosome-lysosome fusion events. We suggest that PtdIns(4)P is localized to the cytoplasmic leaflet of the autophagosome at later stages, which may illuminate the importance of PtdIns(4)P at the later stages of autophagosome formation.


Assuntos
Autofagossomos/ultraestrutura , Técnica de Fratura por Congelamento/métodos , Fosfatidilinositóis/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose , Autofagossomos/metabolismo , Linhagem Celular Tumoral , Humanos , Membranas Intracelulares/metabolismo , Membranas Intracelulares/ultraestrutura , Proteínas Associadas aos Microtúbulos/metabolismo , proteínas de unión al GTP Rab7
9.
Histochem Cell Biol ; 156(2): 109-121, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34052862

RESUMO

Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is generated through phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P) by Mss4p, the only PtdIns phosphate 5-kinase in yeast cells. PtdIns(4,5)P2 is involved in various kinds of yeast functions. PtdIns(4)P is not only the immediate precursor of PtdIns(4,5)P2, but also an essential signaling molecule in the plasma membrane, Golgi, and endosomal system. To analyze the distribution of PtdIns(4,5)P2 and PtdIns(4)P in the yeast plasma membrane at a nanoscale level, we employed a freeze-fracture electron microscopy (EM) method that physically immobilizes lipid molecules in situ. It has been reported that the plasma membrane of budding yeast can be divided into three distinct areas: furrowed, hexagonal, and undifferentiated flat. Previously, using the freeze-fracture EM method, we determined that PtdIns(4)P is localized in the undifferentiated flat area, avoiding the furrowed and hexagonal areas of the plasma membrane. In the present study, we found that PtdIns(4,5)P2 was localized in the cytoplasmic leaflet of the plasma membrane, and concentrated in the furrowed area. There are three types of PtdIns 4-kinases which are encoded by stt4, pik1, and lsb6. The labeling density of PtdIns(4)P in the plasma membrane significantly decreased in both pik1ts and stt4ts mutants. However, the labeling densities of PtdIns(4,5)P2 in the plasma membrane of both the pik1ts and stt4ts mutants were comparable to that of the wild type yeast. These results suggest that PtdIns(4)P produced by either Pik1p or Stt4p is immediately phosphorylated by Mss4p and converted to PtdIns(4,5)P2 at the plasma membrane.


Assuntos
Membrana Celular/química , Fosfatidilinositol 4,5-Difosfato/análise , Saccharomycetales/química , 1-Fosfatidilinositol 4-Quinase/metabolismo , Membrana Celular/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/metabolismo
10.
Phytopathology ; 111(6): 990-1000, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32910743

RESUMO

Scab caused by Venturia nashicola is one of the most serious diseases of Asian pears, including Japanese pear (Pyrus pyrifolia var. culta) and Chinese pears (P. bretschneideri and P. ussuriensis). Breeding scab-resistant pear cultivars is essential to minimize fungicide use and development of fungicide resistance. A survey of pathogenic specialization in V. nashicola is needed to ensure durable scab resistance in cultivated pears. V. nashicola race 1, 2, and 3 isolates, each differing in pathogenicity to Japanese pear cultivar Kousui and Asian pear strain Mamenashi 12, have been reported in Japan. In this study, isolates collected from scabbed pears in China and Taiwan were classified as V. nashicola based on conidial size and mating ability. However, various isolates had pathogenicity distinct from races 1, 2, and 3 according to tests on seven differential host genotypes of pear cultivars from Japan (Kousui and strain Mamenashi 12), China (Jingbaili, Yali, Linyuli, and Nanguoli), and Taiwan (Hengshanli). These new races were designated as races 4 to 7. Progenies characteristic of race 3 isolates were produced using a cross between race 1 and race 2 isolates, suggesting the possible role of sexual recombination in the emergence of novel races. Japanese pear cultivar Kinchaku and Chinese P. sinkiangensis 'Xiangli' (a Korla fragrant pear grown in China) did not show visible symptoms after inoculation with any of the seven races. Broad scab resistance in Kinchaku and Xiangli makes them a promising genetic resource for resistance breeding programs.


Assuntos
Ascomicetos , Pyrus , Fungos do Gênero Venturia , Melhoramento Vegetal , Doenças das Plantas
11.
Paediatr Anaesth ; 31(1): 61-67, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33185306

RESUMO

In this article, we review the potential for adverse impacts on the clinician following a medical error or poor clinical outcome. Second victim syndrome, its symptoms, risk factors, natural history, and possible outcomes are described. We also discuss the important role of organizational leadership and culture and highlight possible programmatic interventions designed to support clinicians following an adverse event.


Assuntos
Cuidadores , Erros Médicos , Humanos , Liderança
12.
Biochim Biophys Acta ; 1858(6): 1298-305, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26972044

RESUMO

Phosphatidylinositol 4-phosphate [PtdIns(4)P] is the immediate precursor of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], which is localized to the cytoplasmic leaflet of the plasma membrane and has been reported to possess multiple cell biological functions. Direct evidence showing the distribution of PtdIns(4)P pools at a nanoscale when the plasma membrane PtdIns(4,5)P2 is hydrolyzed by agonist stimulation is lacking. To analyze the distribution of PtdIns(4)P at a nanoscale, we employed an electron microscopy technique that specifically labels PtdIns(4)P on the freeze-fracture replica of the plasma membrane. This method minimizes the possibility of artificial perturbation, because molecules in the membrane are physically immobilized in situ. Using this technique, we observed no PtdIns(4)P in the caveolae of normal cultured human fibroblasts, although PtdIns(4,5)P2 has been shown to be highly concentrated in them in our previous report. When cells were stimulated with angiotensin II, the level of PtdIns(4)P in the undifferentiated membrane transiently decreased to 64.3% at 10 s, began to increase at 30 s and largely increased to 341.9% at 40 s, and then returned to the initial level at 130 s after the stimulation. Interestingly, PtdIns(4)P localized at the caveolae at 70 and 130 s after the stimulation. These results suggest that the level of the PtdIns(4)P pool in the plasma membrane is sensitive and the distribution of PtdIns(4)P dramatically changes by agonist stimulation, and there are active sites of production or replenishment of PtdIns(4)P at undifferentiated membrane and caveolar areas.


Assuntos
Nanotecnologia , Fosfatos de Fosfatidilinositol/metabolismo , Angiotensina II/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células HeLa , Humanos , Microscopia de Fluorescência
13.
Biochim Biophys Acta Biomembr ; 1859(10): 1880-1890, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28648675

RESUMO

Phosphatidylinositol 4-phosphate (PtdIns(4)P) is the immediate precursor of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), which is located on the cytoplasmic leaflet of the plasma membrane and has been reported to possess multiple cellular functions. Although PtdIns(4)P and PtdIns(4,5)P2 have been reported to localize to multiple intracellular compartments and to each function as regulatory molecules, their generation, regulation and functions in most intracellular compartments are not well-defined. To analyze PtdIns(4)P and PtdIns(4,5)P2 distributions, at a nanoscale, we employed an electron microscopy technique that specifically labels PtdIns(4)P and PtdIns(4,5)P2 on the freeze-fracture replica of intracellular biological membranes. This method minimizes the possibility of artificial perturbation, because molecules in the membrane are physically immobilized in situ. Using this technique, we found that PtdIns(4)P was localized to the cytoplasmic leaflet of Golgi apparatus and vesicular-shaped structures. The PtdIns(4,5)P2 labeling was observed in the cytoplasmic leaflet of the mitochondrial inner membrane and vesicular-shaped structures. Double labeling of PtdIns(4)P and PtdIns(4,5)P2 with endosome markers illustrated that PtdIns(4)P and PtdIns(4,5)P2 were mainly localized to the late endosome/lysosome and early endosome, respectively. PtdIns(4)P and PtdIns(4,5)P2 were colocalized in some endosomes, with the two phospholipids separated into distinct microdomains on the same endosomes. This is the first report showing, at a nanoscale, segregation of PtdIns(4)P- and PtdIns(4,5)P2-enriched microdomains in the endosome, of likely importance for endosome functionality.


Assuntos
Endossomos/metabolismo , Microdomínios da Membrana/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Lisossomos/metabolismo , Vesículas Transportadoras/metabolismo
14.
Exp Cell Res ; 342(1): 1-10, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26896729

RESUMO

EHD3 is localized on the tubular structures of early endosomes, and it regulates their trafficking pathway. However, the regulatory mechanism of EHD3-containing tubular structures remains poorly understood. An in vitro liposome co-sedimentation assay revealed that EHD3 interacted with phosphatidic acid through its helical domain and this interaction induced liposomal tubulations. Additionally, inhibiting phosphatidic acid synthesis with diacylglycerol kinase inhibitor or lysophosphatidic acid acyltransferase inhibitor significantly reduced the number of EHD3-containing tubules and impaired their trafficking from early endosomes. These results suggest that EHD3 and phosphatidic acid cooperatively regulate membrane deformation and trafficking from early endosomes.


Assuntos
Proteínas de Transporte/metabolismo , Extensões da Superfície Celular/metabolismo , Ácidos Fosfatídicos/fisiologia , Sequência de Aminoácidos , Animais , Endocitose , Endossomos/metabolismo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Transporte Proteico , Vesículas Transportadoras/metabolismo
15.
Int J Mol Sci ; 18(12)2017 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-29168788

RESUMO

Microtubule-targeting agents are widely used as clinical drugs in the treatment of cancer. However, some kinase inhibitors can also disrupt microtubule organization by directly binding to tubulin. These unexpected effects may result in a plethora of harmful events and/or a misinterpretation of the experimental results. Thus, further studies are needed to understand these dual inhibitors. In this review, I discuss the roles of dual inhibitors of kinase activity and microtubule function as well as describe the properties underlining their dual roles. Since both kinase and microtubule inhibitors cause cell toxicity and cell cycle arrest, it is difficult to determine which inhibitor is responsible for each phenotype. A discrimination of cell cycle arrest at G0/G1 or G2/M and/or image analyses of cellular phenotype may eventually lead to new insights on drug duality. Because of the indispensable roles of microtubules in mitosis and vesicle transport, I propose a simple and easy method to identify microtubule depolymerizing compounds.


Assuntos
Inibidores Enzimáticos/farmacologia , Microtúbulos/metabolismo , Fosfotransferases/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Animais , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Microtúbulos/química , Imagem Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Moduladores de Tubulina/farmacologia
16.
Eur Heart J ; 36(7): 440-8, 2015 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-25112662

RESUMO

AIMS: Previous studies on biventricular (BIV) pacing and cardiac resynchronization therapy-defibrillator (CRT-D) efficacy have used arbitrarily chosen BIV pacing percentages, and no study has employed implantable cardioverter defibrillator (ICD) patients as a control group. METHODS AND RESULTS: Using Kaplan-Meier plots, we estimated the threshold of BIV pacing percentage needed for CRT-D to be superior to ICD on the end-point of heart failure (HF) or death in 1219 left bundle branch block (LBBB) patients in the MADIT-CRT trial. Patients were censored at the time of crossover. In multivariable Cox analyses, no difference was seen in the risk of HF/death between ICD and CRT-D patients with BIV pacing ≤90% [HR = 0.78 (0.47-1.30), P = 0.344], and with increasing BIV pacing the risk of HF/death was decreased [CRT-D BIV 91-96% vs. ICD: HR = 0.63 (0.42-0.94), P = 0.024 and CRT-D BIV ≥97% vs. ICD: HR = 0.32 (0.23-0.44), P < 0.001]. The risk of death alone was reduced by 52% in CRT-D patients with BIV ≥97% (HR = 0.48, P < 0.016), when compared with ICD patients. Within the CRT-D group, for every 1 percentage point increase in BIV pacing, the risk of HF/death and death alone significantly decreased by 6 and 10%, respectively. Increasing BIV pacing percentage was associated with significant reductions in left ventricular volume. CONCLUSION: In patients with LBBB, who were in sinus rhythm at enrolment, BIV pacing exceeding 90% was associated with a benefit of CRT-D in HF/death when compared with ICD patients. Furthermore, BIV pacing ≥97% was associated with an even further reduction in HF/death, a significant 52% reduction in death alone, and increased reverse remodelling. Clinical trials.gov identifier: NCT00180271.


Assuntos
Bloqueio de Ramo/terapia , Terapia de Ressincronização Cardíaca/métodos , Desfibriladores Implantáveis , Insuficiência Cardíaca/terapia , Idoso , Bloqueio de Ramo/mortalidade , Terapia de Ressincronização Cardíaca/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Remodelação Ventricular/fisiologia
17.
Biochem Biophys Res Commun ; 453(3): 473-9, 2014 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-25281535

RESUMO

Arf GTPase-activating proteins (Arf GAP) play important roles in the formation of the membrane vesicles that traffic between subcellular membranous organelles. The small Arf GTPase-activating protein (SMAP) subfamily of Arf GAPs has two members, SMAP1 and SMAP2, in mammals. The present study investigated whether these two proteins may have an overlapping function in addition to their previously reported distinct functions. Results showed that the presence of either SMAP1 or SMAP2 was sufficient for endocytosis of the transferrin receptor, and that transferrin incorporation was impaired only by the absence of both SMAP1 and SMAP2. This suggests the involvement of both SMAP1 and SMAP2 in transferrin endocytosis. Results also demonstrated a physical association between SMAP1 and SMAP2, which might serve as a basis for a functional interaction, and identified the intramolecular domains responsible for this association.


Assuntos
Endocitose/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Receptores da Transferrina/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Ligação Proteica
18.
Semin Cardiothorac Vasc Anesth ; 28(1): 38-46, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38284295

RESUMO

Since their initial approval by the Food and Drug Administration in 2016, leadless pacemakers have become increasingly prevalent. This growth has been driven by an improved adverse effect profile when compared to traditional pacemakers, including lower rates of infection, as well as eliminated risk of pocket hematoma and lead complications. More recently, technology enabling leadless synchronized atrioventricular pacing in patients with atrioventricular block has vastly expanded the indications for these devices. Anesthesiologists will increasingly be relied upon to safely care for patients with leadless pacemakers undergoing non-electrophysiology procedures and surgery. This article provides an overview of the technology, evidence base, current indications, and unique perioperative considerations for leadless pacemakers.


Assuntos
Marca-Passo Artificial , Humanos , Marca-Passo Artificial/efeitos adversos , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/métodos , Arritmias Cardíacas/terapia , Arritmias Cardíacas/etiologia , Desenho de Equipamento
19.
Semin Cardiothorac Vasc Anesth ; 28(2): 66-79, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38669120

RESUMO

This article reviews noteworthy investigations and society recommendations published in 2023 relevant to the care of critically ill cardiothoracic surgical patients. We reviewed 3,214 articles to identify 18 publications that add to the existing literature across a variety of topics including resuscitation, nutrition, antibiotic management, extracorporeal membrane oxygenation (ECMO), neurologic care following cardiac arrest, coagulopathy and transfusion, steroids in pulmonary infections, and updated guidelines in the management of acute respiratory distress syndrome (ARDS).


Assuntos
Cuidados Críticos , Oxigenação por Membrana Extracorpórea , Humanos , Cuidados Críticos/métodos , Oxigenação por Membrana Extracorpórea/métodos , Estado Terminal , Síndrome do Desconforto Respiratório/terapia , Procedimentos Cirúrgicos Cardíacos/métodos
20.
Semin Cardiothorac Vasc Anesth ; 27(2): 87-96, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37171074

RESUMO

The past year in critical care medicine was notable for ongoing sequelae of the COVID-19 pandemic, including nationwide shortages and critical care demand in many regions in excess of usual operating capacity. Despite these challenges, evidence-based medicine and investigations into the optimal management of the critically ill continued to be at the forefront. This article is a collection of studies published in 2022 which are specifically relevant to cardiothoracic critical care. These noteworthy publications add to the existing literature across a broad spectrum of topics, from optimal timing of mechanical circulatory support (MCS), delirium prevention, updates in nutrition guidelines, alternative defibrillation techniques, novel ventilator management, and observing the downstream psychological impact of extracorporeal membrane oxygenation (ECMO) therapy.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Humanos , Pandemias , COVID-19/terapia , Cuidados Críticos/métodos , Oxigenação por Membrana Extracorpórea/métodos , Progressão da Doença , Estado Terminal/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA