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1.
Intern Med ; 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38462518

RESUMO

Objective We aimed to investigate the relationship between tortuosity of the extracranial internal carotid artery (ICA) or vertebral artery (VA) and vascular risk factors among residents of Asahikawa, northeast Japan. Methods We retrospectively surveyed participants of "brain dock" medical brain checkups, which involved magnetic resonance imaging and angiography. We measured the tortuosity of the ICA and VA, and evaluated vascular risk factors based on medical interviews, questionnaires, and medical records. Results A total of 218 participants were enrolled in the study. ICA tortuosity (right and left) was significantly correlated with age [odds ratio (OR): 2.452, 95% confidence interval (CI): 1.695-3.548, p<0.001]. A more pronounced correlation was observed in females than in males (OR: 1.678, 95% CI: 1.004-2.807, p=0.048). VA tortuosity (right and left) was significantly correlated with age (OR: 1.786, 95% CI: 1.250-2.550, p=0.001) and smoking history (OR: 2.140, 95% CI: 1.235-3.707, p=0.007), and was more pronounced in females than in males (OR: 1.864, 95% CI: 1.107-3.137, p=0.019). Conclusion ICA tortuosity was correlated with age, while VA tortuosity was correlated with age and smoking history. ICA and VA tortuosity were more pronounced in females than in males.

2.
Intern Med ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38494718

RESUMO

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

3.
Neurol Sci ; 45(6): 2747-2757, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38267601

RESUMO

BACKGROUND: Cerebrovascular diseases in cancer patients significantly aggravate their condition and prognosis; therefore, prompt and accurate diagnosis and treatment are important. The purpose of this study was to investigate patient demographics, laboratory data, brain magnetic resonance imaging (MRI) findings, and prognosis among patients with stroke and cancer, especially cancer-associated ischemic stroke (CAIS). METHODS: We performed a retrospective, single-center study. We enrolled consecutive patients who had acute stroke and were admitted to our hospital between January 2011 and December 2021. We collected general demographic characteristics, cancer histopathological type, laboratory data, brain MRI findings, and prognosis data. RESULTS: Among 2040 patients with acute stroke, a total of 160 patients (7.8%) had active cancer. The types of strokes were cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and transient ischemic attack in 124, 25, 5, and 6 patients, respectively. Among the patients with ischemic stroke, there were 69 cases of CAIS. Pancreas and adenocarcinoma were the most frequent types of primary tumor and histopathology. Patients with adenocarcinoma and those with cerebral infarctions in both bilateral anterior and posterior cerebral circulation areas showed higher D-dimer levels. Pancreatic cancer and high plasma D-dimer levels were associated with poor survival rate. CONCLUSION: CAIS was seen more frequently in patients with pancreatic cancer and adenocarcinoma. Pancreatic cancer and high plasma D-dimer levels were potential factors of poor prognosis in patients with CAIS.


Assuntos
Neoplasias , Humanos , Masculino , Feminino , Estudos Retrospectivos , Prognóstico , Pessoa de Meia-Idade , Idoso , Neoplasias/complicações , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/diagnóstico , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/complicações , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Neoplasias Pancreáticas/complicações , Idoso de 80 Anos ou mais , Adulto
4.
Neurosurg Focus ; 55(4): E7, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37778043

RESUMO

OBJECTIVE: Antithrombotic medications pose a challenge for conducting surgical or invasive procedures, because their discontinuation is required to avoid postprocedural hemorrhagic complications but potentially increases the ischemic risk for the patient. This study aimed to estimate the increased risk of developing cerebral ischemic events during hospitalization requiring discontinuation of antithrombotic therapy. METHODS: This investigation was a single-center retrospective observational study. Clinical data in patients scheduled for admission between January 1, 2021, and December 31, 2022, were collected. Patients requiring discontinuation of antithrombotic therapy were identified by referring to the admission database. Patients who developed cerebral ischemia were identified by referring to the institution's stroke center database. RESULTS: Seven hundred ninety-six patients scheduled for nonneurosurgical procedures and 39 scheduled for neurosurgical procedures underwent discontinuation of antithrombotic therapy. Anticoagulation therapy was prescribed in 40.0%, and antiplatelet therapy was prescribed in 69.1% of the patients. A total of 9.2% of the entire cohort of patients were receiving both anticoagulation and antiplatelet therapy. Bridging therapy was administered in 20.9% of nonneurosurgical patients. No ischemic event was observed in the patients undergoing neurosurgical procedures. Among the entire cohort, 3 patients encountered some kind of thrombotic event-2 of which were cerebral ischemia-accounting for an incidence of 0.24%, which was significantly higher than incidental in-hospital stroke unrelated to discontinuation of antithrombotic therapy (p = 0.04). Patients undergoing both anticoagulation and antiplatelet therapy harbored a significantly higher risk for cerebral ischemia related to discontinuation of antithrombotic therapy (p < 0.0001). CONCLUSIONS: Discontinuing antithrombotic therapy during hospitalization for elective invasive procedures-including neurosurgical procedures-entailed a relatively small risk of developing cerebral ischemic events, but the risk was significantly higher compared to hospitalized patients without discontinuation of antithrombotic therapy.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Fibrinolíticos/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/complicações , Anticoagulantes/efeitos adversos
5.
Science ; 382(6668): 329-335, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37856600

RESUMO

Computing, since its inception, has been processor-centric, with memory separated from compute. Inspired by the organic brain and optimized for inorganic silicon, NorthPole is a neural inference architecture that blurs this boundary by eliminating off-chip memory, intertwining compute with memory on-chip, and appearing externally as an active memory chip. NorthPole is a low-precision, massively parallel, densely interconnected, energy-efficient, and spatial computing architecture with a co-optimized, high-utilization programming model. On the ResNet50 benchmark image classification network, relative to a graphics processing unit (GPU) that uses a comparable 12-nanometer technology process, NorthPole achieves a 25 times higher energy metric of frames per second (FPS) per watt, a 5 times higher space metric of FPS per transistor, and a 22 times lower time metric of latency. Similar results are reported for the Yolo-v4 detection network. NorthPole outperforms all prevalent architectures, even those that use more-advanced technology processes.

6.
Rinsho Shinkeigaku ; 63(6): 363-368, 2023 Jun 28.
Artigo em Japonês | MEDLINE | ID: mdl-37197968

RESUMO

The patient, a 58-year-old man, experienced weakness of the proximal muscles in both lower extremities, and Lambert-Eaton myasthenic syndrome and small cell carcinoma of unknown primary origin were diagnosed. He received symptomatic treatment for myasthenia and radiochemotherapy for small cell carcinoma; once this regimen, the myasthenic symptoms improved. However, acute myocardial infarction occurred, after which type II respiratory failure developed, and the patient required ventilator management with tracheal intubation. Acute-phase treatment, such as plasma exchange, intravenous immune globulin therapy, and methylprednisolone pulse therapy, and intensification of symptomatic treatment allowed for extubation, and eventually the patient was able to walk independently. According to electrophysiological examination, compound muscle action potentials were larger at discharge than at the time of exacerbation.


Assuntos
Carcinoma de Células Pequenas , Síndrome Miastênica de Lambert-Eaton , Neoplasias Pulmonares , Infarto do Miocárdio , Insuficiência Respiratória , Carcinoma de Pequenas Células do Pulmão , Masculino , Humanos , Pessoa de Meia-Idade , Síndrome Miastênica de Lambert-Eaton/complicações , Síndrome Miastênica de Lambert-Eaton/diagnóstico , Carcinoma de Células Pequenas/tratamento farmacológico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico
7.
Medicine (Baltimore) ; 102(19): e33789, 2023 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-37171294

RESUMO

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.


Assuntos
Doenças Neurodegenerativas , Distrofias Retinianas , Humanos , Feminino , Pessoa de Meia-Idade , Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Mutação , Distrofias Retinianas/complicações , Distrofias Retinianas/patologia
8.
Angew Chem Int Ed Engl ; 62(33): e202303341, 2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37158760

RESUMO

A rotaxane crosslinker (RC) is known to toughen the resulting rotaxane crosslinked polymer (RCP) via a stress dispersion effect that is attributed to the movable nature of the crosslinking structure. To evaluate this toughening mechanism in detail, a series of structure-definite RCs equipped with different axle end structures or different numbers of wheel components were synthesized, and subjected to free radical polymerization with a vinyl monomer to obtain RCPs. Analyses of the obtained RCPs revealed that the size of the axle end structure should be well-balanced to produce a strong toughening effect, and a [3]rotaxane crosslinker works more effectively than [2]rotaxane to toughen RCPs. The mobility of the crosslinking points, in terms of rotational and flipping movements, was more crucial to toughening the RCP than that of translational movement along the axle. The first observation of the above crucial findings proved the utility of the systematic molecular design used in this study.

9.
FEBS Lett ; 597(8): 1138-1148, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36823439

RESUMO

Centromere-associated protein E (CENP-E) is a kinesin motor protein essential for mitosis and a new target for anticancer agents with less side effects. To rationally design anticancer drug candidates based on structure, it is important to determine the three-dimensional structure of the CENP-E motor domain bound to its inhibitor. Here, we report the first crystal structure of the CENP-E motor domain in complex with a non-hydrolysable ATP analogue, adenylyl-imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP-bound form of the CENP-E motor domain as well as the AMPPNP-bound forms of other kinesins. This study indicates that helix α4 of CENP-E participates in the slow binding of CENP-E to microtubules. These results will contribute to the development of anticancer drugs targeting CENP-E.


Assuntos
Antineoplásicos , Microtúbulos , Adenilil Imidodifosfato/análise , Adenilil Imidodifosfato/metabolismo , Microtúbulos/metabolismo , Mitose , Antineoplásicos/farmacologia , Centrômero/metabolismo
11.
JTCVS Open ; 10: 87-96, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36004275

RESUMO

Objective: To identify whether preoperative magnetic resonance imaging findings of the brain can predict postoperative delirium in patients who undergo arch replacement for aneurysms. Methods: Overall, 193 patients who underwent aortic replacement for the first time at a single institution between April 2014 and September 2020 were enrolled in this retrospective study. After we excluded patients with acute aortic dissection, no preoperative magnetic resonance imaging findings of the brain, and postoperative cerebral infarction, 50 patients were included and divided into 2 groups, according to their confusion scale results: postoperative delirium (group D) and nonpostoperative delirium (group ND). Preoperative magnetic resonance imaging findings of the brain were classified into lacunar stroke, periventricular hyperintensity, and deep subcortical white matter hyperintensity groups; the latter 2 groups were further classified based on the Fazekas scale, grade 0 to 3. Results: There were 23 patients (46%) in group D and 27 (54%) in group ND. The mean age was significantly greater in group D than in group ND (75 vs 70 years; P = .007). The mean operative time was significantly longer in group D than in group ND (447 vs 384 minutes; P = .024). As for preoperative magnetic resonance imaging findings of the brain, there were significantly more lacunar stroke cases in group D than in group ND (P = .027). In multivariable logistic regression with stepwise selection, high-grade periventricular hyperintensity was significantly related to postoperative delirium (odds ratio, 9.38; 95% confidence interval, 1.55-56.56; P = .015). Conclusions: Silent cerebral ischemia detected by preoperative magnetic resonance imaging of the brain was a significant risk factor for postoperative delirium.

12.
Intern Med ; 61(23): 3497-3502, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-35491133

RESUMO

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Masculino , Humanos , Pessoa de Meia-Idade , Carcinoma Hepatocelular/tratamento farmacológico , Bevacizumab/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico
13.
World Neurosurg ; 159: e79-e83, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34883273

RESUMO

OBJECTIVE: The left atrial volume index (LAVI) is considered to be the most accurate index to estimate the size of the left atrium (LA). In this study, we investigated the relationship between LA size measured by LAVI and the occurrence of large-vessel occlusion (LVO) in patients with cardiogenic cerebral infarction (CCI). METHODS: This retrospective single-center cohort study involved 118 patients with CCI within the internal carotid artery (ICA) or middle cerebral artery regions seen between January 2015 and July 2020. In all patients, the type of CCI was determined according to the Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Scores (TOAST) subtype diagnosis criteria. LVO was defined as positive when magnetic resonance imaging and computed tomography angiography showed ICA, M1, or M2 occlusion, with all others defined as non-LVO. Clinical characteristics, including LAVI, were evaluated in the records of several patients to investigate if they were risk factors for developing LVO. RESULTS: Seventy patients (59%) were diagnosed as having LVO infarction (ICA occlusion, n = 19 [16%]; M1 occlusion, n = 26 [22%]; and M2 occlusion, n = 25 [21%]). Echocardiography showed no difference between LVO and non-LVO in terms of the ejection fraction (P = 0.64), LA dimension (P = 0.93), and LA volume (P = 0.06). However, LAVI significantly differed between the LVO and non-LVO groups (P = 0.02). Multivariate logistic regression analysis showed larger LAVI as a significant risk factor for LVO (P = 0.01). CONCLUSIONS: Our findings suggest that a larger LAVI is a predictor of developing LVO in patients with CCI.


Assuntos
Acidente Vascular Cerebral , Angiografia Cerebral/métodos , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico por imagem , Estudos de Coortes , Átrios do Coração/diagnóstico por imagem , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia
14.
Alzheimers Res Ther ; 13(1): 163, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34610837

RESUMO

BACKGROUND: This study examined the usefulness of cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels as a candidate biomarker of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). METHODS: We performed a systematic search of PubMed, the Cochrane Library, Scopus, and Google Scholar to find studies that measured CSF NSE levels in AD, PD, DLB, and/or MSA. For each disease, we pooled all available data and performed a meta-analysis, and meta-regression analyses of age and sex were conducted if the main analysis found a significant association. RESULTS: Twenty studies were included (13 for AD, 8 for PD/PDD/DLB, and 4 for MSA). Significantly elevated CSF NSE levels were detected in AD (Hedges' g = 0.822, 95% confidence interval [95% CI] 0.332 to 1.311, p = 0.0010), but the data exhibited high heterogeneity (I2 = 88.43%, p < 0.001). The meta-regression analysis of AD showed that age (p < 0.001), but not sex, had a significant effect on CSF NSE levels. A meta-analysis of the pooled data for PD/PDD/DLB did not show any significant changes in the CSF NSE level, but a sub-group analysis of PDD/DLB revealed significantly elevated CSF NSE levels (Hedges' g = 0.507, 95% CI 0.020 to 0.993, p = 0.0412). No significant changes in CSF NSE levels were detected in MSA. CONCLUSIONS: The CSF NSE level may be a useful biomarker of neurodegeneration in AD and PDD/DLB. Age was found to affect the CSF NSE levels of AD patients.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Fosfopiruvato Hidratase
15.
Biochem Pharmacol ; 193: 114789, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34582773

RESUMO

Kinesin-5 has received considerable attention as a new target for mitosis. Various small-molecule compounds targeting kinesin-5 have been developed in the last few decades. However, the differences in the cellular effects of kinesin-5 inhibitors remain poorly understood. Here, we used two different kinesin-5 inhibitors, biphenyl-type PVZB1194 and S-trityl-L-cysteine-type PVEI0021, to examine their effects on molecular events involving kinesin-5. Our biochemical study of kinesin-5 protein-protein interactions showed that PVZB1194-treated kinesin-5 interacted with TPX2 microtubule nucleation factor, Aurora-A kinase, receptor for hyaluronan-mediated motility, and γ-tubulin, as did untreated mitotic kinesin-5. However, PVEI0021 prevented kinesin-5 from binding to these proteins. In mitotic HeLa cells recovered from nocodazole inhibition, kinesin-5 colocalized with these binding proteins, along with microtubules nucleated near kinetochores. By acting on kinesin-5 interactions with chromatin-associated microtubules, PVZB1194, rather than PVEI0021, not only affected the formation of dispersed microtubule clusters but also enhanced the stability of microtubules. In addition, screening for mitotic inhibitors working synergistically with the kinesin-5 inhibitors revealed that paclitaxel synergistically inhibited HeLa cell proliferation only with PVZB1194. In contrast, the Aurora-A inhibitor MLN8237 exerted a synergistic anti-cell proliferation effect when combined with either inhibitor. Together, these results have provided a better understanding of the molecular action of kinesin-5 inhibitors and indicate their usefulness as molecular tools for the study of mitosis and the development of anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Cinesinas/antagonistas & inibidores , Sulfonamidas/farmacologia , Azepinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
16.
Rinsho Shinkeigaku ; 61(4): 228-233, 2021 Apr 21.
Artigo em Japonês | MEDLINE | ID: mdl-33762492

RESUMO

A 62-year-old Japanese man with swollen fingers and walking difficulty due to myalgia and muscle weakness in proximal limb muscles was admitted to our hospital. Serum creatine kinase was remarkably increased (7,380 U/l) and rapidly progressing interstitial pneumonia developed. Muscle biopsy showed necrotic and regenerating fibers without mononuclear infiltration and fibrosis. Anti-Th/To antibodies were detected in the serum, and anti-Th/To antibody-positive systemic sclerosis was diagnosed. Anti-Th/To antibody-positive sclerosis-associated myopathy has not yet been reported in the literature. The present case suggests that anti-Th/To antibody-positive systemic sclerosis can be accompanied by immune-mediated necrotizing myopathy and be effectively treated with immunotherapy comprising corticosteroids, tacrolimus and immunoglobulin.


Assuntos
Autoanticorpos , Autoantígenos/imunologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Musculares/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Corticosteroides/uso terapêutico , Humanos , Imunoglobulinas/uso terapêutico , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/patologia , Necrose , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia , Pele/patologia , Tacrolimo/uso terapêutico
17.
Acta Crystallogr D Struct Biol ; 77(Pt 3): 280-287, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645531

RESUMO

Centromere-associated protein E (CENP-E) plays an essential role in mitosis and is a target candidate for anticancer drugs. However, it is difficult to design small-molecule inhibitors of CENP-E kinesin motor ATPase activity owing to a lack of structural information on the CENP-E motor domain in complex with its inhibitors. Here, the CENP-E motor domain was crystallized in the presence of an ATP-competitive inhibitor and the crystal structure was determined at 1.9 Šresolution. In the determined structure, ADP was observed instead of the inhibitor in the nucleotide-binding site, even though no ADP was added during protein preparation. Structural comparison with the structures of previously reported CENP-E and those of other kinesins indicates that the determined structure is nearly identical except for several loop regions. However, the retention of ADP in the nucleotide-binding site of the structure strengthens the biochemical view that the release of ADP is a rate-limiting step in the ATPase cycle of CENP-E. These results will contribute to the development of anticancer drugs targeting CENP-E and to understanding the function of kinesin motor domains.


Assuntos
Proteínas Cromossômicas não Histona/química , Difosfato de Adenosina/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Modelos Moleculares , Domínios Proteicos
18.
Eur J Med Chem ; 215: 113288, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33640763

RESUMO

Kinesin spindle protein (KSP) is expressed only in cells undergoing cell division, and hence represents an attractive target for the treatment of cancer. Several KSP inhibitors have been developed and undergone clinical trial, but their clinical use is limited by their toxicity to rapidly proliferating non-cancerous cells. To create new KSP inhibitors that are highly selective for cancer cells, we optimized the amino acid moiety of S-trityl-l-cysteine (STLC) derivative 1 using in silico modeling. Molecular docking and molecular dynamics simulation were performed to investigate the binding mode of 1 with KSP. Consistent with the structure activity relationship studies, we found that a cysteine amino moiety plays an important role in stabilizing the interaction. Based on these findings and the structure of GSH, a substrate of γ-glutamyltransferase (GGT), we designed and synthesized the prodrug N-γ-glutamylated STLC derivative 9, which could be hydrolyzed by GGT to produce 1. The KSP ATPase inhibitory activity of 9 was lower than that of 1, and LC-MS analysis indicated that 9 was converted to 1 only in the presence of GGT in vitro. In addition, the cytotoxic activity of 9 was significantly attenuated in GGT-knockdown A549 cells. Since GGT is overexpressed on the cell membrane of various cancer cells, these results suggest that compound 9 could be a promising prodrug that selectively inhibits the proliferation of GGT-expressing cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cisteína/farmacologia , Dibenzocicloeptenos/farmacologia , Cinesinas/antagonistas & inibidores , Pró-Fármacos/farmacologia , Compostos de Tritil/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , Cisteína/síntese química , Cisteína/metabolismo , Dibenzocicloeptenos/síntese química , Dibenzocicloeptenos/metabolismo , Humanos , Cinesinas/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica , Compostos de Tritil/síntese química , Compostos de Tritil/metabolismo , gama-Glutamiltransferase/metabolismo
19.
BMJ Open ; 11(2): e045100, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558361

RESUMO

OBJECTIVES: Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA. SETTING: Patient recruitment started in November 2014 and is ongoing at the time of submission. The number of participating facilities was 66. Postal surveys were sent to medical facilities and patients with MSA in Hokkaido, Japan. PARTICIPANTS: After obtaining written consent from 196 participants, 184 overview surveys and 115 detailed surveys were conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: An overview survey evaluated conformity to diagnostic criteria and a detailed survey implemented an annual assessment based on the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: At the time of registration, 58.2% of patients were diagnosed with cerebellar symptoms predominant type MSA (MSA-C) and 29.9% were diagnosed with parkinsonism predominant type MSA (MSA-P). UMSARS Part Ⅳ score of 4 or 5 accounted for 53.8% of participants. The higher the UMSARS Part Ⅳ score, the higher the proportion of MSA-P. At baseline, levodopa was used by 69 patients (37.5%) and the average levodopa dose was 406.7 mg/day. The frequency of levodopa use increased over time. Eleven cases changed from MSA-C to MSA-P during the study, but the opposite was not observed. Information about survival and causes of death was collected on 54 cases. Half of deaths were respiratory-related. Sudden death was recorded even in the group with UMSARS Part Ⅳ score of 1. CONCLUSIONS: This study is the first large-scale prospective MSA cohort study in Asia. MSA-C was dominant, but the use of antiparkinsonian drugs increased over the study period. Changes from MSA-C to MSA-P occurred, but not vice versa.


Assuntos
Atrofia de Múltiplos Sistemas , Ásia , Estudos de Coortes , Humanos , Japão/epidemiologia , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/epidemiologia , Sistema de Registros , Avaliação de Sintomas
20.
Intern Med ; 60(12): 1819-1826, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33456042

RESUMO

Objective Fabry disease (FD) is a hereditary lysosomal storage disease that has been highlighted as a possible etiology of stroke at a young age and presents with other various neurological symptoms. Since FD is rare, limited information is currently available on the prevalence of neurological symptoms in Japanese patients with FD. Therefore, we examined the characteristics of neurological symptoms and brain magnetic resonance imaging (MRI) findings in adult Japanese patients with FD. Methods This was a retrospective, single-center study. We reviewed neurological symptoms and brain MRI findings in the medical records of 12 adult Japanese patients with FD diagnosed by a gene analysis of the α-galactosidase gene. Results Ten out of 12 patients with FD presented with the following neurological symptoms: acroparesthesia (n=6), headache (n=5) [migraine (n=4)], hypohidrosis (n=5), and cerebral infarction (n=3). Two and three of the patients with migraine were complicated by ischemic stroke and coronary spastic angina, respectively. Five and 10 patients presented with periventricular hyperintensity and deep white matter hyperintensity, respectively, on brain MRI. Two out of eight patients had cerebral microbleeds. Seven out of 11 patients had a dilated basilar artery diameter on magnetic resonance angiography. There were no patients with the pulvinar hyperintensity sign. Conclusion Patients with FD present with various neurological symptoms. Headache, particularly migraine, might be a major neurological symptom in patients with FD. Since migraine, ischemic stroke, and coronary spastic angina might occur together in FD, caution is needed when administering triptan to FD patients with migraine.


Assuntos
Doença de Fabry , Adulto , Doença de Fabry/diagnóstico , Doença de Fabry/diagnóstico por imagem , Humanos , Japão/epidemiologia , Imageamento por Ressonância Magnética , Estudos Retrospectivos , alfa-Galactosidase
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