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1.
Exp Dermatol ; 33(1): e14993, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38284191

RESUMO

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.


Assuntos
Furanos , Doença de Paget Extramamária , Policetídeos de Poliéter , Adulto , Humanos , Ensaios Clínicos Fase II como Assunto , Cetonas/uso terapêutico , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Estudos Prospectivos , Estudos Retrospectivos
2.
Stroke ; 54(6): 1494-1504, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37216455

RESUMO

BACKGROUND: Long-term outcomes are unknown in patients with asymptomatic moyamoya disease. In this report, we aimed to clarify their 5-year risk of stroke and its predictors. METHODS: We are conducting a multicenter, prospective cohort study (Asymptomatic Moyamoya Registry) in Japan. Participants were eligible if they were 20 to 70 years, had bilateral or unilateral moyamoya disease, experienced no episodes suggestive of TIA and stroke; and were functionally independent (modified Rankin Scale score 0-1). Demographic and radiological information was collected at enrollment. In this study, they are still followed up for 10 years. In this interim analysis, we defined the primary end point as a stroke occurring during a 5-year follow-up period. Independent predictors for stroke were also determined, using a stratification analysis method. RESULTS: Between 2012 and 2015, we enrolled 109 patients, of whom 103 patients with 182 involved hemispheres completed the 5-year follow-up. According to the findings on DSA and MRA, 143 hemispheres were judged as moyamoya disease and 39 hemispheres as questionable manifestations (isolated middle cerebral artery stenosis). The patients with questionable hemispheres were significantly older, more often male, and more frequently had hypertension than those with moyamoya hemisphere. Moyamoya hemispheres developed 7 strokes, including 6 hemorrhagic and 1 ischemic stroke, during the first 5 years. The annual risk of stroke was 1.4% per person, 0.8% per hemisphere, and 1.0% per moyamoya hemisphere. Independent predictor for stroke was Grade-2 choroidal anastomosis (hazard ratio, 5.05 [95% CI, 1.24-20.6]; P=0.023). Furthermore, microbleeds (hazard ratio, 4.89 [95% CI, 1.13-21.3]; P=0.0342) and Grade-2 choroidal anastomosis (hazard ratio, 7.05 [95% CI, 1.62-30.7]; P=0.0093) significantly predicted hemorrhagic stroke. No questionable hemispheres developed any stroke. CONCLUSIONS: The hemispheres with asymptomatic moyamoya disease may carry a 1.0% annual risk of stroke during the first 5 years, the majority of which are hemorrhagic stroke. Grade-2 choroidal anastomosis may predict stroke, and the microbleeds and Grade-2 choroidal anastomosis may carry the risk for hemorrhagic stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: UMIN000006640.


Assuntos
Acidente Vascular Cerebral Hemorrágico , Doença de Moyamoya , Acidente Vascular Cerebral , Humanos , Masculino , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/epidemiologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Hemorragia Cerebral , Sistema de Registros
3.
Dig Surg ; 40(1-2): 39-47, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36948158

RESUMO

INTRODUCTION: Laparoscopic low anterior resection (L-LAR) has become widely accepted for the treatment of rectal cancer. However, little is known about the superiority of L-LAR in a real-world setting (including low-volume hospitals) and the association between the short-term outcomes and hospital volume focusing on L-LAR. METHODS: This is a retrospective cohort study. A total of 37,821 patients who underwent LAR for rectal cancer were analyzed using the Diagnosis Procedure Combination (DPC) database from January 2014 to December 2017. The short-term surgical outcomes were analyzed using a multilevel analysis. Hospital volumes were divided into quartiles, including low (1-31), middle (32-55), high (56-91), and very-high volume (92-444 resections per 4 years). The effects of hospital volume on the outcomes were investigated. RESULTS: The study population included 8,335 patients (22%) who underwent open low anterior resection (O-LAR) and 29,486 patients (78%) who underwent L-LAR. The in-hospital mortality and morbidity were consistent with previous reports. In patients who underwent L-LAR, the in-hospital mortality (0.12% vs. 0.41%; OR: 0.33; p = 0.005), the rate of reoperation (3.76% vs. 6.48%; OR: 0.67; p < 0.001), and the perioperative transfusion rate (3.81% vs. 5.90%; OR: 0.66; p < 0.001) were significantly lower in very-high-volume hospitals than in low-volume hospitals. These effects of hospital volume were not observed in O-LAR. CONCLUSIONS: Our present study demonstrates that high volume improves outcomes in patients who underwent L-LAR in a real-world setting.


Assuntos
Laparoscopia , Neoplasias Retais , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Laparoscopia/métodos , Neoplasias Retais/cirurgia , Hospitais com Baixo Volume de Atendimentos
4.
Biochem Biophys Res Commun ; 540: 16-21, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33429195

RESUMO

Polyphosphate, which is ubiquitous in cells in nature, is involved in a myriad of cellular functions, and has been recently focused on its metabolism related with microbial acclimation to phosphorus-source fluctuation. In view of the ecological importance of cyanobacteria as the primary producers, this study investigated the responsibility of polyphosphate metabolism for cellular acclimation to phosphorus starvation in a cyanobacterium, Synechocystis sp. PCC 6803, with the use of a disruptant (Δppx) as to the gene of exopolyphosphatase that is responsible for polyphosphate degradation. Δppx was similar to the wild type in the cellular content of polyphosphate to show no defect in cell growth under phosphorus-replete conditions. However, under phosphorus-starved conditions, Δppx cells were defective in a phosphorus-starvation dependent decrease of polyphosphate to show deleterious phenotypes as to their survival and the stabilization of the photosystem complexes. These results demonstrated some crucial role of exopolyphosphatase to degrade polyP in the acclimation of cyanobacterial cells to phosphorus-starved conditions. Besides, it was found that ppx expression is induced in Synechocystis cells in response to phosphorus starvation through the action of the two-component system, SphS and SphR, in the phosphate regulon. The information will be a foundation for a fuller understanding of the process of cyanobacterial acclimation to phosphorus fluctuation.


Assuntos
Hidrolases Anidrido Ácido/genética , Fósforo/deficiência , Fósforo/metabolismo , Synechocystis/genética , Synechocystis/metabolismo , Aclimatação , Proteínas de Bactérias/genética , Viabilidade Microbiana , Polifosfatos/metabolismo , Regulon , Synechocystis/citologia , Synechocystis/enzimologia
5.
Org Biomol Chem ; 19(13): 2891-2894, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33570069

RESUMO

The selective alkylation of nucleic acids is important for a medicinal approach and biological study. We now report a novel selective alkylation of the parallel G-quadruplex structure using the conjugate of the macrocyclic hexaoxazole L2G2-6OTD-1M1PA and vinyl-quinazolinone-S(O)Me (6OTD-VQ-S(O)Me).


Assuntos
DNA/síntese química , Compostos Macrocíclicos/química , Oxazóis/química , Quinazolinonas/química , Compostos de Vinila/química , Alquilação , DNA/química , Quadruplex G , Estrutura Molecular
6.
Nucleic Acids Res ; 47(13): 6578-6589, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31188442

RESUMO

Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.


Assuntos
Alquilantes/farmacologia , DNA/efeitos dos fármacos , Conformação de Ácido Nucleico/efeitos dos fármacos , Alquilantes/síntese química , Alquilantes/química , Alquilação , Pareamento de Bases , DNA/química , DNA de Cadeia Simples/química , DNA de Cadeia Simples/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Purinas/química , Purinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Compostos de Vinila/química , Compostos de Vinila/farmacologia
7.
Ann Rheum Dis ; 79(1): 94-102, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630117

RESUMO

OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Desprescrições , Infliximab/administração & dosagem , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
8.
Pancreatology ; 20(7): 1479-1485, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32948431

RESUMO

BACKGROUND: Abnormal metabolism of hyaluronan (HA), a major component of extracellular matrix, is a hallmark of cancer. Our previous studies have shown the importance of enzymes responsible for HA degradation in the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). In the present study, we investigated the expression and function of transmembrane protein 2 (TMEM2), a recently identified HA-degrading enzyme, in PDAC. MATERIALS & METHODS: We used immunohistochemistry to investigate expression patterns of TMEM2 in archival tissues obtained from 100 patients with PDAC who underwent surgical resection from 1982 to 2012. The correlations between TMEM2 expression and clinicopathological variables, including survival, were determined using univariate and multivariate analyses. The effect of TMEM2 on proliferation and migratory ability (measured using transwell cell migration assay) of PDAC cells was determined by TMEM2 knockdown with small-interfering RNA (siRNA). RESULTS: Immunohistochemical analysis revealed high expression of TMEM2 in 22 (22%) of 100 patients. The overall survival was significantly shorter in patients with high TMEM2 expression than in those with low expression (P = 0.013). Multivariate analysis identified high TMEM2 expression as an independent factor predicting poor prognosis (P = 0.011). Unexpectedly, knockdown of TMEM2 resulted in increased migratory ability of PDAC cells, which was associated with increased expression of KIAA1199, a potent HA-degrading enzyme shown to enhance cell migration. CONCLUSION: TMEM2 overexpression is associated with poor prognosis in PDAC patients. Targeted disruption of this molecule, however, could enhance the aggressiveness of PDAC cells through a possible interaction with KIAA1199.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Hialuronoglucosaminidase/biossíntese , Proteínas de Membrana/biossíntese , Neoplasias Pancreáticas/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Hialuronoglucosaminidase/genética , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Valor Preditivo dos Testes , Prognóstico , RNA Interferente Pequeno/farmacologia , Análise de Sobrevida
9.
Nucleic Acids Res ; 46(3): 1059-1068, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29309639

RESUMO

The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T-T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)-acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T-T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T-T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT-acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1.


Assuntos
Acridinas/química , Pareamento Incorreto de Bases , Replicação do DNA , DNA/química , Timidina/química , Triazinas/química , Compostos de Vinila/química , Alquilação , Pareamento de Bases , Sequência de Bases , DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Humanos , Terapia de Alvo Molecular , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Distrofia Miotônica/terapia , Timidina/metabolismo , Transcrição Gênica , Repetições de Trinucleotídeos
10.
Surg Today ; 50(10): 1255-1261, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32335714

RESUMO

PURPOSE: To compare the short-term outcomes of conventional open colectomy with those of laparoscopic colectomy for colon cancer. METHODS: We retrieved data between January 2014 and March 2016 from the Diagnosis Procedure Combination database. A total of 69,418 patients who underwent colectomy for colon cancer were analyzed from among 15,901,766 cases of colorectal cancer. We applied a multilevel logistic regression model using a 2-level structure of individuals nested from 1065 hospitals. RESULTS: A total of 22,440 open colectomy and 46,978 laparoscopic colectomy procedures were performed. The in-hospital mortality rate was significantly lower in the laparoscopic group than in the open group (0.28% vs. 0.06%, odds ratio [OR] 0.40, p < 0.001). Similarly, the 30-day postoperative mortality rate (0.14% vs. 0.03%, OR 0.47, p = 0.019) and surgical morbidity rate (43.0% vs. 25.3%, OR 0.47, p < 0.001) were significantly lower in the laparoscopic group than in the open group. The postoperative length of stay was significantly longer in the open group (mean difference - 5.6 days, p < 0.001) than in the open group. The admission cost was significantly greater in the open group than in the laparoscopic group (mean difference - 95,080 yen, p < 0.001). CONCLUSIONS: Laparoscopic colectomy is safe and effective in the short term.


Assuntos
Colectomia/métodos , Neoplasias Colorretais/cirurgia , Endoscopia Gastrointestinal/métodos , Laparoscopia/métodos , Idoso , Idoso de 80 Anos ou mais , Colectomia/economia , Colectomia/mortalidade , Neoplasias Colorretais/economia , Neoplasias Colorretais/mortalidade , Custos e Análise de Custo , Bases de Dados Factuais , Endoscopia Gastrointestinal/economia , Endoscopia Gastrointestinal/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Japão , Laparoscopia/economia , Laparoscopia/mortalidade , Tempo de Internação/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Morbidade , Estudos Retrospectivos , Segurança , Resultado do Tratamento
11.
Org Biomol Chem ; 16(9): 1436-1441, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29412214

RESUMO

The G-quadruplex structure has been found in biologically significant regions of the genomic DNA, including the telomere and promoter regions, and is known to play an important role in a number of biological processes. In this paper, we report the development of alkylating probes for the G-quadruplex structure and evaluation of the properties of the modified G-quadruplex structure.


Assuntos
DNA/química , Quadruplex G , Alquilação , Sequência de Bases , DNA/genética , Telômero/genética
12.
Bioorg Med Chem ; 26(12): 3551-3558, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29807700

RESUMO

Higher-order structures of nucleic acids have become widely noted for their biological consequences and the discovery of an alkylating small molecule for these structures has been of interest due to its therapeutic potential. We previously developed the vinyldiaminotriazine (VDAT)-acridine conjugate as a T-T mismatch alkylating agent. In this report, we focused on the finding of the alkylation to the G-quadruplex (G4) DNA with VDAT-acridine conjugates. The VDAT-acridine conjugates exhibited a considerable alkylation ability to G4 under mild conditions. Moreover, the investigation of properties with the alkylated G4 revealed that alkylation by this conjugate significantly increased the stability of the G4 structure. This study provides a starting point in the further development of selective G4 alkylating small molecules.


Assuntos
Acridinas/química , Alquilantes/química , Quadruplex G , Triazinas/química , Alquilação , Pareamento Incorreto de Bases , Sequência de Bases , Timina/química , Timina/metabolismo , Temperatura de Transição
13.
Biochem Biophys Res Commun ; 487(3): 734-739, 2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28450108

RESUMO

Sulfoquinovosyl diacylglycerol (SQDG) is present in the membranes of cyanobacteria or their descendants, plastids at species-dependent levels. We investigated the physiological significance of the intrinsic SQDG content in the cyanobacterium Synechococcus elongatus PCC 7942, with the use of its mutant, in which the genes for SQDG synthesis, sqdB and sqdX, were overexpressed. The mutant showed a 1.3-fold higher content of SQDG (23.6 mol% relative to total cellular lipids, cf., 17.1 mol% in the control strain) with much less remarkable effects on the other lipid classes. Simultaneously observed were 1.6- to 1.9-fold enhanced mRNA levels for the genes responsible for the synthesis of the lipids other than SQDG, as if to compensate for the SQDG overproduction. Meanwhile, the mutant showed no injury to cell growth, however, cell length was increased (6.1 ± 2.3, cf., 3.8 ± 0.8 µm in the control strain). Accordingly with this, a wide range of genes responsible for cell division were 1.6-2.4-fold more highly expressed in the mutant. These results suggested that a regulatory mechanism for lipid homeostasis functions in the mutant, and that SQDG has to be kept from surpassing the intrinsic content in S. elongatus for repression of the abnormal expression of cell division-related genes and, inevitably, for normal cell division.


Assuntos
Tamanho Celular , Glicolipídeos/biossíntese , Metabolismo dos Lipídeos/fisiologia , Synechococcus/citologia , Synechococcus/metabolismo , Regulação para Cima/fisiologia , Glicolipídeos/genética
14.
Hepatology ; 64(2): 632-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26773713

RESUMO

UNLABELLED: Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. CONCLUSIONS: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643).


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Transplante de Fígado , Linfócitos T Reguladores , Tolerância ao Transplante , Adulto , Feminino , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
15.
Pancreatology ; 17(1): 115-122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28012880

RESUMO

BACKGROUND: KIAA1199 (also known as CEMIP or HYBID), a newly identified protein involved in hyaluronan degradation, has been suggested to play a critical role in cancer progression. The aim of this study was to investigate the expression and functional significance of KIAA1199 in pancreatic ductal adenocarcinoma (PDAC). METHODS: Using quantitative real-time RT-PCR, we analyzed KIAA1199 mRNA expression in 6 PDAC cell lines and frozen tissues from 14 patients with PDAC. We also used immunohistochemistry to analyze KIAA1199 protein expression in formalin-fixed, paraffin-embedded tissues from 98 patients with PDAC. The KIAA1199 expression pattern was then correlated with clinicopathological variables and patient outcome. The effect of KIAA1199 on migratory ability of PDAC cells was determined by KIAA1199 knockdown with small-interfering RNA (siRNA). RESULTS: The KIAA1199 mRNA expression was significantly higher in PDAC tissues than in the corresponding non-tumor tissues (P < 0.0001). Immunohistochemical analysis revealed high expression of KIAA1199 in 26 (26.5%) of 98 PDAC tissues. The overall survival was significantly shorter in patients with high KIAA1199 expression than in patients with low KIAA1199 expression (P = 0.0001). In multivariate analysis, high KIAA1199 expression (P = 0.003) and UICC stage (P = 0.003) were independent factors predicting poor prognosis. Furthermore, the KIAA1199 mRNA expression was higher in most PDAC cell lines and siRNA knockdown of KIAA1199 resulted in decreased migration. CONCLUSION: These findings suggest that overexpression of KIAA1199 may contribute to increased migration of PDAC cells and predict shorter survival after surgical resection.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Proteínas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Hialuronoglucosaminidase , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida , Regulação para Cima
16.
J UOEH ; 39(3): 223-227, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28904273

RESUMO

Pediatric cholecystolithiasis is a relatively rare disease, but it is recently increasing in Japan. Laparoscopic cholecystectomy (LC) is a standard procedure for cholecystolithiasis not only in adults but also in children, and we are aggressively introducing single-incision laparoscopic cholecystectomy (SILC) at our hospital. We reviewed the patient characteristics, operation procedures and outcomes of 7 children (15 years old and under) with cholecystolithiasis who underwent LC in our hospital between August 1995 and December 2015. The 7 patients included 5 males and 2 females, with a mean age of 8 years 6 months. Underlying diseases were found in 5 patients (cerebral palsy in 2 patients, pancreaticobiliary maljunction with common bile duct stones in 1, acute lymphocytic leukemia in 1, hereditary stomatocytosis in 1), and none were found in the other 2. LC (3 conventional LC and 2 SILC) was performed in 5 of the patients. Laparoscopic choledocholithotomy was performed in 1 patient and laparoscopic splenectomy (LS) was performed in 1 patient at the same time. The mean operative time in all the cases of LC was 108 (70-140) minutes (conventional LC 113 (70-140) min, SILC 100 (90-100) min). Intraoperative cholangiography was performed in 4 cases and omitted in 3 cases. The only postoperative complication was a wound infection in 1 patient. The umbilical skin incision length in the SILC was 2.0 cm. We conclude that LC can be safely performed for children with cholecsytolithiasis, and that SILC is feasible and advantageous in terms of its improved cosmesis.


Assuntos
Colecistolitíase/cirurgia , Adolescente , Criança , Pré-Escolar , Colecistectomia Laparoscópica , Feminino , Humanos , Masculino , Infecção da Ferida Cirúrgica , Resultado do Tratamento
17.
J UOEH ; 39(2): 167-173, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28626128

RESUMO

A 61-year-old woman was referred to our hospital because of a right breast mass. A 19 mm hard mass was palpable in the A area of the right breast. A contrast-enhanced MRI showed rim enhancement at the peripheral region of the tumor, which was thought to represent the carcinoma component mainly at the periphery and the matrix component inside the tumor. A low density mass with rim enhancement at the peripheral region was observed in a contrast-enhanced CT, the same as in the MRI. Neither axillary lymph node metastasis nor distant metastasis was observed. A core needle biopsy of the tumor lead to a diagnosis of matrix-producing carcinoma (MPC). A breast-conserving mastectomy with sentinel lymph nodes biopsy was performed on the right breast MPC (T1c, N0, M0 Stage I). Histopathologically, the tumor demonstrated overt carcinoma with direct transition to a cartilaginous or osseous matrix and lacked an intervening spindle cell component. Immunohistochemistry showed estrogen receptor (ER) (-), progesterone receptor (PgR) (-), human epidermal growth factor receptor 2 (HER2) (-), and Ki67 index of 50%, so-called triple negative breast cancer. The tumor was also positive for SRY-related HMG box-9 (SOX9), which is a useful marker of chondroid differentiation in normal and neoplastic tissues. The patient lived free from recurrence for 5 years, even though her adjuvant therapy was only radiation therapy without adjuvant chemotherapy. MPC is an uncommon and relatively rare variant of metaplastic carcinoma, and the prognosis for patients with MPC is poorer than that for patients with ordinary breast cancer. Here we report a case of MPC of the breast with characteristic rim enhancement in contrast-enhanced MRI and CT. The intrinsic subtype and prognosis of MPC is controversial, and then we may need more experience with MPC cases.


Assuntos
Neoplasias da Mama/patologia , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Metaplasia , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia Computadorizada por Raios X , Resultado do Tratamento
18.
J Toxicol Pathol ; 30(3): 201-207, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28798527

RESUMO

The Standard for Exchange of Nonclinical Data (SEND), introduced by the US Food and Drug Administration (FDA), is a scheme for the computerization, electronic application, and screening of preclinical data. Since its establishment, related organizations have been working together to implement SEND. However, it is difficult for individual pharmaceutical companies that often outsource to achieve complete compliance with SEND; hence, the cooperation of contract research organizations (CROs) and SEND Registered Solution Providers (RSPs) is indispensable. In SEND, most data, including those on pathology findings, are converted into controlled terminology (CT), but it is not a simple process to convert findings or levels of severity in the field of pathology, which is a descriptive science. The authors have successfully completed an FDA trial submission for a toxicology test conducted at a CRO and in doing so acquired important knowledge. This article presents a clear picture of such important knowledge from a pathologist's viewpoint.

19.
Cancer Sci ; 107(5): 569-75, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26918382

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains the most deadly disease worldwide, with the lowest survival rate among all cancer types. Recent evidence suggests that hyaluronan (HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma is typically characterized by a dense desmoplastic stroma containing a large amount of HA. Accumulation of HA promotes tumor growth in mice and correlates with poor prognosis in patients with PDAC. Because HA is involved in various malignant behaviors of cancer (such as increased cell proliferation, migration, invasion, angiogenesis, and chemoresistance), inhibiting HA synthesis/signaling or depleting HA in tumor stroma could represent a promising therapeutic strategy against PDAC. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.


Assuntos
Progressão da Doença , Ácido Hialurônico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/biossíntese , Neoplasias Pancreáticas/metabolismo
20.
Biochem Biophys Res Commun ; 477(4): 854-860, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27372425

RESUMO

Sulfoquinovosyl diacylglycerol, which mainly comprises thylakoid membranes in oxygenic photosynthetic organisms, plays species-dependent roles in freshwater microbes. In this study, a sulfoquinovosyl-diacylglycerol deficient mutant was generated in a cyanobacterium, Synechococcus sp. PCC 7002, for the first time among marine microbes to gain more insight into its physiological significance. The mutation had little deleterious impact on photoautotrophic cell growth, and functional and structural properties of the photosystem II complex. These findings were similar to previous observations for a freshwater cyanobacterium, Synechococcus elongatus PCC 7942, but were distinct from those for another freshwater cyanobacterium, Synechocystis sp. PCC 6803, and a green alga, Chlamydomonas reinhardtii, both of which require sulfoquinovosyl diacylglycerol for cell growth and/or photosystem II. Therefore, the functionality of PSII to dispense with sulfoquinovosyl diacylglycerol in Synechococcus sp. PCC 7002, similar to that in Synechococcus elongatus PCC 7942, seemed to have been excluded from the evolution of the PSII complex from cyanobacteria to green algal chloroplasts. Meanwhile, sulfoquinovosyl diacylglycerol was found to contribute to photoheterotrophic growth of Synechococcus sp. PCC 7002, which revealed a novel species-dependent strategy for utilizing SQDG in physiological processes.


Assuntos
Processos Autotróficos/fisiologia , Proliferação de Células/fisiologia , Glicolipídeos/metabolismo , Fotossíntese/fisiologia , Synechococcus/fisiologia , Synechococcus/efeitos da radiação , Organismos Aquáticos , Processos Autotróficos/efeitos da radiação , Proliferação de Células/efeitos da radiação , Glucosiltransferases/metabolismo , Luz , Lipídeos/fisiologia , Fotossíntese/efeitos da radiação , Especificidade da Espécie , Synechococcus/classificação
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