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1.
IJU Case Rep ; 4(6): 433-435, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34755077

RESUMO

Introduction: We encountered a urethrovaginal fistula diagnosed 11 years after a bone anchor sling. Case presentation: A 58-year-old woman underwent a bone anchor sling to treat stress urinary incontinence. At age 69, mid-urethral sling was planned because of a recurrent stress urinary incontinence diagnosis, but a urethrovaginal fistula was found immediately before the procedure. After removing woven polyester, the previous sling material, simple fistula closure was carried out but failed. Usage of a vaginal speculum and powerful medical lamps during a stress test revealed leakage from both the urethrovaginal fistula and the external urethral meatus. She underwent another fistula closure using a Martius flap. Subsequently, a 1-h pad test improved from 195 to 5.1 g/h. The remaining mild stress urinary incontinence did not necessitate further treatment. Conclusion: Anti-incontinence procedures using synthetic materials can cause urethrovaginal fistula. Attention must be paid to the possibility of urethrovaginal fistula when patients complain of worsened incontinence postoperatively.

2.
Front Oncol ; 11: 758503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804954

RESUMO

Background: Acquired therapeutic resistance and metastasis/recurrence remain significant challenge in advance renal cell carcinoma (RCC), thus the establishment of patient-derived cancer models may provide a clue to assess the problem. We recently characterized that neuritogenesis-related protein neuritin 1 (NRN1) functions as an oncogene in testicular germ cell tumor. This study aims to elucidate the role of NRN1 in RCC. Methods: NRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-associated genes in RCC were screened by the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). RCC patient-derived cancer cell (RCC-PDC) spheroid cultures were established and their viabilities were evaluated under the condition of gene silencing/overexpression. The therapeutic effect of NRN1-specific siRNA was evaluated in RCC-PDC xenograft models. Results: NRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed. Conclusion: NRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.

3.
Int J Mol Sci ; 22(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34768935

RESUMO

Octamer transcription factor 1 (OCT1) is a transcriptional factor reported to be a poor prognostic factor in various cancers. However, the clinical value of OCT1 in breast cancer is not fully understood. In the present study, an immunohistochemical study of OCT1 protein was performed using estrogen receptor (ER)-positive breast cancer tissues from 108 patients. Positive OCT1 immunoreactivity (IR) was associated with the shorter disease-free survival (DFS) of patients (p = 0.019). Knockdown of OCT1 inhibited cell proliferation in MCF-7 breast cancer cells as well as its derivative long-term estrogen-deprived (LTED) cells. On the other hand, the overexpression of OCT1 promoted cell proliferation in MCF-7 cells. Using microarray analysis, we identified the non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) as a novel OCT1-taget gene in MCF-7 cells. Immunohistochemical analysis showed that NCAPH IR was significantly positively associated with OCT1 IR (p < 0.001) and that positive NCAPH IR was significantly related to the poor DFS rate of patients (p = 0.041). The knockdown of NCAPH inhibited cell proliferation in MCF-7 and LTED cells. These results demonstrate that OCT1 and its target gene NCAPH are poor prognostic factors and potential therapeutic targets for patients with ER-positive breast cancer.

4.
Commun Biol ; 4(1): 1320, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34811492

RESUMO

Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon-intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

5.
Dent Mater J ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34602588

RESUMO

This study aimed to evaluate the pulpal responses of monkey's pulp after direct pulp capping (DPC) with the novel mineral trioxide aggregate containing phosphorylated pullulan-based material (MTAPPL). Seventy-two teeth were randomly divided into four groups: MTAPPL; Nex-Cem MTA (NX); TheraCal LC (TH); and Dycal (DY). Histopathological changes in the pulps were observed at days 3, 7 and 70. On day 3, mild inflammatory responses were observed in the MTAPPL, no to moderate inflammatory responses in the TH, whereas moderate inflammatory responses in the NX and DY. No mineralized tissue formation (MTF) was observed in all groups. On day 7, no or mild inflammatory responses were observed in all groups. Initial MTF was observed except for DY. No inflammation with complete MTF including presence of odontoblast-like cells was observed in the MTAPPL, NX and TH groups at day 70. These findings indicate that MTAPPL could be an efficient DPC material.

6.
PLoS One ; 16(10): e0258677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34662365

RESUMO

This study analyzed meteorological constraints on winter wheat yield in the northern Japanese island, Hokkaido, and developed a machine learning model to predict municipality-level yields from meteorological data. Compared to most wheat producing areas, this island is characterized by wet climate owing to greater annual precipitation and abundant snowmelt water supply in spring. Based on yield statistics collected from 119 municipalities for 14 years (N = 1,516) and high-resolution surface meteorological data, correlation analyses showed that precipitation, daily minimum air temperature, and irradiance during the grain-filling period had significant effects on the yield throughout the island while the effect of snow depth in early winter and spring was dependent on sites. Using 10-d mean meteorological data within a certain period between seeding and harvest as predictor variables and one-year-leave-out cross-validation procedure, performance of machine learning models based on neural network (NN), random forest (RF), support vector machine regression (SVR), partial least squares regression (PLS), and cubist regression (CB) were compared to a multiple linear regression model (MLR) and a null model that returns an average yield of the municipality. The root mean square errors of PLS, SVR, and RF were 872, 982, and 1,024 kg ha-1 and were smaller than those of MLR (1,068 kg ha-1) and null model (1,035 kg ha-1). These models outperformed the controls in other metrics including Pearson's correlation coefficient and Nash-Sutcliffe efficiency. Variable importance analysis on PLS indicated that minimum air temperature and precipitation during the grain-filling period had major roles in the prediction and excluding predictors in this period (i.e. yield forecast with a longer lead-time) decreased forecast performance of the models. These results were consistent with our understanding of meteorological impacts on wheat yield, suggesting usefulness of explainable machine learning in meteorological crop yield prediction under wet climate.


Assuntos
Triticum/crescimento & desenvolvimento , Cidades , Japão , Análise dos Mínimos Quadrados , Aprendizado de Máquina , Meteorologia , Redes Neurais de Computação , Estações do Ano , Máquina de Vetores de Suporte
7.
Gastroenterology ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34687740

RESUMO

BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

8.
Int J Mol Sci ; 22(20)2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34681900

RESUMO

Patients with advanced ovarian cancer usually exhibit high mortality rates, thus more efficient therapeutic strategies are expected to be developed. Recent transcriptomic studies revealed that long intergenic noncoding RNAs (lincRNAs) can be a new class of molecular targets for cancer management, because lincRNAs likely exert tissue-specific activities compared with protein-coding genes or other noncoding RNAs. We here show that an unannotated lincRNA originated from chromosome 10q21 and designated as ovarian cancer long intergenic noncoding RNA 1 (OIN1), is often overexpressed in ovarian cancer tissues compared with normal ovaries as analyzed by RNA sequencing. OIN1 silencing by specific siRNAs significantly exerted proliferation inhibition and enhanced apoptosis in ovarian cancer cells. Notably, RNA sequencing showed that OIN1 expression was negatively correlated with the expression of apoptosis-related genes ras association domain family member 5 (RASSF5) and adenosine A1 receptor (ADORA1), which were upregulated by OIN1 knockdown in ovarian cancer cells. OIN1-specifc siRNA injection was effective to suppress in vivo tumor growth of ovarian cancer cells inoculated in immunodeficient mice. Taken together, OIN1 could function as a tumor-promoting lincRNA in ovarian cancer through modulating apoptosis and will be a potential molecular target for ovarian cancer management.

9.
Exp Cell Res ; 409(1): 112889, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34678306

RESUMO

Although stem cell aging leads to a decline in tissue homeostasis and regenerative capacity, it remains unclear whether salivary gland stem cell function changes during this process. However, the salivary glands are gradually replaced by connective tissue during aging. Here, we show a decline in the stem cell ability of CD133-positive stem/progenitor cells in the salivary glands of aged mice. The CD133-positive cells were isolated from young, adult, and aged mice. The number of CD133-positive cells was significantly decreased in aged mice. They also showed a lower sphere formation capacity compared to young and adult mice. RNA sequencing revealed that CD133-positive cells in aged mice exhibited lower gene expression of several aging-related genes, including FoxO3a, than those in young and adult mice. Salivary gland cells infected with a recombinant lentivirus encoding the FoxO3a gene showed a reduction in oxidative stress induced by hydrogen peroxide compared with those infected with a control virus. Thus, FoxO3a may inhibit stem cell aging via oxidative stress.

10.
J Travel Med ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542626

RESUMO

A 32-year-old man, who visited Japan from the Philippines in 2020, was diagnosed with rabies. This is the first reported case in Japan since 2006. This is the fourth imported case of rabies since 1957; one case in 1970 was imported from Nepal and two in 2006 from the Philippines.

11.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502206

RESUMO

The process of fracture healing varies depending upon internal and external factors, such as the fracture site, mode of injury, and mechanical environment. This review focuses on site-specific fracture healing, particularly diaphyseal and metaphyseal healing in mouse long bones. Diaphyseal fractures heal by forming the periosteal and medullary callus, whereas metaphyseal fractures heal by forming the medullary callus. Bone healing in ovariectomized mice is accompanied by a decrease in the medullary callus formation both in the diaphysis and metaphysis. Administration of estrogen after fracture significantly recovers the decrease in diaphyseal healing but fails to recover the metaphyseal healing. Thus, the two bones show different osteogenic potentials after fracture in ovariectomized mice. This difference may be attributed to the heterogeneity of the skeletal stem cells (SSCs)/osteoblast progenitors of the two bones. The Hox genes that specify the patterning of the mammalian skeleton during embryogenesis are upregulated during the diaphyseal healing. Hox genes positively regulate the differentiation of osteoblasts from SSCs in vitro. During bone grafting, the SSCs in the donor's bone express Hox with adaptability in the heterologous bone. These novel functions of the Hox genes are discussed herein with reference to the site-specificity of fracture healing.


Assuntos
Consolidação da Fratura , Fraturas Ósseas/terapia , Osteogênese , Animais , Diáfises , Camundongos
12.
J Vet Med Sci ; 83(10): 1563-1569, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34470975

RESUMO

The rabies virus is one of the most neurotropic of all viruses infecting mammals. During the terminal phases of infection, the virus spreads to peripheral tissues, including the skin. The external skin of the nose, called the nasal planum, is a sensory organ where numerous nerve bundles and terminal nerves are distributed. Therefore, the nasal planum is expected to serve as a postmortem diagnostic material. However, the distribution of rabies virus antigens in the nasal planum in rabid animals has not yet been studied. In this study, the nasal planum was obtained from 45 rabid dogs. In all rabid dogs, the viral antigen was detected in the peripheral nerve tissues, Merkel cells, and squamous cells. The viral antigen in the epidermis exhibited three patterns: first, a diffuse positive pattern from the basal layer to the squamous layer; second, a reticular positive pattern along the cell membrane in the squamous layer; and third, a basal layer pattern of the epidermis. In the dermis, viral antigens were detected more often in lamellated corpuscles just beneath the rete pegs. These results suggest that the nasal planum could serve as a useful alternative source for postmortem diagnosis in rabies endemic countries.


Assuntos
Antígenos Virais , Animais , Autopsia/veterinária , Cães
13.
J Med Case Rep ; 15(1): 404, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34384492

RESUMO

BACKGROUND: A high-grade pancreatic injury is a life-threatening injury that is associated with high mortality and morbidity. It is currently unclear which treatment strategy results in good clinical outcomes. CASE PRESENTATION: A 23-year-old Japanese woman sustained severe injury in a motor vehicle accident. Abdominal computed tomography revealed severe pancreatic head injury with extravasation of contrast media. Since it was not possible to insert an endoscopic pancreatic stenting tube into the main pancreatic duct, damage control surgery was performed. On day 3, we could insert the endoscopic pancreatic stenting tube from the ampulla of Vater and an endoscopic nasopancreatic drainage tube in the distal pancreatic duct from the accessory ampulla before the second operation. Drainage tubes were placed around the pancreatic head in the second operation. The endoscopic nasopancreatic drainage tube tube was converted to endoscopic pancreatic stenting tube on day 9. On day 51, the patient was discharged on foot from our hospital without serious complications. CONCLUSION: Early and effective hemostasis, staged pancreatic duct drainage with stenting, and surgical external drainage around the pancreas in combination with an endoscopic procedure and damage control surgery were considered appropriate therapeutic strategy for high-grade pancreatic injury.


Assuntos
Traumatismos Abdominais , Traumatismos Craniocerebrais , Pancreatopatias , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Drenagem , Feminino , Humanos , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgia , Ductos Pancreáticos/diagnóstico por imagem , Ductos Pancreáticos/cirurgia , Stents , Adulto Jovem
14.
Am J Trop Med Hyg ; 105(3): 788-793, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34339383

RESUMO

Vietnam is a rabies-endemic country where eating dog meat is customary. However, the risks of rabies transmission to dog slaughtering and processing workers have not been identified. This study aimed to determine the rabies neutralizing antibody (NTA) and risk factors in dog slaughterers to propose appropriate intervention methods for this occupational group. In 2016, a cross-sectional study on NTA against rabies virus and related factors was conducted among 406 professional dog slaughterers in Vietnam. The participants were interviewed using a structured questionnaire, and their sera were tested for rabies NTA by a rapid focus fluorescence inhibition test. Statistical algorithms were used to analyze the data. The results showed that most of the professional dog butchers (344/406 subjects, 84.7%) had no rabies NTA. Interestingly, 7.8% (29/373) had NTA without a rabies vaccination history. Over 5 years of experience as a dog butcher was positively associated with the presence of NTA in unvaccinated individuals (OR = 6.16, P = 0.001). The NTA in vaccinated butchers was present in higher titer and for longer persistence to those of other previously reported professionals, which is possibly as a result of multiple exposures to low levels of rabies virus antigens during dog slaughtering. Our study demonstrated that professional dog butchers in Vietnam are at a high risk of rabies virus infection, apart from those with common bite experiences. In countries where dog meat consumption is customary, rabies control and prevention activities should focus on safety during dog trading and slaughtering.


Assuntos
Matadouros , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Exposição Ocupacional , Vírus da Raiva/imunologia , Raiva/epidemiologia , Adolescente , Adulto , Idoso , Animais , Mordeduras e Picadas , Cães , Feminino , Luvas Protetoras , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traumatismos Ocupacionais/epidemiologia , Raiva/imunologia , Raiva/prevenção & controle , Vacinas Antirrábicas/uso terapêutico , Fatores de Risco , Fatores de Tempo , Vietnã/epidemiologia , Adulto Jovem
15.
Proc Natl Acad Sci U S A ; 118(35)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34433666

RESUMO

Increasing attention has been paid to roles of tripartite motif-containing (TRIM) family proteins in cancer biology, often functioning as E3 ubiquitin ligases. In the present study, we focus on a contribution of TRIM47 to breast cancer biology, particularly to endocrine therapy resistance, which is a major clinical problem in breast cancer treatment. We performed immunohistochemical analysis of TRIM47 protein expression in 116 clinical samples of breast cancer patients with postoperative endocrine therapy using tamoxifen. Our clinicopathological study showed that higher immunoreactivity scores of TRIM47 were significantly associated with higher relapse rate of breast cancer patients (P = 0.012). As functional analyses, we manipulated TRIM47 expression in estrogen receptor-positive breast cancer cells MCF-7 and its 4-hydroxytamoxifen (OHT)-resistant derivative OHTR, which was established in a long-term culture with OHT. TRIM47 promoted both MCF-7 and OHTR cell proliferation. MCF-7 cells acquired tamoxifen resistance by overexpressing exogenous TRIM47. We found that TRIM47 enhances nuclear factor kappa-B (NF-κB) signaling, which further up-regulates TRIM47. We showed that protein kinase C epsilon (PKC-ε) and protein kinase D3 (PKD3), known as NF-κB-activating protein kinases, are directly associated with TRIM47 and stabilized in the presence of TRIM47. As an underlying mechanism, we showed TRIM47-dependent lysine 27-linked polyubiquitination of PKC-ε. These results indicate that TRIM47 facilitates breast cancer proliferation and endocrine therapy resistance by forming a ternary complex with PKC-ε and PKD3. TRIM47 and its associated kinases can be a potential diagnostic and therapeutic target for breast cancer refractory to endocrine therapy.

16.
Trop Med Health ; 49(1): 59, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321105

RESUMO

BACKGROUND: The Philippines is one of the major endemic countries for canine rabies in Southeast Asia. However, detailed description and analysis of laboratory-confirmed animal rabies are limited. Highly accurate surveillance requires a thorough understanding of the target area-specific problems and obstacles. Therefore, we aim to describe and analyze the rabies suspect animals in Central Luzon, Philippines, to clarify the characteristics of management and clinical signs by conducting interviews with the owners. METHODS: We prospectively collected information on the rabies suspect animals submitted to the Regional animal laboratory in Central Luzon through passive laboratory-based rabies surveillance between 1st April 2019 and 30th September 2020. We performed active interviews directly or telephonically with the owner. The direct fluorescent antibody test was performed on the hippocampus, brain stem, and cerebellum for laboratory confirmation. Descriptive statistics were used to characterize the number of rabies cases according to management methods and characteristics of suspected animals during the observation period. Clinical symptoms of suspected rabid animals were analyzed by univariate logistic regression analysis. RESULTS: There were 292 sample submissions during the study period. Of these, 160 were positive for dFAT. Samples of pet animals (85.3%) provided by owners or their acquaintances (59.2%) accounted for the majority of laboratory confirmed cases. Case mapping showed that more rabies-suspected cases were sent from areas near the regional laboratory than from those far from the laboratory, despite the incidence of rabies being high in these areas. The management and clinical symptoms of 227 animal cases showed that most owners were managing their animals at home and were allowing them to roam outside (69.6%) and be unvaccinated (78.9%). Rabid animals were more likely to manifest aimless running, restlessness, and agitation. CONCLUSIONS: Our study provided some features of animals with laboratory-confirmed rabies in Central Luzon. However, most of the samples were submitted from areas near the rabies diagnosis laboratory, and the number of samples submitted from remote areas was low. To improve the surveillance capacity, it is necessary to increase sample submissions from remote areas.

17.
Microbiol Immunol ; 65(10): 438-448, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34270107

RESUMO

Rabies is a type of acute fetal encephalitis caused by rabies virus (RABV). While it becomes incurable after symptom onset, it can be prevented by post-exposure prophylaxis (PEP) during the long incubation period. While preclinical diagnosis aids the appropriate PEP administration, it is mostly nonfeasible owing to the absence of viremia or a specific antibody response during the incubation period. Here, an attempt was made to identify a serum biomarker for the preclinical diagnosis of rabies. Using the serum from a mouse inoculated intramuscularly (i.m.) with 5 × 105 focus-forming units (FFU) of recombinant RABV expressing red firefly luciferase (1088/RFLuc) immediately before symptom onset, two-dimensional differential gel electrophoresis was conducted, followed by mass spectrometry, and it was confirmed that apolipoprotein A1 (ApoA1) was up-regulated. ELISA showed that the serum ApoA1 and specific antibody levels increased during the incubation period and on the day of symptom onset. Since a lower infectious dose can be used to induce the unstable and long incubation period generally observed in natural infection, the ApoA1 level in mice inoculated i.m. with 103 FFU of 1088/RFLuc was examined by monitoring viral dynamics using in vivo imaging. The serum ApoA1 and specific antibody levels were up-regulated in 50% and 58.3% of mice exhibiting robust RABV replication, respectively, but not in mice exhibiting weak RABV replication. In addition, it was reported that ApoA1 was found to be a biomarker for neuronal damage. Additional biomarker candidates will be needed for the effective preclinical diagnosis of rabies.


Assuntos
Vírus da Raiva , Raiva , Animais , Anticorpos Antivirais , Apolipoproteína A-I , Biomarcadores , Camundongos , Raiva/diagnóstico
18.
Bioorg Med Chem Lett ; 48: 128247, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34271070

RESUMO

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.

19.
Nat Commun ; 12(1): 3766, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145268

RESUMO

Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Regulação da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 1 Nuclear Respiratório/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Ribavirina/farmacologia , Transdução de Sinais , Transcriptoma/genética
20.
Arch Gerontol Geriatr ; 96: 104439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34090127

RESUMO

BACKGROUND: Post-stroke dysphagia is a common and expensive complication of acute stroke. The relationship between dysphagia and skeletal muscle loss (sarcopenia) has been recently highlighted. This study aimed to determine the relationship between temporal muscle thickness (TMT) measured by head magnetic resonance imaging (MRI) and dysphagia in patients with acute stroke. METHODS: Seventy participants (43 men and 27 women; mean age, 75.6 ± 12.7 years) were included in this study. TMT was measured by T2-magnetic resonance images within seven days of hospitalization. The severity of dysphagia was assessed using the Functional Oral Intake Scale (FOIS). Participants were classified into three categories according to the severity of dysphagia (severe: FOIS score, 1-3; mild: FOIS score, 4-6; normal: FOIS score, 7). Linear regression analysis was used to determine the independent explanators of dysphagia severity. RESULTS: Twenty participants (28.6%) had severe dysphagia, 31 participants (44.3%) had mild dysphagia, and 19 participants (27.1%) had normal swallowing function at discharge. The results of the linear regression analysis showed that TMT was a significant explanator of dysphagia severity following stroke, along with age and National Institute of Health Stroke Scale (NIHSS) score (P < 0.05, effect size: f2 = 0.72). CONCLUSIONS: TMT was an independent risk factor for dysphagia in patients with acute stroke. Skeletal muscle loss may be secondarily involved in dysphagia with acute stroke, and measurement of TMT with head MRI is a useful method to assess skeletal muscle loss.


Assuntos
Transtornos de Deglutição , Sarcopenia , Acidente Vascular Cerebral , Idoso , Deglutição , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Músculo Temporal
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