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1.
Clin Endosc ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33789416

RESUMO

Acute liver failure due to malignant melanoma is uncommon. We presents a case of acute liver failure secondary to hepatic infiltration of a malignant melanoma. An 86-year-old man was admitted with elevated liver enzymes and an increased lactate dehydrogenase level. His condition progressed to acute liver failure, but the etiology of liver failure was unclear. Esophagogastroduodenoscopy was performed to evaluate dyspepsia, which showed signs indicative of malignant melanoma. Based on the endoscopy findings and elevated liver enzyme levels, liver biopsy was performed to confirm the presence of malignant melanoma. Hepatic infiltration of malignant melanoma was observed histologically. However, massive and diffuse liver metastasis is very rare and difficult to identify on imaging studies. If the etiology of liver failure is unclear, diffuse metastatic melanoma infiltration should be considered as differential diagnosis. Early liver biopsy can help to clarify the diagnosis.

2.
HERD ; : 1937586720988616, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33511880

RESUMO

The main purpose of this research is to examine the lighting condition and residents' perception of lighting in a senior retirement community in order to understand various environmental issues related to lighting. Also, this research aims to suggest a new lighting solution to compensate for older adults' vision impairment and challenges at home for a successful aging place. In the normal aging process, more than 30% of older adults have a vision impairment, which negatively affects health and well-being of older adults such as limited activities, falling, loneliness, depression, anxiety, and a sense of control. Via a mixed method study design, residents in senior living communities were asked to describe the adequacy of light levels and specific tasks and needs related to lighting at their home. In addition to the survey and interview, indoor lighting assessments were conducted during the in-home session. The research findings highlighted older adults' experience and perception of lighting in their homes. Paired-sample t test indicated that there were statistically significant differences in light levels between normal conditions and full capacity conditions in all spaces. In order to address various challenges which older adults have been experiencing in their home for a long time, this research suggests new smart lighting platform which provides a proper level of illumination in older adult's homes. Such a smart platform is proactive and can dynamically adjust the smart devices or lighting fixtures in situ, while older adults are performing certain tasks.

3.
Biologicals ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33277119

RESUMO

FGF21 (Fibroblast Growth Factor 21), which is expressed in the liver, adipose tissue, and pancreas, has been widely known as a therapeutic candidate for metabolic diseases. Though FGF21 is crucial to glucose, lipid, and energy homeostasis, it is not straightforward to develop a new drug with FGF21 due to its short half-life in serum. Here, we derived a novel long-acting FGF21 (LAPS-FGF21), which is chemically conjugated to the human IgG4 Fc fragment for longer half-life in serum. The recombinant human IgG4 Fc fragment and FGF21 were prepared by the refolding of inclusion body and periplasmic expression in Escherichia coli overexpression systems, respectively. The efficacy study of LAPS-FGF21 in a Diet-Induced Obesity (DIO) mouse model revealed that LAPS-FGF21 reduced body weight effectively accompanied by improved glucose tolerance in a dose-dependent manner. The administration of LAPS-FGF21 also improved the blood profiles with a significant reduction in cholesterol and triglyceride levels. Additionally, the pharmacokinetic (PK) studies of LAPS-FGF21 using normal ICR mice demonstrated that the half-life of LAPS-FGF21 was approximately 64-fold longer than FGF21. Taken together, the LAPS-FGF21 could be a feasible drug candidate with excellent bodyweight loss efficacy and longer dosing interval by half-life increase in serum.

4.
Bioorg Med Chem Lett ; : 127676, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33166687

RESUMO

We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50=19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50=0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.

5.
Psychiatry Res Neuroimaging ; 304: 111133, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-32805441

RESUMO

There is accruing evidence of cerebellar abnormalities in individuals with schizophrenia as measured by performance on a variety of tasks believed to be dependent on cerebellar integrity, including delay eyeblink conditioning. There is also evidence of cerebellar dysfunction on a neural level in schizophrenia from both task-based and resting state neuroimaging studies, however few studies have examined cerebellar neural function while the cerebellum is directly recruited in individuals with schizophrenia. In the current pilot study, we examined neural activity during an explicitly cerebellar task in individuals with schizophrenia or schizoaffective disorder and non-psychiatric controls. Participants underwent delay eyeblink conditioning during fMRI. Results indicated eyeblink conditioning impairment in patients as evidenced by a group by time interaction for conditioned responses. A significant cluster of cerebellar activation was present in controls but not patients during the first half of conditioning; there were no significant differences in activation between groups. An ROI analysis focused on the cerebellum in patients revealed two significant clusters that were inversely associated with negative symptom severity. These results are broadly consistent with the theory of cognitive dysmetria, wherein cerebellar abnormalities are theorized to contribute to motor as well as cognitive and affective disturbances in schizophrenia.

6.
Toxicol Appl Pharmacol ; 402: 115126, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32645313

RESUMO

Anemia is a frequent complication of chronic kidney disease (CKD) that causes an increase in morbidity and mortality and accelerates the rate of disease progression. Treatment with recombinant human erythropoietin (rhEPO) is a major breakthrough in the therapy of renal anemia. HM10760A, a long-acting EPO, has been developed as a treatment for anemia in CKD patients. A series of preclinical toxicology studies, such as acute, 4 week repeat-dose, and 13 week repeat-dose, was completed to support the safety of human exposure to HM10760A for up to 13 weeks. The rodent and non-rodent species used in the pivotal preclinical general toxicity studies were rats and monkeys, respectively. A once-a-week or once-every-two-week i.v dosing regimen was applied for 4 week and 13 week repeat-dose toxicity studies, respectively, in consideration of the expected administration frequency in humans. Based on the 13 week repeat-dose toxicity studies, 2.61 µg/kg and 22.03 µg/kg can be considered as the NOAELs (no observed adverse effect levels) in rats and monkeys, respectively. Almost all observations recorded at the low- and mid-dose levels are typical pharmacological effects of EPO and not uniquely attributed HM10760A toxicity. To account for the differences between human being and animal physiologies, the safety of HM10760A needs to be further confirmed in future clinical studies.

7.
Carcinogenesis ; 41(10): 1329-1340, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32649737

RESUMO

In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.

8.
Comput Struct Biotechnol J ; 18: 1761-1773, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695269

RESUMO

The brain is a complex network. Growing evidence supports the critical roles of a set of brain regions within the brain network, known as the brain's cores or hubs. These regions require high energy cost but possess highly efficient neural information transfer in the brain's network and are termed the rich-club. The rich-club of the brain network is essential as it directly regulates functional integration across multiple segregated regions and helps to optimize cognitive processes. Here, we review the recent advances in rich-club organization to address the fundamental roles of the rich-club in the brain and discuss how these core brain regions affect brain development and disorders. We describe the concepts of the rich-club behind network construction in the brain using graph theoretical analysis. We also highlight novel insights based on animal studies related to the rich-club and illustrate how human studies using neuroimaging techniques for brain development and psychiatric/neurological disorders may be relevant to the rich-club phenomenon in the brain network.

9.
Hum Brain Mapp ; 41(11): 3119-3132, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32250008

RESUMO

Abnormalities of cerebellar function have been implicated in the pathophysiology of schizophrenia. Since the cerebellum has afferent and efferent projections to diverse brain regions, abnormalities in cerebellar lobules could affect functional connectivity with multiple functional systems in the brain. Prior studies, however, have not examined the relationship of individual cerebellar lobules with motor and nonmotor resting-state functional networks. We evaluated these relationships using resting-state fMRI in 30 patients with a schizophrenia-spectrum disorder and 37 healthy comparison participants. For connectivity analyses, the cerebellum was parcellated into 18 lobular and vermal regions, and functional connectivity of each lobule to 10 major functional networks in the cerebrum was evaluated. The relationship between functional connectivity measures and behavioral performance on sensorimotor tasks (i.e., finger-tapping and postural sway) was also examined. We found cerebellar-cortical hyperconnectivity in schizophrenia, which was predominantly associated with Crus I, Crus II, lobule IX, and lobule X. Specifically, abnormal cerebellar connectivity was found to the cerebral ventral attention, motor, and auditory networks. This cerebellar-cortical connectivity in the resting-state was differentially associated with sensorimotor task-based behavioral measures in schizophrenia and healthy comparison participants-that is, dissociation with motor network and association with nonmotor network in schizophrenia. These findings suggest that functional association between individual cerebellar lobules and the ventral attentional, motor, and auditory networks is particularly affected in schizophrenia. They are also consistent with dysconnectivity models of schizophrenia suggesting cerebellar contributions to a broad range of sensorimotor and cognitive operations.

10.
Gut Liver ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32000469

RESUMO

Background/Aims: Recently, the European Society of Gastrointestinal Endoscopy (ESGE) proposed criteria for "difficult biliary cannulation" during endoscopic retrograde cholangiopancreatography (ERCP). This study aimed to investigate the clinical relevance of the ESGE criteria from the perspective of post-ERCP pancreatitis (PEP). Methods: An ERCP database was prospectively maintained between November 2014 and December 2015 across six teaching hospitals in South Korea. The ESGE criteria (biliary cannulation time, the number of cannulation attempts, and inadvertent pancreatic duct [PD] manipulation) were recorded in this database as well as other technical factors. Logistic regression analysis was used to identify risk factors for PEP. Then, the PEP prediction model was investigated using decision tree analysis. Results: We analyzed 1,067 consecutive patients with naïve papilla. The overall rate of PEP was 6.6%. Multivariate analysis revealed that female sex (odds ratio [OR], 1.860; 95% confidence interval [CI], 1.124 to 3.078), a selective biliary cannulation duration >5 minutes (OR, 3.282; 95% CI, 1.641 to 6.566), and inadvertent PD manipulation (OR, 2.614; 95% CI, 1.480 to 4.617) were significant factors affecting PEP. Decision tree analysis revealed that biliary cannulation time (χ2=49.857, p<0.001) and inadvertent PD manipulation (χ2=8.556, p=0.010) were decisive factors. PEP occurred in 3.9%, 11.8%, and 16.2% of patients with biliary cannulation duration lasting 3 to 5 minutes, >5 minutes, and >5 minutes with inadvertent PD manipulation, respectively. Conclusions: Biliary cannulation time and inadvertent PD manipulation could be relevant indicators of PEP, and 5 minutes might be used as a cutoff value for the implementation of the rescue cannulation technique.

11.
Mol Carcinog ; 59(2): 154-167, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31746054

RESUMO

CD248, also called endosialin or tumor endothelial marker-1, is markedly upregulated in almost all cancers, including colon cancers. Changes in microRNA profiles are one of the direct causes of cancer development and progression. In this study, we investigated whether a change in CD248 expression in colon cancer cells could induce drug resistance after chemotherapy, and we explored the relationship between miR-125b-5p levels and CD248 expression in Toll-like receptor (TLR)-modified chemoresistant colon cancer cells. TLR2/6 and TLR5 upregulation in drug-resistant colon cancer cells contributed to miR-125b-5p downregulation and specificity protein 1 (Sp1)-mediated CD248 upregulation via nuclear factor-kappa B (NF-κB) activation. Exposure to specific TLR2/6 or TLR5 ligands enhanced the expression of mesenchymal markers as well as the migratory activity of oxaliplatin- or 5-fluorouracil-resistant colon cancer cells. The transfection of a synthetic miR-125b-5p mimic into chemoresistant cells prevented Sp1 and CD248 activation and significantly impaired invasive activity. Furthermore, Sp1 or CD248 gene silencing as well as miR-125b-5p overexpression markedly reversed drug resistance and inhibited epithelial-mesenchymal transition in colon cancer cells. Taken together, these results suggest that changes in miR-125b-5p levels play an important role in Sp1-mediated CD248 expression and the development of drug resistance in TLR-mutated colon cancer cells.


Assuntos
Antígenos CD/genética , Antígenos de Neoplasias/genética , Neoplasias Colorretais/genética , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Receptores Toll-Like/genética , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , NF-kappa B/metabolismo , Interferência de RNA , Receptores Toll-Like/metabolismo
12.
Brain Imaging Behav ; 14(5): 2062-2071, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302844

RESUMO

Human and animal studies have shown that heavy cannabis (CB) use interacts with glutamatergic signaling. Additionally, recent studies have suggested that glutamate (Glu) may drive resting state functional connectivity (RSfc). The aims of the current preliminary study were to: 1) determine whether dorsal anterior cingulate cortex (dACC) Glu is related to RSfc between the dACC and two nodes of the reward network, the nucleus accumbens (NAc) and hippocampus (Hp); and 2) determine whether CB use interacts with the relationship between dACC Glu and RSfc. A group of 23 chronic CB users and 23 healthy controls participated in this multimodal MRI study. Glu levels were assessed in the dACC using magnetic resonance spectroscopy (MRS). Linear regression models were used to determine whether dACC Glu and CB use predicts RSfc between the dACC and the NAc and Hp. While the effect size is small, the results showed that the connectivity between the dACC and right NAc was predicted by the interaction between dACC Glu levels and monthly CB use. Additionally, while there is some suggestion that dACC Glu is correlated with dACC-hippocampal connectivity, unlike for dACC/NAc connectivity the relationship between them does not appear to be affected by CB use. These preliminary findings are significant in that they demonstrate the need for future studies with larger sample sizes to better characterize the relationship between resting state connectivity and neurochemistry as well as to characterize how CB use interacts with that relationship.

13.
Arch Dermatol Res ; 312(1): 59-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31602487

RESUMO

Acne is a chronic skin disease of the pilosebaceous unit resulting from Propionibacterium acnes (P. acnes), a commensal microorganism. Although numerous therapies are available for acne, there is still a need for the development of effective therapies. Erythroid differentiation regulator 1 (Erdr1) has been suggested to be beneficial during inflammatory skin diseases. In the current study, we first showed that Erdr1 expression level was lower in inflammatory acne skin compared to the normal skin, suggesting that Erdr1 was negatively regulated in acne skin. To evaluate the effect of Erdr1 further, Erdr1 was injected subcutaneously in the acne mouse model. Results revealed that the necrotic lesions by inflamed acne were dramatically decreased and collagen synthesis and fibroblasts activation were induced by Erdr1. In addition, Erdr1 reduced the infiltration of inflammatory cells in vivo and accelerated collagen production in P. acnes-treated human dermal fibroblasts through TGF-ß/Smad signaling. Taken together, Erdr1 enhanced wound healing through acceleration of collagen synthesis and activation of fibroblasts in acne skin, suggesting its potential use for acne improvement.


Assuntos
Acne Vulgar/patologia , Colágeno/biossíntese , Proteínas de Membrana/metabolismo , Proteínas de Membrana/farmacologia , Propionibacterium acnes , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/farmacologia , Cicatrização/fisiologia , Acne Vulgar/microbiologia , Animais , Células Cultivadas , Feminino , Fibroblastos/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Pelados , Pele/metabolismo , Proteínas Supressoras de Tumor/genética
14.
Data Brief ; 27: 104593, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31660423

RESUMO

This article provides acoustic measurements data for vowel nasalization which are based on speech recorded from fifteen (8 female and 7 male) native speakers of American English in a laboratory setting. Each individual speaker's production patterns for the vowel nasalization in tautosyllabic CVN and NVC words are documented in terms of three acoustic parameters: the duration of nasal consonant (N-Duration), the duration of vowel (V-Duration) and the difference between the amplitude of the first formant (A1) and the first nasal peak (P0) obtained from the vowel (A1-P0) as an indication of the degree of vowel nasalization. The A1-P0 is measured at three different time points within the vowel -i.e., the near point (25%), midpoint (50%), and distant point (75%), either from the onset (CVN) or the offset (NVC) of the nasal consonant. These measures are taken from the target words in various prosodic prominence and boundary contexts: phonologically focused (PhonFOC) vs. lexically focused (LexFOC) vs. unfocused (NoFOC) conditions; phrase-edge (i.e., phrase-final for CVN and phrase-initial for NVC) vs. phrase-medial conditions. The data also contain a CSV file with each speaker's mean values of the N-Duration, V-Duration, and A1-P0 (z-scored) for each prosodic context along with the information about the speakers' gender. For further discussion of the data, please refer to the full-length article entitled "Prosodically-conditioned fine-tuning of coarticulatory vowel nasalization in English"(Cho et al., 2017).

15.
Mar Drugs ; 17(9)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505769

RESUMO

Intracellular reactive oxygen species (ROS) play an important role in the proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). HSPCs are difficult to be expanded ex vivo while maintaining their stemness when they are exposed to oxidative damage after being released from the bone marrow. There have been efforts to overcome this limitation by using various cytokine cocktails and antioxidants. In this study, we investigated the effects of echinochrome A (Ech A)-a well-established and non-toxic antioxidant-on the ex vivo expansion of HSPCs by analyzing a CD34+ cell population and their biological functions. We observed that Ech A-induced suppression of ROS generation and p38-MAPK/JNK phosphorylation causes increased expansion of CD34+ cells. Moreover, p38-MAPK/JNK inhibitors SB203580 and SP600125 promoted ex vivo expansion of CD34+ cells. We also demonstrated that the activation of Lyn kinase and p110δ is a novel mechanism for Ech A to enhance ex vivo expansion of CD34+ cells. Ech A upregulated phospho-Src, phospho-Lyn, and p110δ expression. Furthermore, the Ech A-induced ex vivo expansion of CD34+ cells was inhibited by pretreatment with the Src family inhibitor PP1 and p110δ inhibitor CAL-101; PP1 blocked p110δ upregulation and PI3K/Akt activation, whereas CAL-101 and PI3K/Akt pathway inhibitor LY294002 did not block Src/Lyn activation. These results suggest that Ech A initially induces Src/Lyn activation, upregulates p110δ expression, and finally activates the PI3K/Akt pathway. CD34+ cells expanded in the presence of Ech A produced equal or more hematopoietic colony-forming cells than unexpanded CD34+ cells. In conclusion, Ech A promotes the ex vivo expansion of CD34+ cells through Src/Lyn-mediated p110δ expression, suppression of ROS generation, and p38-MAPK/JNK activation. Hence, Ech A is a potential candidate modality for the ex vivo, and possibly in vivo, expansion of CD34+ cells.


Assuntos
Antígenos CD34/metabolismo , Células Sanguíneas/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Naftoquinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo , Antracenos/farmacologia , Antioxidantes/metabolismo , Células Sanguíneas/metabolismo , Células Cultivadas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Piridinas/farmacologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
16.
Mar Drugs ; 17(7)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336860

RESUMO

Death-associated protein kinase 1 (DAPK1) expression induced by diverse death stimuli mediates apoptotic activity in various cancers, including ovarian cancer. In addition, mutual interaction between the tumor suppressor p53 and DAPK1 influences survival and death in several cancer cell lines. However, the exact role and connection of DAPK1 and p53 family proteins (p53, p63, and p73) in drug-resistant ovarian cancer cells have not been studied previously. In this study, we investigated whether DAPK1 induction by gliotoxin derived from marine fungus regulates the level of transcriptionally active p63 (TAp63) to promote apoptosis in an autophagy-dependent manner. Pre-exposure of paclitaxel-resistant ovarian cancer cells to gliotoxin inhibited the expression of multidrug resistant-associated proteins (MDR1 and MRP1-3), disrupted the mitochondrial membrane potential, and induced caspase-dependent apoptosis through autophagy induction after subsequent treatment with paclitaxel. Gene silencing of DAPK1 prevented TAp63-mediated downregulation of MDR1 and MRP1-3 and autophagic cell death after sequential treatment with gliotoxin and then paclitaxel. However, pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, had no effect on the levels of DAPK1 and TAp63 or on the inhibition of MDR1 and MRP1-3. These results suggest that DAPK1-mediated TAp63 upregulation is one of the critical pathways that induce apoptosis in chemoresistant cancer cells.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Gliotoxina/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Associadas com Morte Celular/genética , Proteínas Quinases Associadas com Morte Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Gliotoxina/uso terapêutico , Humanos , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Brain Lang ; 191: 31-45, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30807893

RESUMO

fMRI has been used as an outcome measure in dementia treatment studies, with many previous studies comparing only single pre- and post-treatment fMRI scans to determine treatment-induced neural changes, while utilizing single subject experimental designs. The purpose of the current study was to evaluate fMRI test-retest reliability in dementia patients and typical older adults using noun and verb confrontation naming to evaluate the validity of using a single pre/post-treatment scan comparison. Seven individuals with dementia and 9 control participants were tested three times over two months using the same fMRI procedures. Differences in individual and group level activation patterns were observed that varied across time. Additionally, the extent of variability fluctuated across individuals, groups, and the grammatical category of target words. Our findings suggested that one time fMRI scanning may inadequately represent an individual's typical brain activation pattern, particularly an individual with dementia. Thus, multiple imaging baselines are recommended.


Assuntos
Mapeamento Encefálico/normas , Encéfalo/diagnóstico por imagem , Demência/diagnóstico por imagem , Idioma , Imagem por Ressonância Magnética/normas , Idoso , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
18.
J Diabetes Res ; 2019: 2376512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729133

RESUMO

Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.


Assuntos
Ciclo Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Glucose/farmacologia , Insulina/farmacologia , Metformina/farmacologia , Pioglitazona/farmacologia , Bexiga Urinária/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Humanos , Hipoglicemiantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bexiga Urinária/citologia
19.
Neoplasia ; 21(2): 206-215, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30622051

RESUMO

CD97 shows a strong relationship with metastasis and poor clinical outcome in various tumors, including ovarian cancer. The expression of CD97 in metastatic ovarian cancer cells was higher than that in primary ovarian cancer cells. Mature miRNAs are frequently de-regulated in cancer and incorporated into a specific mRNA, leading to post-transcriptional silencing. In this study, we investigated whether the miR-503-5p targeting of the CD97 3'-untranslated region (3'-UTR) contributes to ovarian cancer metastasis as well as the underlying mechanism regulating cancer progression. In LPS-stimulated or paclitaxel-resistant ovarian cancer cells, stimulation with recombinant human CD55 (rhCD55) of CD97 in ovarian cancer cells activated NF-κB-dependent miR-503-5p down-regulation and the JAK2/STAT3 pathway, consequently promoting the migratory and invasive capacity. Furthermore, restoration of miR-503-5p by transfection with mimics or NF-κB inhibitor efficiently blocked CD97 expression and the downstream JAK2/STAT3 signaling pathway. Target inhibition of JAK with siRNA also impaired colony formation and metastasis of LPS-stimulated and paclitaxel-resistant ovarian cancer cells. Taken together, these results suggest that high CD97 expression, which is controlled through the NF-κB/miR-503-5p signaling pathway, plays an important role in the invasive activity of metastatic and drug-resistant ovarian cancer cells by activating the JAK2/STAT3 pathway.


Assuntos
Antígenos CD/genética , Regulação Neoplásica da Expressão Gênica , Janus Quinase 2/metabolismo , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , NF-kappa B , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Ligação Proteica , Interferência de RNA , Receptores Acoplados a Proteínas-G
20.
Schizophr Bull ; 45(3): 531-541, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29800417

RESUMO

Prominent conceptual models characterize schizophrenia as a dysconnectivity syndrome, with recent research focusing on the contributions of the cerebellum in this framework. The present study examined the role of the cerebellum and its effective connectivity to the cerebrum during sensorimotor synchronization in schizophrenia. Specifically, the role of the cerebellum in temporally coordinating cerebral motor activity was examined through path analysis. Thirty-one individuals diagnosed with schizophrenia and 40 healthy controls completed a finger-tapping fMRI task including tone-paced synchronization and self-paced continuation tapping at a 500 ms intertap interval (ITI). Behavioral data revealed shorter and more variable ITIs during self-paced continuation, greater clock (vs motor) variance, and greater force of tapping in the schizophrenia group. In a whole-brain analysis, groups showed robust activation of the cerebellum during self-paced continuation but not during tone-paced synchronization. However, effective connectivity analysis revealed decreased connectivity in individuals with schizophrenia between the cerebellum and primary motor cortex but increased connectivity between cerebellum and thalamus during self-paced continuation compared with healthy controls. These findings in schizophrenia indicate diminished temporal coordination of cerebral motor activity by cerebellum during the continuation tapping portion of sensorimotor synchronization. Taken together with the behavioral finding of greater temporal variability in schizophrenia, these effective connectivity results are consistent with structural and temporal models of dysconnectivity in the disorder.


Assuntos
Cerebelo/fisiopatologia , Conectoma , Córtex Motor/fisiopatologia , Rede Nervosa/fisiopatologia , Desempenho Psicomotor/fisiologia , Esquizofrenia/fisiopatologia , Tálamo/fisiopatologia , Percepção do Tempo/fisiologia , Adulto , Cerebelo/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Fatores de Tempo
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