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1.
Med Phys ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38063140

RESUMO

BACKGROUND: Accurate and automated segmentation of thoracic organs-at-risk (OARs) is critical for radiotherapy treatment planning of thoracic cancers. However, this has remained a challenging task for four major reasons: (1) thoracic OARs have diverse morphologies; (2) thoracic OARs have low contrast with the background; (3) boundaries of thoracic OARs are blurry; (4) class imbalance issue caused by small organs. PURPOSE: To overcome the above challenges and achieve accurate and automated segmentation of thoracic OARs on thoracic CT. METHODS: A novel cascaded framework based on mixed attention and multiscale information for thoracic OARs segmentation, called Cascaded-TOARNet. This cascaded framework comprises two stages: localization and segmentation. During the localization stage, TOARNet locates each organ to crop the regions of interest (ROIs). During the segmentation stage, TOARNet accurately segments the ROIs, and the segmentation results are merged into a complete result. RESULTS: We evaluated our proposed method and other common segmentation methods on two public datasets: the AAPM Thoracic Auto-Segmentation Challenge dataset and the Segmentation of Thoracic Organs at Risk (SegTHOR) dataset. Our method demonstrated superior performance, achieving a mean Dice score of 92.6% on the SegTHOR dataset and 90.8% on the AAPM dataset. CONCLUSIONS: This segmentation method holds great promise as an essential tool for enhancing the efficiency of thoracic radiotherapy planning.

2.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-993658

RESUMO

Objective:To analyze the influence of E-Coaching self-management model on health behavior change in perimenopausal women.Methods:In this randomized controlled trial, 230 perimenopausal women who participated in health management prograam in the Health Management Center of Hangzhou Wuyunshan Hospital from January 2020 to October 2021 were selected as study objects by convenience sampling method. The subjects were divided into the experimental group and the control group with random number table (115 cases in each group). The experimental group was managed by health coaches with E-Coaching self-management model, and the control group was routinely managed by health managers. The intervention lasted for 6 months. Finally, 29 cases were lost to follow-up due to the failure of the subjects to comply with protocol requirements or voluntary withdrawal. So, a total of 201 subjects were included in the analysis (107 cases in the experimental group and 94 cases in the control group). χ2 test and t test were used to analyze the differences in modified Kupperman symptom score, perimenopausal knowledge and belief, regular exercise and dietary healthy behavior stage between the two groups. And the influence of E-Coaching self-management model on health behavior change in perimenopausal women was analyzed too. Results:After the intervention, the total score of modified Kupperman scale and the scores of insomnia, anxiety and fatigue in the experimental group were all lower than those in the control group [(7.36±2.91) vs (10.01±2.78) points, (0.49±1.13) vs (1.27±1.20) points, (0.80±0.99) vs (1.68±1.39) points, (0.67±0.55) vs (0.93±0.64) points]( t=6.553, 4.785, 5.219, 3.013, all P<0.05); and the total score of knowledge and belief questionnaire and the score of knowledge or belief dimension in the experimental group were significantly higher than those in control group [(25.15±1.55) vs (21.05±1.64) points, (9.61±0.56) vs (9.03±0.68) points, (15.54±1.53) vs (12.02±1.28) points] ( t=-18.238, -6.570, -17.801, all P<0.05). After the intervention, the proportions of the experimental group in the precontemplation and contemplation stage of exercise and diet were both significantly lower than those before intervention ( χ2=116.616, 139.964, both P<0.001), and were lower than those in the control group (the proportion of precontemplation stage of exercise was 7.5% vs 38.3%, and the contemplation stage of exercise was 26.2% vs 34.0%, χ2=38.330; the proportion of precontemplation stage of diet was 3.7% vs 23.4%, and the contemplation stage of diet was 18.7% vs 29.8%, χ2=25.399; all P<0.001). After the intervention, the proportion of the subjects in the preparation stage and action stage the experimental group were significantly higher than those before intervention ( χ2=116.616, 139.964, both P<0.001), and were higher than those in the control group (the proportion in preparation stage of exercise 18.7% vs 8.5%, and the action stage of exercise 47.7% vs 19.1%, χ2=38.330; the proportion in preparation stage of diet 20.6% vs 14.9%, and the action stage of diet 57.0% vs 31.9%, χ2=25.399; all P<0.001). Conclusion:E-Coaching self-management model can improve women′s perimenopausal symptoms in certain degrees, it improves their understanding of perimenopausal knowledge, enhances self-management beliefs and promotes healthy behavior changes.

3.
Future Med Chem ; 14(20): 1471-1489, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36214138

RESUMO

Proteolysis-targeting chimera (PROTAC) is an emerging revolutionary technology that promotes degradation of target proteins by proteolysis. AR-targeting PROTACs marked many milestones in the history of PROTAC development. In this review, the author discusses the development of AR-targeting PROTACs over the last two decades. Also included in this focused review are medicinal chemistry strategies, pharmacokinetic profiles and clinical development. Taking AR targeting PROTACs for case study, this review provides a target specific overview of how PROTAC technology has advanced from a revolutionary concept and achieved proof of concept leading to drug candidates that benefit patients.


Assuntos
Proteínas , Humanos , Proteínas/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
4.
Bioorg Med Chem Lett ; 76: 128989, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36150638

RESUMO

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.


Assuntos
Códon sem Sentido , Quinazolinas , Quinazolinas/farmacologia , Pirimidinas/farmacologia , Guanidinas , Nitrogênio , Aminas
5.
Org Biomol Chem ; 19(13): 2895-2900, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33725062

RESUMO

The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2 as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.

6.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-883766

RESUMO

Objective:To investigate the relationship between mild cognitive impairment (MCI) and body mass index (BMI) in older adult patients with type 2 diabetes mellitus (T2DM).Methods:A total of 327 patients with T2DM who received treatment in Wuyunshan Sanatorium from January 2016 to May 2019 were included in the T2DM group. Patients in theT2DM group were subdivided into an MCI group ( n = 73) and a non-MCI group ( n = 254) according to whether they had MCI. An additional 100 older adult volunteers who concurrently received physical examination were included in the control group. Sex, age, years of education, monthly family income, body mass index, living habits (drinking, smoking) and laboratory indexes were compared among the groups. The influential factors of MCI in patients with T2DM were analyzed by logistic regression model. The predictive value of BMI for MCI in older adult patients with T2DM was evaluated by receiver operating characteristic (ROC) curve. Results:Age, monthly family income, the proportion of patients with a history of diabetes mellitus, BMI, fasting blood glucose, glycosylated hemoglobin (HbA1C), low-density lipoprotein cholesterol (LDL-C) in the T2DM group were (73.10 ± 9.56) years old, 8 926 yuan RMB, 189/327, (24.18 ± 2.64) kg/m 2, (6.96 ± 0.88) mmol/L, (7.10 ± 0.84)%, (7.32 ± 0.84) mmol/L, respectively, which were higher than those in the control group [(68.28 ± 8.21) years old, 6 715 yuan RMB, 13/100, (22.30 ± 1.74) kg/m 2, (4.51 ± 0.72) mmol/L, (5.62 ± 0.68)%, (7.04 ± 0.67) mmol/L, t = 4.554, χ2 = 18.601, 61.654, t = 6.668, t = 25.360, 16.077, 3.049, all P < 0.05]. In the MCI group, the proportion of patients having a monthly family income < 5 000 yuan RMB, the proportion of patients having a history of diabetes mellitus, BMI, HbA1c value were 29/73, 60/73, (24.92 ± 2.43) kg/m 2, (7.54 ± 0.88)%, respectively , while they were 70/254, 129/254, (23.77 ± 2.59) kg/m 2, (6.92 ± 0.81)%, respectively in the non-MCI group. There were significant differences in these indexes between MCI and non-MCI groups ( χ2 = 6.144, 22.927, t = 3.389, 5.652, all P < 0.05). Multivariate logistic regression analysis showed that BMI and HbA1c were the influential factors of MCI complicated by T2DM in older adult patients ( OR = 0.274, 0.192, both P < 0.05). Monthly family income and family history of diabetes mellitus were not closely related to the development of MCI in older adult patients with T2DM ( OR = - 0.154, 0.093, both P > 0.05). The ROC curve revealed that when BMI value was 24.49 kg/m 2, Youden index was the largest (0.510), the corresponding sensitivity was 83.86%, and the specificity was 67.12%. The area under the ROC curve was 0.766 [95% CI (0.699 - 0.832)]. Conclusion:BMI is an influential factor of MCI development in older adult patients with T2DM, and may be one of the important indicators for early prediction of MCI.

7.
Int. braz. j. urol ; 46(5): 705-715, Sept.-Oct. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1134219

RESUMO

ABSTRACT Sarcopenia, a concept reflecting the loss of skeletal muscle mass, was reported to be associated with the prognosis of several tumors. However, the prognostic value of sarcopenia in patients with renal cancer remains unclear. We carried out this metaanalysis and systematic review to evaluate the prognostic value of sarcopenia in patients with renal cell carcinomas. We comprehensively searched PubMed, Embase, and Cochrane Library from inception to December 2018. Hazard ratio (HR) and 95% confidence interval (CI) were pooled together. A total of 5 studies consisting of 771 patients were enrolled in this quantitative analysis, 347 (45.0%) of which had sarcopenia. Patients with sarcopenia had a worse OS compared with those without sarcopenia (HR=1.76; 95%CI, 1.35-2.31; P <0.001). In the subgroup of patients with localized and advanced/metastatic diseases, sarcopenia was also associated with poor OS (HR=1.48, P=0.039; HR=2.14, P <0.001; respectively). With a limited sample size, we did not observe difference of PFS between two groups (HR=1.56, 95% CI, 0.69-3.50, P=0.282). In the present meta-analysis, we observed that patients with sarcopenia had a worse OS compared with those without sarcopenia in RCC. Larger, preferably prospective studies, are needed to confirm and update our findings.


Assuntos
Humanos , Carcinoma de Células Renais/complicações , Sarcopenia/complicações , Neoplasias Renais/complicações , Prognóstico , Estudos Prospectivos
8.
J Med Chem ; 63(19): 11012-11033, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32924477

RESUMO

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.


Assuntos
Antineoplásicos , Desenho de Fármacos , Neoplasias , Ftalazinas , Piperazinas , Poli(ADP-Ribose) Polimerase-1 , Animais , Humanos , Camundongos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ligantes , Neoplasias/tratamento farmacológico , Ftalazinas/química , Piperazinas/química , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteólise
9.
Ann Clin Lab Sci ; 50(2): 161-171, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32366552

RESUMO

Increasing evidence suggested that inflammation is associated with the pathogenesis and progression of several solid tumors. This study was conducted to explore the association between C-reactive protein (CRP) and survival of prostate cancer (PCa). An electronic search was completed on the basis of PubMed, Embase and Cochrane Central Register of Controlled Trials. The hazard ratio (HR) and 95% confidence interval (CI) were extracted. Studies evaluating the relation between pretreatment levels of CRP and survival of PCa were included. Sixteen articles incorporating 17,833 patients were eligible for the present meta-analysis. Elevated pretreatment CRP level was significantly associated with poorer overall survival (OS) (HR=1.58, 95% CI 1.31-1.91, P<0.001), cancer-specific survival (CSS) (HR=1.83, 95% CI 1.19-2.80, P=0.006), progression-free survival (PFS) (HR=1.64, 95%CI 1.03-2.61, P=0.036), and biochemical-recurrence free survival (BC-RFS) (HR=1.29, 95% CI 1.11-1.51, P=0.001). Elevated pretreatment serum CRP level is strongly correlated with worse prognosis in patients with PCa, including OS, CSS, PFS and BC-RFS.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Neoplasias da Próstata/patologia , Progressão da Doença , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/metabolismo
10.
Clin Chim Acta ; 507: 143-148, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32333859

RESUMO

BACKGROUND: Progressive hemorrhagic injury (PHI) greatly affects prognosis of traumatic brain injury (TBI). D-dimer/fibrinogen ratio (D/F ratio) may be a potential predictor for venous thromboembolism. This study sought to describe and evaluate any relationship between D/F ratio and PHI after TBI. METHODS: This retrospective study included a cohort of 192 TBI patients. Plasma D-dimer and fibrinogen were measured, and subsequently D/F ratio was calculated. Multivariate logistic regression analysis was applied to identify predictors of PHI. Receiver operating characteristic (ROC) curve was conFig.d to analyze predictive capability for PHI. RESULTS: A total of 43 patients (22.4%) experienced PHI. Both Glasgow coma scale (GCS) score (odds ratio [OR], 0.565; 95% CI, 0.464-0.689) and D/F ratio (OR, 4.026; 95% CI, 2.219-7.305) were the two independent predictor for PHI. Area under ROC curve (AUC) of D/F ratio was similar to that of GCS score (AUC, 0.816; 95% CI, 0.754-0.868 vs. AUC, 0.834; 95% CI, 0.773-0.883; P = 0.699). Moreover, D/F ratio significantly improved AUC of GCS score to 0.928 (95% CI, 0.881-0.960; P < 0.001). CONCLUSIONS: D/F ratio was strongly predictive of PHI in the studied cohort and, thereby should be considered in the clinical management of TBI patients.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Progressão da Doença , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Hemorragia/sangue , Hemorragia/diagnóstico , Adulto , Estudos de Coortes , Feminino , Hemorragia/complicações , Hemorragia/patologia , Humanos , Masculino , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco
11.
Biochem Pharmacol ; 177: 113946, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32247852

RESUMO

Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Difenilamina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Proteínas/antagonistas & inibidores , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Animais , Linhagem Celular Tumoral , Difenilamina/síntese química , Difenilamina/química , Células HEK293 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Químicos , Estrutura Molecular , Células PC-3 , Neoplasias da Próstata/metabolismo , Proteínas/metabolismo
12.
Int Braz J Urol ; 46(5): 705-715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32213202

RESUMO

Sarcopenia, a concept reflecting the loss of skeletal muscle mass, was reported to be associated with the prognosis of several tumors. However, the prognostic value of sarcopenia in patients with renal cancer remains unclear. We carried out this meta-analysis and systematic review to evaluate the prognostic value of sarcopenia in patients with renal cell carcinomas. We comprehensively searched PubMed, Embase, and Cochrane Library from inception to December 2018. Hazard ratio (HR) and 95% confidence interval (CI) were pooled together. A total of 5 studies consisting of 771 patients were enrolled in this quantitative analysis, 347 (45.0%) of which had sarcopenia. Patients with sarcopenia had a worse OS compared with those without sarcopenia (HR=1.76; 95%CI, 1.35-2.31; P<0.001). In the subgroup of patients with localized and advanced/metastatic diseases, sarcopenia was also associated with poor OS (HR=1.48, P=0.039; HR=2.14, P<0.001; respectively). With a limited sample size, we did not observe difference of PFS between two groups (HR=1.56, 95% CI, 0.69-3.50, P=0.282). In the present meta-analysis, we observed that patients with sarcopenia had a worse OS compared with those without sarcopenia in RCC. Larger, preferably prospective studies, are needed to confirm and update our findings.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Sarcopenia , Carcinoma de Células Renais/complicações , Humanos , Neoplasias Renais/complicações , Prognóstico , Estudos Prospectivos , Sarcopenia/complicações
13.
Eur J Med Chem ; 187: 111952, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846828

RESUMO

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM). In human prostate cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteólise/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Células PC-3 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Chem Commun (Camb) ; 55(95): 14383-14386, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31723947

RESUMO

An AgI-promoted regioselective [4+2] annulation reaction of indoles with alkenes has been established. During the transformation, N-centered radicals are generated by the oxidation of the N-H bond of N-alkoxyamides. Control experiments and DFT calculations reveal a plausible mechanism. This synergistic process achieves the direct construction of new C-C and C-N bonds under relatively mild conditions with broad substrate scope, high atom economy, and easy-to-handle nature.

15.
Oncogene ; 38(10): 1702-1716, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30348991

RESUMO

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.


Assuntos
Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Complexo Repressor Polycomb 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Criança , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Sensors (Basel) ; 18(4)2018 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-29614739

RESUMO

Locality descriptions are generally communicated using reference objects and spatial relations that reflect human spatial cognition. However, uncertainty is inevitable in locality descriptions. Positioning locality with locality description, with a mapping mechanism between the qualitative and quantitative data, is one of the important research issues in next-generation geographic information sciences. Spatial relations play an important role in the uncertainty of positioning locality. In indoor landmark reference systems, the nearest landmarks can be selected when describing localities by using direction relations indoors. By using probability operation, we combine a set of uncertainties, that is, near and direction relations to positioning locality. Some definitions are proposed from cognitive and computational perspectives. We evaluate the performance of our method through indoor cognitive experiments. Test results demonstrate that a positioning accuracy of 3.55 m can be achieved with the semantically derived direction relationships in indoor landmark reference systems.


Assuntos
Cognição , Humanos , Incerteza
17.
Bioorg Med Chem Lett ; 27(22): 5014-5021, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29032026

RESUMO

The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8 µg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.


Assuntos
Antibacterianos/metabolismo , Compostos Azabicíclicos/química , DNA/metabolismo , Niacina/análogos & derivados , Piridinas/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , DNA/química , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Niacina/metabolismo , Niacina/farmacologia , Niacina/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Relação Estrutura-Atividade
18.
Chin J Cancer ; 36(1): 11, 2017 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-28088228

RESUMO

BACKGROUND: Ankyrin repeat and SOCS box protein 3 (ASB3) is a member of ASB family and contains ankyrin repeat sequence and SOCS box domain. Previous studies indicated that it mediates the ubiquitination and degradation of tumor necrosis factor receptor 2 and is likely involved in inflammatory responses. However, its effects on oncogenesis are unclear. This study aimed to investigate the effects of ASB3 on the growth and metastasis of colorectal cancer (CRC). METHODS: We used next-generation sequencing or Sanger sequencing to detect ASB3 mutations in CRC specimens or cell lines, and used real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical or immunofluorescence assay to determine gene expression. We evaluated cell proliferation by MTT and colony formation assays, tested cell cycle distribution by flow cytometry, and assessed cell migration and invasion by transwell and wound healing assays. We also performed nude mouse experiments to evaluate tumorigenicity and hepatic metastasis potential of tumor cells. RESULTS: We found that ASB3 gene was frequently mutated (5.3%) and down-regulated (70.4%) in CRC cases. Knockdown of endogenous ASB3 expression promoted CRC cell proliferation, migration, and invasion in vitro and facilitated tumorigenicity and hepatic metastasis in vivo. Conversely, the ectopic overexpression of wild-type ASB3, but not that of ASB3 mutants that occurred in clinical CRC tissues, inhibited tumor growth and metastasis. Further analysis showed that ASB3 inhibited CRC metastasis likely by retarding epithelial-mesenchymal transition, which was characterized by the up-regulation of ß-catenin and E-cadherin and the down-regulation of transcription factor 8, N-cadherin, and vimentin. CONCLUSION: ASB3 dysfunction resulted from gene mutations or down-regulated expression frequently exists in CRC and likely plays a key role in the pathogenesis and progression of CRC.


Assuntos
Neoplasias Colorretais , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Povo Asiático/genética , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Mutação , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Cicatrização
19.
Bioorg Med Chem Lett ; 26(6): 1529-1535, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26898814

RESUMO

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.


Assuntos
Carbolinas/química , Carbolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Carbolinas/síntese química , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
20.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-503576

RESUMO

ObjectiveTo analyze the influencing factors and explore the countermeasures of patients with complication of lower respiratory tract infection after tracheotomy in intensive care unit (ICU).Methods The clinical data of 382 patients with tracheotomy admitted to ICU of Hangzhou Third People's Hospital from March 2015 to March 2016 were retrospectively analyzed, including 153 patients with complicated lower respiratory tract infection as the infected group, and 229 cases without the infection as the no-infected group. The gender, age, emphysema, respiratory failure, time of admission to ICU, the kinds of antimicrobial agents used, time length of applying antimicrobial agents, aerosol inhalation, airway opening time, invasive operation, surgical opportunity and so on were analyzed in the two groups by univariate analysis. In order to screen out the independent risk factors for patients with complication of lower respiratory tract infection after tracheotomy in ICU, the multiple logistic regression analysis was used on the statistically significant risk factors found by using univariate analysis.Results There were statistically significant differences in age, emphysema, primary disease, respiratory failure, time of admission to ICU, the kinds of antimicrobial agents used,time length of using antimicrobial agents, aerosol inhalation, airway opening time, invasive operation and the time of mechanical ventilation between infected group and non-infected group (allP < 0.05). The single factor analysis showed that age [odds ratio (OR) = 5.868, 95% confidence interval (95%CI) = 2.790-10.342,P = 0.000), cerebral hemorrhage (OR = 3.920, 95%CI = 2.250-6.540,P = 0.034), cerebral infarction (OR = 1.048, 95%CI = 1.005-1.092,P = 0.027), emphysema (OR = 5.995, 95%CI = 2.851-8.374,P = 0.001), respiratory failure (OR = 5.022, 95%CI = 2.107-10.244, P = 0.009), time of admission to ICU (OR = 4.968,95%CI = 2.461-8.236,P = 0.003), airway opening time (OR = 4.149, 95%CI = 1.298-9.027,P = 0.019), the kinds of antimicrobial agents used (OR = 4.364, 95%CI = 1.166-9.339,P =0.029), time length of using antimicrobial agents (OR = 3.944, 95%CI = 1.546-7.622,P = 0.027), aerosol inhalation (OR = 2.052, 95%CI = 1.150-5.042,P = 0.014), invasive operation (OR = 3.467, 95%CI = 2.869-8.956,P = 0.000), surgical opportunity (OR = 0.366, 95%CI = 0.175-0.763,P = 0.037), the time of mechanical ventilation (OR = 0.981, 95%CI = 0.966-0.996,P = 0.041)were risk factors for patients with lower respiratory tract infection after tracheotomy in ICU. The multivariate logistic regression analysis showed that the risk factor sequence of influencing degree from high to low on occurrence of lower respiratory tract infection in patients after tracheotomy in ICU was as follows: time of admission to ICU (OR = 5.697, 95%CI = 2.891-8.739,P = 0.001), respiratory failure (OR = 5.543, 95%CI = 2.347-9.882, P = 0.012), emphysema (OR = 5.388, 95%CI = 2.671-7.963,P = 0.002), invasive operation (OR = 4.987, 95%CI =3.644-9.876,P = 0.014), time of using antimicrobial agents (OR = 4.823, 95%CI = 1.369-8.542,P = 4.823), the kinds of antimicrobial agents used (OR = 4.514, 95%CI = 1.369-8.542,P = 0.022), age (OR = 4.395, 95%CI = 2.194-8.786, P = 0.013), airway opening time (OR = 3.287, 95%CI = 2.542-9.677,P = 0.036) and aerosol inhalation (OR = 2.141, 95%CI = 1.242-5.211,P = 0.045).Conclusions The time of admission to ICU, invasive operation, emphysema and so on are the main risk factors of patients with complication of lower respiratory tract infection after tracheotomy in ICU, thus, corresponding measures should be directed to the risk factors and formulated to strengthen the prevention in order to control the occurrence of lower respiratory tract infections after tracheotomy in ICU.

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