Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 870
Filtrar
1.
Numer Algorithms ; : 1-28, 2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33935468

RESUMEN

In this paper, we consider the sample average approximation (SAA) approach for a class of stochastic nonlinear complementarity problems (SNCPs) and study the corresponding convergence properties. We first investigate the convergence of the SAA counterparts of two-stage SNCPs when the first-stage problem is continuously differentiable and the second-stage problem is locally Lipschitz continuous. After that, we extend the convergence results to a class of multistage SNCPs whose decision variable of each stage is influenced only by the decision variables of adjacent stages. Finally, some preliminary numerical tests are presented to illustrate the convergence results.

2.
Eur J Med Chem ; 221: 113481, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33945934

RESUMEN

Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.

3.
Alzheimers Res Ther ; 13(1): 74, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33827675

RESUMEN

INTRODUCTION: Subjective cognitive decline (SCD) represents a cognitively normal state but at an increased risk for developing Alzheimer's disease (AD). Recognizing the glucose metabolic biomarkers of SCD could facilitate the location of areas with metabolic changes at an ultra-early stage. The objective of this study was to explore glucose metabolic biomarkers of SCD at the region of interest (ROI) level. METHODS: This study was based on cohorts from two tertiary medical centers, and it was part of the SILCODE project (NCT03370744). Twenty-six normal control (NC) cases and 32 SCD cases were in cohort 1; 36 NCs, 23 cases of SCD, 32 cases of amnestic mild cognitive impairment (aMCIs), 32 cases of AD dementia (ADDs), and 22 cases of dementia with Lewy bodies (DLBs) were in cohort 2. Each subject underwent [18F]fluoro-2-deoxyglucose positron emission tomography (PET) imaging and magnetic resonance imaging (MRI), and subjects from cohort 1 additionally underwent amyloid-PET scanning. The ROI analysis was based on the Anatomical Automatic Labeling (AAL) template; multiple permutation tests and repeated cross-validations were conducted to determine the metabolic differences between NC and SCD cases. In addition, receiver operating characteristic curves were used to evaluate the capabilities of potential glucose metabolic biomarkers in distinguishing different groups. Pearson correlation analysis was also performed to explore the correlation between glucose metabolic biomarkers and neuropsychological scales or amyloid deposition. RESULTS: Only the right middle temporal gyrus (RMTG) passed the methodological verification, and its metabolic levels were correlated with the degrees of complaints (R = - 0.239, p = 0.009), depression (R = - 0.200, p = 0.030), and abilities of delayed memory (R = 0.207, p = 0.025), and were weakly correlated with cortical amyloid deposition (R = - 0.246, p = 0.066). Furthermore, RMTG metabolism gradually decreased across the cognitive continuum, and its diagnostic efficiency was comparable (NC vs. ADD, aMCI, or DLB) or even superior (NC vs. SCD) to that of the metabolism of the posterior cingulate cortex or precuneus. CONCLUSIONS: These findings suggest that the hypometabolism of RMTG could be a typical feature of SCD, and the large-scale hypometabolism in patients with symptomatic stages of AD may start from the RMTG, which gradually progresses starting in the preclinical stage. The specificity of identifying SCD from the perspective of self-perceived symptoms is likely to be increased by the detection of RMTG metabolism.

4.
Biol Chem ; 2021 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-33823093

RESUMEN

Porphyromonas gingivalis is a bacterial species known to be involved in the pathogenesis of chronic periodontitis, that more recently has been as well associated with Alzheimer's disease. P. gingivalis expresses a glutaminyl cyclase (PgQC) whose human ortholog is known to participate in the beta amyloid peptide metabolism. We have elucidated the crystal structure of PgQC at 1.95 Å resolution in unbound and in inhibitor-complexed forms. The structural characterization of PgQC confirmed that PgQC displays a mammalian fold rather than a bacterial fold. Our biochemical characterization indicates that PgQC uses a mammalian-like catalytic mechanism enabled by the residues Asp149, Glu182, Asp183, Asp218, Asp267 and His299. In addition, we could observe that a non-conserved Trp193 may drive differences in the binding affinity of ligands which might be useful for drug development. With a screening of a small molecule library, we have identified a benzimidazole derivative rendering PgQC inhibition in the low micromolar range that might be amenable for further medicinal chemistry development.

5.
Qual Life Res ; 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33821418

RESUMEN

PURPOSE: The purpose of this study was to compare the measurement properties of two versions of EQ-5D (i.e.EQ-5D-3L and EQ-5D-5L) in hypertensive patients in rural China. METHODS: A cross-sectional survey was carried out in hypertensive patients in rural China. We compared the ceiling effects, redistribution properties, informativity, known-groups validity, and relative efficiency of the 3L and 5L and examined their agreement. RESULTS: A total of 11,412 patients were enrolled in our study. The mean EQ-5D index score was 0.84 (SD 0.21) according to the 5L and 0.86 (SD 0.17) according to the 3L. A good agreement was observed between the 3L and 5L. The overall ceiling effect decreased from 46.4% (3L) to 29.4% (5L). The Shannon index, H' improved in all dimensions when used 5L. When used 3L, the median responses of all groups were consistent with 5L across the three dimensions of 'mobility', 'self-care', 'usual activities', while the median responses were inconsistent for the 'pain/discomfort' and 'anxiety/depression' dimensions. The 3L performed better in eight comorbidities in terms of F-statistics and six comorbidities in terms of the area under the receiver operating characteristic curves (AUROCs). The 5L performed better both in terms of the F-statistics and AUROCs in age, education level, anti-hypertensive medication use. CONCLUSION: Taking all comparisons into account, we recommend the EQ-5D-5L for use in patients with hypertension in rural China.

6.
Oxid Med Cell Longev ; 2021: 1470380, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33854690

RESUMEN

Uric acid is the end product of purine metabolism in humans. Hyperuricemia is a metabolic disease caused by the increased formation or reduced excretion of serum uric acid (SUA). Alterations in SUA homeostasis have been linked to a number of diseases, and hyperuricemia is the major etiologic factor of gout and has been correlated with metabolic syndrome, cardiovascular disease, diabetes, hypertension, and renal disease. Oxidative stress is usually defined as an imbalance between free radicals and antioxidants in our body and is considered to be one of the main causes of cell damage and the development of disease. Studies have demonstrated that hyperuricemia is closely related to the generation of reactive oxygen species (ROS). In the human body, xanthine oxidoreductase (XOR) catalyzes the oxidative hydroxylation of hypoxanthine to xanthine to uric acid, with the accompanying production of ROS. Therefore, XOR is considered a drug target for the treatment of hyperuricemia and gout. In this review, we discuss the mechanisms of uric acid transport and the development of hyperuricemia, emphasizing the role of oxidative stress in the occurrence and development of hyperuricemia. We also summarize recent advances and new discoveries in XOR inhibitors.

7.
Hepatology ; 2021 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-33896016

RESUMEN

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the MYC oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop new therapies for MYC-driven HCC. Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosoamine (DEN). Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in a MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from HCC patients. Mechanistically, Prmt5, encoding protein arginine methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited anti-proliferative activity via upregulation of the tumor suppressor gene Cdkn1b/p27. In addition, GSK3326595 induced lymphocyte infiltration and MHC II expression, which might contribute to the enhanced anti-tumor immune response. Combination of GSK3326595 with anti-PD-1 immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. This study revealed that PRMT5 is an epigenetic executer of MYC leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC via PRMT5 inhibition through synergistically suppressed proliferation and enhanced anti-tumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.

8.
Autophagy ; : 1-19, 2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33866937

RESUMEN

The hepatitis B virus X protein (HBx) is involved in the process of hepatocellular carcinoma via the activation of various oncogenes. Our previous study indicated that ARBB1 (arrestin beta 1) promotes hepatocellular carcinogenesis (HCC). However, the role of ARRB1 in HBx-related HCC remains unclear. Herein, we identified that ARRB1 was upregulated by HBx in vivo and in vitro. Arrb1 deficiency suppressed HBx-induced hepatocellular carcinogenesis in several mouse models. Furthermore, knockdown of ARRB1 blocked HBx-induced macroautophagic/autophagic flux and disrupted the formation of autophagosomes. ARRB1 interacted with HBx, and the autophagic core protein MAP1LC3/LC3, a scaffolding protein, was essential for complete autophagy. Inhibition of autophagy by 3-methyladenine or interference of ATG5 or ATG7 attenuated HBx-induced cell cycle acceleration and the subsequent proliferative response via the induction of G1/S arrest. The absence of autophagy abolished the phosphorylation of CDK2 and the activity of the CDK2-CCNE1 complex. Our results demonstrate that ARRB1 plays a critical role in HBV-related HCC via modulating autophagy and the CDKN1B-CDK2-CCNE1-E2F1 axis and indicate that ARRB1 may be a potential therapeutic target for HCC.

9.
Immunotherapy ; 13(8): 661-668, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33876668

RESUMEN

Aim: To evaluate the cost-effectiveness of ribociclib plus fulvestrant versus fulvestrant in hormone receptor-positive/human EGF receptor 2-negative advanced breast cancer. Materials & methods: A three-state Markov model was developed to evaluate the costs and effectiveness over 10 years. Direct costs and utility values were obtained from previously published studies. We calculated incremental cost-effectiveness ratio to evaluate the cost-effectiveness at a willingness-to-pay threshold of $150,000 per additional quality-adjusted life year. Results: The incremental cost-effectiveness ratio was $1,073,526 per quality-adjusted life year of ribociclib plus fulvestrant versus fulvestrant. Conclusions: Ribociclib plus fulvestrant is not cost-effective versus fulvestrant in the treatment of advanced hormone receptor-positive/human EGF receptor 2-negative breast cancer. When ribociclib is at 10% of the full price, ribociclib plus fulvestrant could be cost-effective.

10.
Artículo en Inglés | MEDLINE | ID: mdl-33915015

RESUMEN

Aberrant activation of FGFR signaling occurs in many cancers, and ATP-competitive FGFR inhibitors have received regulatory approval. Despite demonstrating clinical efficacy, these inhibitors exhibit dose-limiting toxicity, potentially due to a lack of selectivity amongst the FGFR family and are poorly tolerated. Here, we report the discovery and characterization of DGY-09-192, a bivalent degrader that couples the pan-FGFR inhibitor BGJ398 to a CRL2 VHL E3 ligase recruiting ligand, which preferentially induces FGFR1&2 degradation while largely sparing FGFR3&4. DGY-09-192 exhibited two -digit nanomolar DC 50 s for both wildtype FGFR2 and several FGFR2-fusions, resulting in degradation-dependent antiproliferative activity in representative gastric cancer and cholangiocarcinoma cells. Importantly, DGY-09-192 induced degradation of a clinically relevant FGFR2 fusion protein in a xenograft model. Taken together, we demonstrate that DGY-09-192 has potential as a prototype FGFR degrader.

11.
Genes (Basel) ; 12(5)2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925652

RESUMEN

The Mediator complex transduces information from the DNA-bound transcription factors to the RNA polymerase II transcriptional machinery. Research on plant Mediator subunits has primarily been performed in Arabidopsis, while very few of them have been functionally characterized in rice. In this study, the rice Mediator subunit 16, OsMed16, was examined. OsMed16 encodes a putative protein of 1301 amino acids, which is longer than the version previously reported. It was expressed in various rice organs and localized to the nucleus. The knockout of OsMed16 resulted in rice seedling lethality. Its overexpression led to the retardation of rice growth, low yield, and spontaneous cell death in the leaf blade and sheath. RNA sequencing suggested that the overexpression of OsMed16 altered the expression of a large number of genes. Among them, the upregulation of some defense-related genes was verified. OsMed16 can regulate the expression of a wealth of genes, and alterations in its expression have a profound impact on plant growth, development, and defense responses in rice.

12.
Environ Sci Technol ; 55(9): 6257-6269, 2021 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-33856183

RESUMEN

Packing carriers into the anaerobic side-stream reactor (ASSR) can enhance sludge reduction and save footprint by investigating ASSR-coupled membrane bioreactors (AP-MBRs) under different hydraulic residence times of the ASSR (HRTSR). Three AP-MBRs and an anoxic-aerobic MBR (AO-MBR) showed efficient chemical oxygen demand (>94.2%) and ammonium nitrogen removal (>99.3%). AP-MBRs have higher (p < 0.05) total nitrogen (61.4-67.7%) and total phosphorus (57.5-63.8%) removal than AO-MBRs (47.8 and 47.7%). AP-MBRs achieved sludge reduction efficiencies of 11.8, 31.8, and 36.2% at HRTSR values of 2.5, 5.0, and 6.7 h. Packing carriers greatly improved sludge reduction under low HRTSR and is promising for accelerating sludge reduction in compact space. Metagenomic sequencing analysis showed that genes responsible for metabolism were enriched in AO-MBRs, while genes related to cellular motility and cell signaling were more abundant in the AP-MBRs. A longevity-regulating pathway showed that long lifespan provided more opportunities for worms to prey bacteria. Microscopic examination revealed that some specific protozoa (Arcella, Clathrulina, Aspidisca, Litonotus, Chiloclonella, and Vorticella) and metazoa (Rotaria and Aeolosoma hemprichi) were enriched in ASSRs. Aeolosoma hemprichi was only detected in ASSRs, and unique Cylops appeared on carriers. These results contribute to growing understanding of micrometabolic mechanisms including functional genes and microfauna-driving sludge reduction.

13.
Int J Surg Pathol ; : 10668969211002264, 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33749361

RESUMEN

Hamartomas are primary, benign neoplastic lesions that most commonly derive from a single variably differentiated cell lineage. Here, we report an unusual case of a cardiac hamartoma. A 62-year-old woman presented with chest pain and palpitations. Serial imaging revealed a large slowly growing and highly vascularized left ventricular mass, which required surgical resection. Microscopically, the lesion was composed of nodular fibrovascular proliferation with haphazardly embedded muscle bundles and peripheral calcifications. Immunohistochemical studies revealed prominent muscle-specific actin positive and smooth muscle actin positive muscle fiber bundles within a disorganized fibrovascular stroma. This characterization is most consistent with cardiac mesenchymal hamartoma. Relevant differential diagnoses for this lesion include hamartoma of mature cardiac myocytes (HMCMs) and intramuscular hemangioma. The prominent smooth muscle differentiation of muscle bundles was incompatible with defining features of HMCM. Absence of S100-positive nerve and mature adipose cells distinguished this lesion from the recently defined, heterogeneous cardiac mesenchymal hamartoma. Forty-seven cases of cardiac hamartoma reported from 1970 to 2020 were reviewed to provide histopathologic context.

14.
Bioresour Technol ; 329: 124903, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33662853

RESUMEN

Synchronous sludge reduction and nitrogen removal have attracted increasing attention, while the underlying mechanisms of diverse nitrogen metabolism within the complicated processes remain unclear. Four anoxic/oxic membrane bioreactors, three of which were upgraded by anaerobic side-stream reactors (ASSR) and carriers (APSSR-MBRs), were operated to determine effects of hydraulic retention time of ASSRs. APSSR-MBRs achieved more significant nitrogen removal and higher nitrate uptake rate because of more denitrifying bacteria and the supernumerary release of secondary substrates. Ammonia uptake rate showed the diverse Nitrospira preceded over anaerobic decay and sulfide inhibition in the ASSR, and made the reactor exhibit higher nitrification capacity. Metagenomic analysis indicated that APSSR-MBRs showed higher abundances of genes related to nitrogen consumption processes, and higher abundances on the carriers, confirming their pivotal roles in nitrogen metabolism. This study provided novel perspectives to build a bridge between process model and nitrogen metabolism in the sludge reduction system..


Asunto(s)
Nitrógeno , Eliminación de Residuos Líquidos , Anaerobiosis , Reactores Biológicos , Desnitrificación , Redes y Vías Metabólicas , Aguas del Alcantarillado
15.
Artículo en Inglés | MEDLINE | ID: mdl-33760799

RESUMEN

ABSTRACT: Coronary artery disease (CAD) and associated comorbidities such as heart failure (HF) remain as the leading cause of morbidity and mortality worldwide attributed to, at least partially, the lack of biomarkers for efficient disease diagnosis. Here, we evaluated the diagnostic potential of serum peptidoglycan recognition protein 1 (PGLYRP1), an important component of the innate immunity and inflammation system, for both CAD and HF. A machine-learning method (random forest) was used to evaluate the clinical utility of circulating PGLYRP1 for diagnosis of CAD and HF in a total of 370 individuals. Causal links of chronic serum PGLYRP1 elevation to both diseases were further explored in ApoE-/- mice. The serum levels of PGLYRP1 were significantly higher in individuals with either chronic CAD or acute coronary syndrome than that in those without coronary artery stenosis (the control group) and even more pronounced in CAD individuals with concomitant HF. Our random forest classifier revealed that this protein performed better than other recommended clinical indicators in distinguishing the CAD from the control individuals. In addition, this protein associates more with the biomarkers of HF including left ventricular ejection fraction than inflammation. Notably, our mice experiment indicated that long-term treatment with recombinant PGLYRP1 could significantly impair the cardiovascular system as reflected from both increased atherogenic lesions and reduced fractional shortening of the left ventricle. Our findings therefore supported the circulating levels of PGLYRP1 as a valuable biomarker for both CAD and HF.

16.
Schizophr Res ; 230: 53-60, 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33677199

RESUMEN

AIM: Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker. METHODS: In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off. RESULTS: Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%. CONCLUSIONS: The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.

17.
Mol Oncol ; 2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33751805

RESUMEN

Long noncoding RNAs (lncRNAs) have a profound effect on biological processes in various malignancies. However, few studies have investigated their functions and specific mechanisms in endometrial cancer. In this study, we focused on the role and mechanism of lncRNA-ZXF1 in endometrial cancer. Bioinformatics and in viro and in vivo experiments were used to explore the expression and function of lncRNA-ZXF1. We identified lncRNA-ZXF1 altered the migration and invasion of endometrioid endometrial cancer (EEC) cells. Furthermore, our results suggest that lncRNA-ZXF1 regulates EEC cell proliferation. This regulation may be achieved by the lncRNA-ZXF1-mediated alteration in the expression of P21 through two mechanisms. One is that lncRNA-ZXF1 functions as a molecular sponge of miR-378a-3p to regulate PCDHA3 expression and then modulate the expression of P21. The other is that lncRNA-ZXF1 inhibits CDC20-mediated degradation of ubiquitination by directly binding to P21. To the best of our knowledge, this study is the first to explore lncRNA-ZXF1 functioning as a tumor-suppressing lncRNA in EEC. LncRNA-ZXF1 may become therapeutic, diagnostic, and prognostic indicator in the future.

18.
Nat Chem Biol ; 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753926

RESUMEN

Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. In the present study, we report the rational design and characterization of a CDK12-specific degrader, BSJ-4-116. BSJ-4-116 selectively degraded CDK12 as assessed through quantitative proteomics. Selective degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibited potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor olaparib, as well as when used as a single agent against cell lines resistant to covalent CDK12 inhibitors. Two point mutations in CDK12 were identified that confer resistance to BSJ-4-116, demonstrating a potential mechanism that tumor cells can use to evade bivalent degrader molecules.

19.
Biochem Biophys Res Commun ; 548: 148-154, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33640608

RESUMEN

Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo. The above datas suggest that targeting CNR1 may reverse the progesterone resistance in endometrial cancer and may coordinate the role of ERK pathway activation.

20.
Medicine (Baltimore) ; 100(4): e24484, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530265

RESUMEN

BACKGROUND: Ewing sarcoma (ES), the second most prevalent bone malignant tumor has no widely known prognostic biomarker. Earlier studies have suggested that chaperonin containing TCP1 complex 6A (CCT6A), which encodes a molecular protein chaperone, is involved in the pathogenesis of many cancers. However, there are no known reports providing clear evidence of its role in ES pathogenesis. METHODS: We performed a bioinformatic analysis of 32 ES specimens from the GSE17618 dataset concentrating on the differences in gene expression, OS, event-free survival (EFS) in the different subgroups. Immunohistochemical studies were also performed to identify the expression levels of selected genes in ES and immediate paracancerous tissues. RESULTS: After 3 screenings, CCT6A was identified to be highly correlated with ES prognosis. Our survival analysis revealed a low overall survival (OS) for high CCT6A expression (P-value = .024). Our Cox regression analysis identified CCT6A expression, lEFS, and age were strongly associated with prognosis of ES. Our multivariate Cox regression analysis shows that CCT6A (P-value = .015), age (P-value = .026), and EFS (P-value = .002) were independent poor prognostic biomarkers. Our immunohistochemical analysis showed that the expression levels of CCT6A were significantly higher in ES tissues compared to the paracancerous tissues. CONCLUSION: From the results of our study, we identified the expression levels of CCT6A to be strongly associated with prognosis of ES. Thus, the expression levels of the CCT6A gene could serve as a biomarker for the prediction of ES prognosis.


Asunto(s)
Neoplasias Óseas/genética , Chaperonina con TCP-1/metabolismo , Sarcoma de Ewing/genética , Adolescente , Factores de Edad , Biomarcadores de Tumor/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Bases de Datos Genéticas , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...