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1.
BMC Cancer ; 19(1): 893, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492157

RESUMO

AIMS: To evaluate the short- and long-term outcomes of 3 different endoscopic dissection techniques for upper gastrointestinal (GI) submucosal tumours (SMTs). METHODS: Data for 135 patients withGI SMTs who underwent multiband mucosectomy (MBM), endoscopic submucosal dissection (ESD), or endoscopic submucosal excavation (ESE) were retrospectively assessed. The en bloc resection rate, endoscopic complete resection rate, operation time, potential complications and local recurrence rate were compared. RESULTS: No significant differences were observed in the rate of endoscopic complete resections and pathologic complete resections among the three groups. For SMTs > 15 mm in width, the lowest en bloc resection rate was found for MBM (P = 0.000). MBM was also associated with the shortest procedure time, lowest perforation rate and lowest rate of major bleeding. ESE was the most effective procedure for muscularis propria (MP) lesions but was associated with the longest operation time (P < 0.01). The ESD and ESE groups had similar perforation rates (P > 0.05). No differences were observed in 4-year local recurrence rates among the groups (P = 0.945). CONCLUSIONS: MBM is a simple and effective method for the treatment of small SMTs and achieves clinical success rates similar to those of ESD and ESE. However, ESD and ESE are preferable for larger and deep lesions and are associated with a longer operation time. Nonetheless, all 3 techniques resulted in a low 4-year local recurrence rate. Large-scale randomized clinical trials are needed to further investigate these results.

2.
Infect Dis Poverty ; 8(1): 65, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31378202

RESUMO

BACKGROUND: In addition to providing free hepatitis B vaccine (HBvacc) series to all infants in China since 2005, the national programme on prevention of mother-to-child transmission (PMTCT) of hepatitis B virus (HBV) started providing free hepatitis B immunoglobulin for all new-borns born to hepatitis B surface-antigen (HBsAg) positive mothers in 2010. However, few studies have evaluated the effectiveness of the PMTCT programme. Therefore, we aimed to investigate the outcomes of the programme and identify associated factors. METHOD: Using a cross-sectional study design, we collected data on 4112 pairs of HBsAg-positive mothers and their children aged 7-22 months in four representative provinces through interviews and medical record review. We tested HBsAg and hepatitis B surface antibody (anti-HBs) of children by enzyme-linked immunosorbent assay at designated maternal and child hospital laboratories. We used logistic regression to analyse factors associated with child HBsAg and anti-HBs positivity. RESULTS: Thirty-five children were HBsAg positive, indicating the mother-to-child transmission (MTCT) rate was 0.9% (0.6-1.1%). The anti-HBs positive rate was 96.8% (96.3-97.4%). Children receiving HBvacc between 12 and 24 h of birth were 2.9 times more likely to be infected than those vaccinated in less than 12 h (adjusted odds ratio [aOR] = 2.9, 95% confidence interval [CI]: 1.4-6.3, P = 0.01). Maternal hepatitis B e-antigen (HBeAg) positivity was associated with higher MTCT rate (aOR = 79.1, 95% CI: 10.8-580.2, P <  0.001) and lower anti-HBs positive rate (aOR = 0.4, 95% CI: 0.3-0.6, P <  0.001). Children with low birth weight (LBW) were 60% less likely to be anti-HBs positive than those with normal birth weight (aOR = 0.4, 95% CI: 0.2-0.8, P = 0.01). CONCLUSIONS: The MTCT rate was lower than the 2030 WHO elimination goal, which implies the programme is on track to achieve this target. As earlier HBvacc birth dose (HBvcc-BD) was associated with lower MTCT rate, we suggest that the PMTCT programme work with the Expanded Programme on Immunization (EPI) to modify the current recommendation for early HBvcc-BD to a requirement. Our finding that LBW was associated with lower anti-HBs positivity points to the need for further studies to understand factors associated with these risks and opportunities for program strengthening. The programme needs to ensure providing essential test to identify HBeAg-positive mothers and their infants and provide them with appropriate medical care and follow-up.

3.
J Hand Surg Eur Vol ; : 1753193419865894, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399012

RESUMO

We investigated the maximal advancement of the homodigital neurovascular island flap with the digit in full extension and its correlation to the digital length. In 32 adult cadaveric digits, flaps measuring 1 × 1 cm were sequentially elevated to different dissection points. Dissection of the flap to the proximal interphalangeal joint crease, palmo-digital crease, division of adjacent digital artery and the superficial arch resulted in flap advancement of 8, 12, 15 and 18 mm, respectively. The degree of advancement correlated to the length of the finger and was approximately 19% of the finger length. We conclude that dissection of a homodigital antegrade neurovascular island flap to the proximal interphalangeal joint, palmo-digital crease, after ligation of adjacent digital artery and the superficial arch allows progressively more advancement. The advancement obtained by flap dissection to the palmo-digital crease was about 19% of the finger length.

4.
Theranostics ; 9(17): 4935-4945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410192

RESUMO

Background: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. Methods: We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. Results: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. Conclusions: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.

5.
Bioresour Technol ; 291: 121848, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31377513

RESUMO

Butyrate is an important precursor for fine chemicals and biofuels. The aim of this study is to investigate butyrate production as affected by transition metal addition of food waste fermentation including, nickel, Raney nickel and copper particles. Performance of fermentation showed nickel particles achieved the highest butyrate concentration, 7.3 g/L, which was 38.5% higher than that in the control trial. Raney nickel also showed similar effect on the enhancement of butyrate production. However, increased dosage of transition metal particle addition led to decreased butyrate production. The theoretical link between metal-assisted dark fermentation and butyrate production was tentatively explored. Redox potential affected by nickel addition was assumed to be an essential factor for butyrate production. Microbial community analysis found Clostridium sensu stricto 11 may be the dominant functional species for butyrate production. The study demonstrates that development on transition metal catalyst may contribute to waste biorefinery for added value products/energy production.


Assuntos
Butiratos/metabolismo , Fermentação , Alimentos , Elementos de Transição/farmacologia , Clostridium/metabolismo , Fermentação/efeitos dos fármacos , Microbiota
6.
J Org Chem ; 84(14): 9344-9352, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31264870

RESUMO

A convenient and straightforward synthesis of diverse 2-C-alkenyl-glycosides through a palladium-catalyzed cross-coupling reaction between 2-iodoglycals and N-tosylhydrazones has been developed. Further transformation of 2-C-branched sugars by Diels-Alder reactions provided oxadecalins in good yields.

7.
Asian J Androl ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31169138

RESUMO

This study aimed to further validate the prognostic role of fibrinogen in upper tract urothelial carcinoma (UTUC) in a large Chinese cohort. A total of 703 patients who underwent radical nephroureterectomy were retrospectively identified. Fibrinogen levels of ≥4.025 g l-1 were defined as elevated. Logistic regression analysis was performed to determine the association between fibrinogen and adverse pathological features. Kaplan-Meier analysis and Cox regression models were used to assess the associations of fibrinogen with cancer-specific survival (CSS), disease recurrence-free survival (RFS), and overall survival (OS). Harrell c-index and decision curve analysis were used to assess the clinical utility of multivariate models. The median follow-up duration was 42 (range: 1-168) months. Logistic regression analysis revealed that elevated fibrinogen was associated with higher tumor stage and grade, lymph node involvement, lymphovascular invasion, sessile carcinoma, concomitant variant histology, and positive surgical margins (all P < 0.05). Multivariate Cox regression analysis demonstrated that elevated fibrinogen was independently associated with decreased CSS (hazard ratio [HR]: 2.33; P < 0.001), RFS (HR: 2.09; P < 0.001), and OS (HR: 2.09; P < 0.001). The predictive accuracies of the multivariate models were improved by 3.2%, 2.0%, and 2.8% for CSS, RFS, and OS, respectively, when fibrinogen was added. Decision curve analysis showed an added benefit for CSS prediction when fibrinogen was added to the model. Preoperative fibrinogen may be a strong independent predictor of worse oncologic outcomes in UTUC; therefore, it may be valuable to apply this marker to the current risk stratification in UTUC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31229458

RESUMO

BACKGROUND: Previous studies have revealed lymph node density (LND) to be an independent prognostic factor in cancer. However, data from 20 years ago failed to demonstrate the prognostic value of LND in node-positive renal-cell carcinoma (RCC). This study was undertaken to comprehensively investigate the prognostic value of LND in node-positive RCC. PATIENTS AND METHODS: Within the Surveillance, Epidemiology and End Results database, we accessed data on patients diagnosed with histologically confirmed node-positive RCC from 2004 to 2014. The cubic spline smoothing technique and Cox regression were used to evaluate the correlation between LND and cancer-specific mortality (CSM). The X-Tile program was used to identify the optimal cut point of LND in node-positive RCC. Robustness of the results in various subgroups was also explored. Univariable and multivariable analyses were performed to determine predictors of CSM. Sensitivity analyses were performed. RESULTS: A total of 1750 node-positive RCCs were identified. We found a nonlinear positive correlation between the likelihood of CSM and LND. X-Tile analysis identified best cut point of LND as 35% with a maximum chi-square of 18.58. Every 10% increase in LND increased CSM by 5% (hazard ratio = 1.05; 95% confidence interval, 1.02-1.07; P < .0001), and LND ≥ 35% was associated with 41% increase in CSM (hazard ratio = 1.41; 95% confidence interval, 1.20-1.65; P < .0001) in fully adjusted Cox regression. Results of sensitivity analyses were consistent with those of the primary analysis. CONCLUSION: LND is an independent prognostic factor in node-positive RCC and should be incorporated into the cancer staging system.

9.
J Affect Disord ; 256: 125-131, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31176184

RESUMO

BACKGROUND: Both peer victimization and internet addiction are common public health problems for children and adolescents. Several studies found an association between peer victimization and internet addiction, but the mechanism underlying this association remained unclear. This study aimed to determine the mechanisms underlying this association. METHODS: Data was extracted from an epidemiologic study involving middle and high school adolescents, in which 15,415 individuals (14.6 ±â€¯1.7 years) were recruited. The moderated mediation models were examined using SPSS PROCESS macro 2.16 software, in which the mediation variables were depressive symptoms and anxiety symptoms, and the moderation variable was school functioning. RESULTS: The total indirect effect of verbal victimization on internet addiction through depressive symptoms and anxiety symptoms was found to be 0.4531, which accounted for 63.7% of the total effect of verbal victimization on internet addiction. Depressive symptoms and anxiety symptoms totally mediated the association between relational victimization and internet addiction and the association between the physical victimization and internet addiction. There were gender differences in the mediating effects of depressive and anxiety symptoms on the association between peer victimization and internet addiction. The indirect effect of the three different types of peer victimization (physical, verbal, relational) on internet addiction became stronger as school functioning increased. LIMITATIONS: We included two mediators in one model, and the data used in this study was self-reported and cross-sectional. CONCLUSIONS: Depressive symptoms and anxiety symptoms mediate the association between peer victimization and internet addiction. Students who score higher in school functioning were more likely to develop internet addiction when they encounter peer victimization.

10.
J Immunol ; 203(2): 557-568, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31182480

RESUMO

Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv versus Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection as GVHD severity was similar in the recipients of wild-type Tconv combined with Notch-deprived versus wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and Th cell polarization. In contrast, Notch inhibition dampened IFN-γ and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with the pathogenic effects of Notch in T cells at the earliest stages of GVHD.

11.
J Cell Biochem ; 120(10): 17872-17886, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161623

RESUMO

BACKGROUND: Partial bladder outlet obstruction (PBOO) promotes bladder detrusor hyperplasia, increases bladder pressure, and decreases bladder compliance. To extensively explore its underlying mechanism, our study aimed to investigate the effect of pathological hydrostatic pressure on human bladder smooth muscle cell (hBSMC) proliferation and contraction through ß-adrenoceptor (ADRB) signaling in vitro. METHODS: hBSMCs were subjected to pathological hydrostatic pressure (100 cm H2 O) to investigate the effect of ADRBs on the proliferation and contraction of hBSMCs treated with its agonists and/or antagonists. RESULTS: Firstly, exposure to 100 cm H2 O hydrostatic pressure significantly upregulated the expression of α-smooth muscle actin (α-SMA) in hBSMCs at 6 hours, and promoted cell proliferation at 24 hours. When subjected to hydrostatic pressure alone, hBSMCs treated with ADRB2 and ADRB3 agonists for 6 hours inhibited α-SMA expression compared with untreated cells. By contrast, hBSMCs treated with ADRB2 agonists for 24 hours suppressed cell proliferation compared with untreated cells. The two classical pathways of ADRB, protein kinase A (PKA), and exchange factor directly activated by cAMP (EPAC) inhibited the contraction of hBSMCs under hydrostatic pressure via regulating mothers against decapentaplegic homolog 2 (SMAD2) activity. The proliferation of hBSMCs was mainly regulated by the EPAC pathway through extracellular signal-regulated kinase 1/2 (ERK1/2) activity. CONCLUSION: The contraction of hBSMCs under hydrostatic pressure was regulated by ADRB2 and ADRB3 via the PKA/EPAC-SMAD2 pathway, and the proliferation of hBSMCs was regulated by ADRB2 via the EPAC-ERK1/2 pathway. Compared with ADRB3, ADRB2 played a predominant role under pathological hydrostatic pressure. These findings markedly uncovered the underlying mechanism of ADRBs in PBOO and provided new insights into the efficient treatment of patients with PBOO.

12.
Prostate ; 79(10): 1180-1190, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31104320

RESUMO

INTRODUCTION: Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation; however, the mechanisms underlying these processes remain unclear. Thus, we selected interleukin-8 (IL-8) as the bridge between inflammation and cancer cell oxidative stress-induced death and aimed to confirm its connection with mTOR and Glycogen synthase kinase-3 beta (GSK-3ß). METHODS: We overexpressed GSK-3ß and observed its effect on reactive oxygen species (ROS) and oxidative stress-induced cell death. IL-8 was then upregulated or downregulated to determine its impact on preventing cell damage due to GSK-3ß-induced oxidative stress. In addition, we overexpressed or knocked down mTOR to confirm its role in this process. Real-time PCR, Western blotting, transcription, Cell Counting Kit 8 (CCK-8), and flow cytometry analyses were performed in addition to the use of other techniques. RESULTS: IL-8 promotes prostate cancer cell proliferation and decreases apoptosis, whereas GSK-3ß activates the caspase-3 signaling pathway by increasing ROS and thereby induces oxidative stress-mediated cell death. In addition, mTOR can also decrease activation of the caspase-3 signaling pathway by inhibiting GSK-3 and thus decreasing ROS production. Moreover, the inhibitory effect of IL-8 on GSK-3ß occurs through the regulation of mTOR. CONCLUSION: The results of this study highlight the importance of GSK-3ß, which increases the production of ROS and thereby induces oxidative stress in tumor cells, whereas IL-8 and mTOR attenuate oxidative stress to protect prostate cancer cells through inhibition of GSK-3ß.

13.
Clin Plast Surg ; 46(3): 451-468, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103089

RESUMO

Carpal instability and distal radioulnar joint instability represent an important set of conditions responsible for pain and disability in the wrist. Either condition can occur as a result of ligamentous failure or loss of articular congruity from fractures or a combination of both. Instability itself is a clinical diagnosis supported by relevant imaging modalities. Carpal and distal radioulnar joint instability needs to be considered according to its stage and severity as well as other factors like etiology and chronicity to determine the optimal treatment option. This article summarizes the conditions most relevant to the practice of a hand surgeon, with emphasis divided equally between assessment and diagnosis, staging, and treatment. The 3 most common carpal instability conditions are outlined in this article together with a review on acute and chronic distal radioulnar joint instability.


Assuntos
Articulações do Carpo , Instabilidade Articular/terapia , Articulação do Punho , Humanos , Instabilidade Articular/diagnóstico , Instabilidade Articular/etiologia
14.
Sci Adv ; 5(3): eaat9820, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30854423

RESUMO

Human endogenous retroviruses (HERVs) play pivotal roles in the development of breast cancer. However, the detailed mechanisms of noncoding HERVs remain elusive. Here, our genome-wide transcriptome analysis of HERVs revealed that a primate long noncoding RNA, which we dubbed TROJAN, was highly expressed in human triple-negative breast cancer (TNBC). TROJAN promoted TNBC proliferation and invasion and indicated poor patient outcomes. We further confirmed that TROJAN could bind to ZMYND8, a metastasis-repressing factor, and increase its degradation through the ubiquitin-proteasome pathway by repelling ZNF592. TROJAN also epigenetically up-regulated metastasis-related genes in multiple cell lines. Correlations between TROJAN and ZMYND8 were subsequently confirmed in clinical samples. Furthermore, our study verified that antisense oligonucleotide therapy targeting TROJAN substantially suppressed TNBC progression in vivo. In conclusion, the long noncoding RNA TROJAN promotes TNBC progression and serves as a potential therapeutic target.

15.
Carbohydr Res ; 475: 69-73, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877936

RESUMO

A general protocol for direct glucuronic linkages formation featuring Au(I)-catalyzed appropriately protected glucuronyl o-alkynylbenzoate-involved glycosylation reaction, as well as a concise approach for easy access of scutellarein prominent for the mild and efficient hydroxyl group installation via borylation-oxidation sequence from flavanone derivative, has been established, based on which a novel route for scutellarin derivatives preparation has been devised. The developed strategies, among which the stepwise deprotection process was also included, guarantee the high whole synthetic efficiency, and definitely will find broad application in diversity-oriented synthesis of bioactive flavonoid glycosides.


Assuntos
Apigenina/síntese química , Glucuronatos/síntese química , Apigenina/química , Glucuronatos/química , Estrutura Molecular
16.
Int J Cancer ; 145(3): 842-856, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30720865

RESUMO

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let-7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF-7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF-7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer-regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

17.
Curr Top Med Chem ; 19(1): 33-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30706785

RESUMO

BACKGROUND: Prostate cancer (PCa) is the most common sex-related malignancy with high mortality in men worldwide. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most prostate tumor cells and considered a valuable target for both diagnosis and therapy of prostate cancer. A series of radiolabeled agents have been developed based on the featured PSMA ligands in the previous decade and have demonstrated promising outcomes in clinical research of primary and recurrent PCa. Furthermore, the inspiring response and safety of lutetium-177-PSMA-617 (177Lu-PSMA-617) radiotherapy represent the potential for expanded therapeutic options for metastatic castration-resistant PCa. Retrospective cohort studies have revealed that radiolabeled PSMA agents are the mainstays of the current success, especially in detecting prostate cancer with metastasis and biochemical recurrence. OBJECTIVE: This review is intended to present a comprehensive overview of the current literature on PSMA ligand-based agents for both radionuclide imaging and therapeutic approaches, with a focus on those that have been clinically adopted. CONCLUSION: PSMA-based diagnosis and therapy hold great promise for improving the clinical management of prostate cancer.


Assuntos
Antígenos de Superfície/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Compostos Radiofarmacêuticos/análise , Compostos Radiofarmacêuticos/uso terapêutico , Humanos , Ligantes , Masculino , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/química
18.
Nat Cell Biol ; 21(3): 328-337, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778220

RESUMO

Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1α-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1α knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-RasG12D activates IRE1α-XBP1, through MEK-GSK3ß, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1α-XBP1 abolished N-RasG12D-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of NrasG12D HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.


Assuntos
Autorrenovação Celular/genética , Estresse do Retículo Endoplasmático/genética , Endorribonucleases/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Adaptação Fisiológica , Animais , Sobrevivência Celular/genética , Endorribonucleases/genética , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Lesões Pré-Cancerosas , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Proteína 1 de Ligação a X-Box/genética
19.
J Nucl Med ; 60(9): 1240-1246, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30796167

RESUMO

Peptide receptor radionuclide therapy in advanced neuroendocrine tumors (NETs) demonstrates a limited objective response rate. The therapeutic efficacy might be further increased by peptide receptor chemoradionuclide therapy. In this preclinical study, we explored the effects of 5-fluorouracil plus the DNA methyltransferase inhibitor decitabine or the histone deacetylase inhibitor tacedinaline on NET cells in vitro. Methods: Human NET cell lines BON1 and QGP1 were treated with 5-fluorouracil alone or in combination with decitabine or tacedinaline, respectively. Radiosensitivity was tested in combination with γ-irradiation at doses of 0, 2, 4, or 6 Gy by colony formation assay. Somatostatin receptor type 2 (SSTR2) expression and 68Ga-DOTATOC uptake by human NET cell lines were investigated by Western blot analysis and by a radioligand binding assay. Results: Treatment with 5-fluorouracil alone or in combination with decitabine or tacedinaline reduced tumor cell viability and induced apoptosis, enhanced radiosensitivity in BON1 and QGP1 cells, induced SSTR2 expression, and resulted in increased radioligand binding of 68Ga-DOTATOC in NET cells. Conclusion: This preclinical study demonstrated that 5-fluorouracil alone or in combination with decitabine or tacedinaline caused radiosensitization of tumor cells, upregulation of SSTR2 expression in tumor cells, and increased radioligand binding of 68Ga-DOTATOC to these tumor cells. These preclinical in vitro findings indicate that 5-fluorouracil in combination with epigenetic modifiers might be a putative strategy to improve the treatment efficacy of peptide receptor chemoradionuclide therapy in NET.

20.
Breast ; 43: 97-104, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529406

RESUMO

OBJECTIVES: Patients with T1N0M0 breast cancers are considered to have an excellent prognosis, even in triple-negative breast cancer (TNBC), which is often associated with diminished recurrence-free survival (RFS) and overall survival. Chemotherapy remains the only adjuvant treatment for TNBC, but evidence that adjuvant chemotherapy is beneficial for stage T1N0M0 TNBC patients is limited. In this study, we aimed to evaluate the effect of adjuvant chemotherapy and the benefit of taxanes in T1N0M0 TNBC patients. MATERIAL AND METHODS: A cohort of 354 consecutive patients with newly diagnosed T1N0M0 TNBC between January 2008 and December 2015 were included from the Fudan University Shanghai Cancer Center. Univariate and multivariate survival analyses were performed to compare patients treated with adjuvant chemotherapy with/without taxane addition. RESULTS: Median follow-up was 45 months. Chemotherapy was used in 92.4% of patients. The 5-year estimated RFS rates of patients with and without adjuvant chemotherapy were 94.5% and 83.6%, respectively. In multivariate analysis, adjuvant chemotherapy and a lack of lymphovascular invasion were associated with a significant benefit for RFS. A significant RFS benefit from adjuvant chemotherapy was observed in T1c (hazard ratio, HR = 0.24, 95% CI [0.08-0.76], P = 0.014) but not in T1b (HR = 0.32, 95% CI [0.03-3.18], P = 0.330) subgroups. Addition of taxane to an anthracycline-based regimen was not significantly associated with improved RFS in T1N0M0 TNBC patients. CONCLUSION: Adjuvant chemotherapy improves recurrence-free survival in T1c TNBC patients but not in T1b. Anthracycline-based taxane-free regimens might be sufficient to achieve RFS benefits in T1N0M0 TNBC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Mastectomia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas , Carcinoma/patologia , Quimiorradioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Radioterapia Adjuvante , Estudos Retrospectivos , Taxoides , Neoplasias de Mama Triplo Negativas/patologia
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