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1.
EMBO Mol Med ; 11(10): e10168, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31475771

RESUMO

Accurate risk stratification for patients with stage II/III colon cancer is pivotal for postoperative treatment decisions. Here, we aimed to identify and validate a circRNA-based signature that could improve postoperative prognostic stratification for these patients. In current retrospective analysis, we included 667 patients with R0 resected stage II/III colon cancer. Using RNA-seq analysis of 20 paired frozen tissues collected postoperation, we profiled differential circRNA expression between patients with and without recurrence, followed by quantitative validation. With clinical information, we generated a four-circRNA-based cirScore to classify patients into high-risk and low-risk groups in the training cohort. The patients with high cirScores in the training cohort had a shorter disease-free survival (DFS) and overall survival (OS) than patients with low cirScores. The prognostic capacity of the classifier was validated in the internal and external cohorts. Loss-of-function assays indicated that the selected circRNAs played functional roles in colon cancer progression. Overall, our four-circRNA-based classifier is a reliable prognostic tool for postoperative disease recurrence in patients with stage II/III colon cancer.

2.
Eur J Surg Oncol ; 45(11): 2070-2077, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31279595

RESUMO

BACKGROUND: Hepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection. METHODS: The nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured. RESULTS: Based on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection. CONCLUSIONS: The proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.

3.
J Natl Compr Canc Netw ; 17(7): 805-811, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319395

RESUMO

BACKGROUND: Previous meta-analyses have suggested primary tumor location as a predictive factor for efficacy of anti-epidermal growth factor receptor (EGFR) therapies in patients with metastatic colorectal cancer (mCRC). However, the recent phase III TAILOR trial addressing this issue was not included in those analyses. This meta-analysis incorporated data from the TAILOR trial to evaluate the efficacy of chemotherapy plus anti-EGFR agents (cetuximab [Cet] or panitumumab [Pani]) versus chemotherapy alone for RAS wild-type (wt) right- and left-sided mCRC. PATIENTS AND METHODS: A PubMed-based literature search was conducted to identify randomized controlled trials (RCTs) studying the additional efficacy of Cet/Pani in combination with chemotherapy versus chemotherapy alone in RAS wt left- and right-sided mCRC. Study-level pooled analyses of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for objective response rate (ORR) were performed. RESULTS: Three first-line RCTs (CRYSTAL, PRIME, and TAILOR) and one second-line RCT (20050181) were included. Significant OS benefits from Cet/Pani were observed in the left-sided (HR, 0.76; 95% CI, 0.66-0.86) but not right-sided subgroups (HR, 0.99; 95% CI, 0.78-1.27). However, the addition of Cet/Pani to chemotherapy significantly improved PFS and ORR in both the left-sided (HR, 0.70; 95% CI, 0.57-0.86, and OR, 3.28; 95% CI, 1.95-5.51, respectively) and right-sided subgroups (HR, 0.76; 95% CI, 0.59-0.99, and OR, 1.78; 95% CI, 1.08-2.93, respectively). CONCLUSIONS: The addition of Cet/Pani to chemotherapy significantly benefits PFS and ORR in patients with RAS wt right-sided mCRC, indicating that anti-EGFR therapies may remain an option for selected patients.

4.
N Engl J Med ; 381(12): 1124-1135, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31150573

RESUMO

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Adolescente , Adulto , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Análise de Sobrevida , Adulto Jovem
5.
Int J Cancer ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162842

RESUMO

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

6.
Cancer Commun (Lond) ; 39(1): 26, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068222

RESUMO

BACKGROUND: Oxaliplatin, irinotecan, 5-fluorouracil, and L-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. METHODS: Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2; irinotecan, 150 mg/m2; L-leucovorin, 200 mg/m2; and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). RESULTS: Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1-12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76-14.44) and 5.77 (95% CI 5.00-6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. CONCLUSIONS: Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC. Trial registration ClinicalTrials.gov, NCT02028806. Registered 7 January 2014, https://clinicaltrials.gov/ct2/show/NCT02028806.

7.
BMC Cancer ; 19(1): 460, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31096937

RESUMO

BACKGROUND: Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC). METHODS: In the dose-escalation phase, patients received AA (0.2-1.5 g/kg, 3-h infusion, once daily, days 1-3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed. RESULTS: Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1-3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3-4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF. CONCLUSIONS: The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT02969681 .

8.
JAMA Netw Open ; 2(5): e193433, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050784

RESUMO

Importance: Immune checkpoint inhibitors (ICIs) have unique patterns of response and survival that differ from conventional chemotherapies. Novel intermediate end points are urgently required to detect the early signals of ICI activity. Objective: To evaluate milestone rate (Kaplan-Meier estimates of survival probabilities at given time points) and milestone restricted mean survival time (RMST, the area under survival curves up to given time points) as potential intermediate end points for ICI trials. Data Sources: Electronic databases (pre-MEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) were searched for randomized clinical trials published between January 1, 2000, and December 31, 2017. Study Selection: Phase 2 and phase 3 randomized clinical trials evaluating ICIs in advanced solid tumors. Data Extraction and Synthesis: Two investigators extracted the data and reconstructed individual patient data to estimate the milestone rate or milestone RMST from the published Kaplan-Meier curves. Main Outcomes and Measures: Trial-level milestone rates or milestone RMSTs were estimated for 6-month and 9-month progression-free survival (PFS) and 9-month and 12-month overall survival (OS). A weighted linear regression model evaluated the correlations of ratios of milestone rates or milestone RMSTs with OS hazard ratios (HRs). Results: Twenty-six trials examining 8 different tumor types were identified, including 12 892 patients. Overall survival HR was correlated with the ratio of 9-month OS milestone rate (R2 = 0.45; 95% CI, 0.27-0.74), and with the ratio of 12-month OS milestone rate (R2 = 0.40; 95% CI, 0.22-0.70). The ratio of 9-month OS milestone RMST (R2 = 0.60; 95% CI, 0.28-0.74) and ratio of 12-month OS milestone RMST were correlated with OS HR (R2 = 0.64; 95% CI, 0.42-0.78). No correlations were observed between OS HR and the ratio of 6-month or 9-month PFS milestone rates or milestone RMSTs. Conclusions and Relevance: Ratios of OS milestone RMSTs had a stronger correlation with OS HRs than ratios of OS milestone rates, whereas ratios of PFS milestone rates and ratios of PFS milestone RMSTs were not correlated with OS HRs. The OS milestone RMST could be further studied as an intermediate end point in future ICI trials.

9.
Arch Oral Biol ; 101: 122-129, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30927661

RESUMO

OBJECTIVE: To investigate whether the recombinant FimH-S.T protein could modulate immune response to anti-caries vaccine in vitro and in vivo. DESIGN: Recombinant FimH protein derived from Salmonella was constructed and purified. The expression of dendritic cell maturation markers and cytokines release were performed by flow cytometry, Real-time PCR and ELISA. In addition, BALB/c mice were administered with anti-caries PAc vaccine plus FimH-S.T, antibody responses were evaluated by ELISA. Splenocytes of immunized mice were detected for their proliferative ability in response to in vitro retreatment with PAc antigen by flow cytometry. Caries protection against dental caries formation was also investigated. RESULTS: The purified FimH-S.T induced phenotypic maturation of DC2.4 by up-regulating the expression of costimulatory molecules and MHC II, provoked the production and secretion of cytokines via TLR4-dependent signaling pathway in vitro. Furthermore, the mice immunized with the mixture of FimH-S.T and PAc significantly enhanced the PAc-specific antibodies in the serum along with saliva and promoted splenocyte proliferation. Our results also confirmed that PAc+FimH-S.T decreased the caries lesions formation which provided high protective efficacy against dental caries. CONCLUSION: Our study demonstrates that recombinant FimH-S.T could enhance specific IgA responses and protection of anti-caries vaccine, possessing mucosal adjuvant ability by activating DC2.4 via TLR4 signaling pathway.

10.
Cancer Med ; 8(3): 1209-1217, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729718

RESUMO

An increasing amount of evidence suggests that high-density lipoprotein cholesterol (HDL-C) is related to a positive prognosis in various cancers. However, the correlation between HDL-C and the immune signature and the prognostic role of HDL-C in stage II/III colorectal cancer (CRC) has not been previously reported. A total of 667 CRC patients were enrolled and divided into two groups based on the lower limit of normal HDL-C values (0.78 mmol/L). We used Kaplan-Meier curves and the Cox regression model to analyze the prognostic role of HDL in both disease-free survival (DFS) and overall survival (OS). Fifty-five pairs of tumor tissues were selected according to the variation in HDL-C levels (high or low) and the matched characterizes (ages, T stage, and N stage). Using immunohistochemistry, tumor tissues were stained with antibodies against CD3, CD8, CD163, iNOS, Forkhead box P3 (FOXP3), and CD33. We calculated the density of positively-stained infiltrating cells in the tumor center (TC) and invasive margin (IM). We then used Spearman rank correlation to further investigate the relationship between HDL-C levels and the immune signatures. Our results revealed that compared to patients with high HDL-C levels, patients with low HDL-C levels had poor 3-year DFS (68.9% vs 83.1%, P = 0.032) and 5-year OS rates (66.6% vs 85.3%, P = 0.002). We also identified a positive correlation between HDL-C and CD3+ , CD8+ and iNOS+ cells and a negative correlation between HDL-C and CD163+ cells in both the TC and IM. This study reveals that a low HDL-C level in stage II/III CRC patients predicts poor prognosis. The correlation between the HDL-C level and immune signature in tissue specimens suggested that HDL-C is likely to play an inhibitory role in tumor development via affecting immune responses.

11.
J Cell Physiol ; 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786008

RESUMO

P300 and HDAC1 can be involved in the development of various liver diseases by regulating gene transcription. Endoplasmic reticulum stress (ERS) is one of the main pathways of apoptosis and is activated during inflammatory responses, but the roles of P300 and HDAC1 in ERS in antituberculosis drug-induced liver injury (ADLI) are not clear. This study confirms that isoniazid can change the states of P300 and HDAC1 in HL-7702 hepatocyte metabolism and induce ERS, causing hepatocyte injury and apoptosis. When combined with C646, however, P300 can be reduced. HL-7702 cells were flattened, and the cytoplasm became crinkled. To a certain extent, ERS was relieved, but hepatocytes suffered worse damage, and the rate of cell apoptosis markedly increased. When MS-275 was applied, HDAC1 level was increased, cell fusion appeared, and fluorescence intensity of endoplasmic reticulum was weakened. In addition, ERS was aggravated, but liver injury was relieved, and the apoptosis rate significantly decreased. Therefore, alteration of P300 and HDAC1 status and ERS are involved in ADLI, and changes in P300 and HDAC1 can regulate ERS and then affect cell damage.

12.
Cancer Sci ; 109(11): 3575-3582, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30281875

RESUMO

The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S-1 plus nanoparticle albumin-bound paclitaxel (Nab-PTX) as first-line chemotherapy for advanced gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S-1 in oral doses of 40 mg (BSA <1.25 m2 ), 50 mg (1.25 ≤ BSA < 1.50 m2 ) and 60 mg (BSA ≥1.50 m2 ) b.i.d. on days 1-14 in combination with Nab-PTX (120 mg/m2 , on days 1 and 8) for each 21-day cycle. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate (ORR), overall survival (OS), disease control rate (DCR), and toxicity. A total of 73 gastric cancer patients with metastatic and measurable lesions were enrolled in the first-line setting. Median PFS and OS were 9.63 months and 14.60 months, respectively. Four (5.5%) patients had complete responses, 39 (53.4%) had partial responses (PRs), 21 (28.8%) had stable disease, four (5.5%) progressed and five (6.8%) were not evaluable. ORR and DCR were 58.9% and 87.7%, respectively. Most toxicities were mild, and no treatment-related deaths occurred. Grade 3 to 4 toxicities occurred in 22 patients (30.1%) as follows: leukopenia (13.7%), neutropenia (12.3%), anemia (5.5%), thrombocytopenia (1.4%), diarrhea (6.8%), vomiting (2.7%), stomatitis (1.4%), peripheral neuropathy (1.4%), and hand-foot syndrome (1.4%). Seven patients achieved good responses and underwent gastrectomy plus metastasectomy. Thirty (41.1%) patients had S-1 maintenance with a median of four cycles. S-1 plus Nab-PTX is an efficient and safe regimen as first-line treatment for patients with AGC.


Assuntos
Paclitaxel Ligado a Albumina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Paclitaxel Ligado a Albumina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , China , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Ácido Oxônico/efeitos adversos , Análise de Sobrevida , Tegafur/efeitos adversos , Resultado do Tratamento
13.
Gut ; 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30269082

RESUMO

OBJECTIVE: To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC). DESIGN: Targeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes. RESULTS: The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance. CONCLUSION: Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.

14.
Biomed Res Int ; 2018: 9075318, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345311

RESUMO

We investigated the beneficial effects and underlying mechanisms of Zhuanggu Guanjie (ZGGJ) pill in osteoporosis in vitro and in vivo. Bone marrow macrophages from 4-6-week-old mice were cultured in the presence of macrophage colony-stimulating factor (15 ng/mL) and receptor activator of nuclear factor-κB ligand (30 ng/mL). Osteoclast differentiation was determined by quantification of tartrate-resistant acid phosphatase activity. Gelatin zymography was used to detect the activity of matrix metalloproteinases in osteoclasts. Ovariectomized rats were administered orally with estradiol valerate or ZGGJ for 8 weeks. Blood was collected to measure serum indices. Tibiae were harvested to carry out bone microcomputed tomography scanning, histomorphological analysis, and bone strength determination. ZGGJ inhibited tartrate-resistant acid phosphatase activity, matrix metalloproteinase 9 expression, and bone resorption in vitro. At doses of 0.55, 1.1, and 2.2 g/kg, ZGGJ exerted significant osteoprotective effects including inhibition of bone turnover markers and improved tibia bone strength in ovariectomized rats. Microcomputed tomographic analysis showed that ZGGJ improved the trabecular architecture with increased connectivity density and trabecular thickness and decreased trabecular spacing. These results revealed that ZGGJ prevents bone loss induced by ovariectomy in rats and that inhibition of bone resorption is involved in the bone-protective effects of ZGGJ.

15.
Curr Med Sci ; 38(3): 524-529, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30074222

RESUMO

The purpose of this study was to determine the ion release from four commercially available pit-and-fissure sealants [3M Clinpro, 3M Concise™, BeautiSealant (BS), and GI FX-II)]. With each brand, 18 specimens were prepared. Their fluoride release in de-ionized water was measured by fluoride electrode, while the release of silicate (Si), aluminum (Al), sodium (Na), calcium (Ca), strontium (Sr), and phosphorus (P) was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) on days 1, 3, 7, 14, 21, and 28. The result showed that fluoride was not released from 3M Concise™. GI FX-II displayed the largest fluoride release, which, however, dropped rapidly on day 3. 3M Clinpro exhibited less fluoride release than GI FX-II and BS did. At any time during the 28-day experimental period, GI FX-II released more Na than the other sealants (P<0.001). BS ranked the second in Na release, and a small amount of Na ions was released from the 3M Clinpro and 3M Concise™ samples. Al ions were only detected from BS and GI FX-II, but not from the 3M Clinpro and 3M Concise™. Additionally GI FX-II had the largest Si release among the four brands at any time during the experimental period (P<0.001). Ca ions were detected from 3M Clinpro and 3M Concise™, but not from GI FX-II. BS released more Sr than the other sealants at any time during the experimental period (P<0.001). All the samples released similar amounts of P continuously during these 28 days. In conclusion, based on the type and the amount of ion release, BS is the best pit-and-fissure sealant among the four brands.


Assuntos
Íons/análise , Selantes de Fossas e Fissuras/análise , Elementos , Fluoretos/análise
16.
Toxicol Res (Camb) ; 7(1): 41-47, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090561

RESUMO

This study explores the mechanism of histone acetylation under the effect of oxidative stress in rat liver injury induced by isoniazid (INH). Fifty-six adult SD rats were selected and divided randomly into INH groups (48) and control (8). Rats in INH groups were intragastrically injected with 55 mg kg-1 day-1 for 3, 7, 10, 14, 21, and 28 days, and control rats were given an equal volume of distilled water. Pathological changes in liver tissues were observed by HE staining. Western blot analysis was conducted to measure the expression levels of H3k14ac and H4k8ac. The activities of HAT, HDAC and IL-1ß, and TNF-α were detected by ELISA in liver tissues. Real-time RT-PCR analysis was performed to determine the protein expression levels of HAT, HDAC, and IL-1ß and the mRNA expression of TNF-α. The levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed by biochemical methods in liver tissues. At different time points, the SOD activity decreased, whereas the MDA content significantly increased after 14 days (FSOD = 11.15, FMDA = 7.42, P < 0.01). During this period, the expression of histone acetylated H3K14 and H4K8 acetylation decreased compared with the control group (FH3K14 = 4.18, FH4K8 = 3.87, P < 0.05); by contrast, HDAC1 and HDAC2 showed a high expression level compared with those in the control group (FHDAC1 = 29.13, FHDAC2 = 58.34, P < 0.01). Moreover, the expression of CBP/P300 was lower than that in the control group (FCBP/P300 = 12.18, P = 0.001), and the protein contents of IL-1ß and TNF-α in rat liver tissues were up-regulated (FIL-1ß = 44.88, FTNF-α = 41.56, P < 0.01). These results suggest that histone acetylation is involved in INH-induced rat liver injury. Furthermore, the hypoacetylation of histones H3K14 and H4K8 is negatively correlated with oxidative stress-mediated rat liver injury.

17.
Cancer Med ; 7(8): 3662-3672, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29984918

RESUMO

The hematogenous metastatic pattern of gastric cancer (GC) was not fully explored. Here we analyzed the frequency and clinicopathological features of metastasis to liver, lung, bone, and brain from GC patients. Data queried for this analysis included GC patients from the Surveillance, Epidemiology, and End Results Program database from 2010 to 2014. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two-sided. Totally, there were 19 022 eligible patients for analysis. At the time of diagnosis, there were 7792 patients at stage IV, including 3218 (41.30%) patients with liver metastasis, 1126 (14.45%) with lung metastasis, 966 (12.40%) with bone metastasis and 151 (1.94%) with brain metastasis. GC patients with lung or liver metastasis have a higher risk of bone and brain metastasis than those without lung nor liver metastasis. Intestinal subtype had significantly higher rate of liver and lung metastasis, while diffuse type was more likely to have bone metastasis. Proximal stomach had significantly higher risk to develop metastasis than distal stomach. African-Americans had the highest risk of liver metastasis and Caucasian had the highest prone to develop lung and brain metastasis. The median survival for patients with liver, lung, bone, and brain metastasis was 4 months, 3 months, 4 months and 3 months, respectively. It is important to evaluate the status of bone and brain metastasis in GC patients with lung or liver metastasis. Knowledge of metastatic patterns is helpful for clinicians to design personalized pretreatment imaging evaluation for GC patients.

18.
Artigo em Inglês | MEDLINE | ID: mdl-29980903

RESUMO

Postpartum depression is a common complication of childbearing and up to 12 months postpartum. This study aimed to determine the prevalence of postpartum depressive mood (PDM) in China by performing a meta-analysis of published studies. Studies that reported the prevalence of PDM in China were identified by searching the PubMed, Embase, CNKI, and CQVIP databases. Three thousand, one hundred, and two articles were obtained, and after careful evaluation, 26 studies were finally included in the meta-analysis. The combined studies included a total of 7618 cases with 1621 cases of PDM. The studies were assessed on the basis of heterogeneity testing and the potential for publication bias. Stata software 11.0 was used to perform the meta-analysis. The random-effect model showed that the prevalence of PDM was 21% with a 95% confidence interval (CI) of 17-25%. PDM was the highest 0 to 1.5 months after delivery. PDM levels decreased to 10.4% (95% CI 9.7-11.1%, P < 0.001) after publication bias were corrected. Sensitivity analyses evaluated the stability of our results and showed no significant change when any single study was excluded. Subgroup analyses showed that region, instruments used, cut-off score, and time points for depression assessment were positively associated with PDM prevalence. The prevalence of PDM differed among regions, with South Central China and East China exhibiting the lowest prevalence. The prevalence was higher in regions with poor economic development, suggesting that more attention should be devoted to Southwest and North China and that the prevalence of PDM should be evaluated 0 to 1.5 months after delivery.

19.
Biol Pharm Bull ; 41(9): 1406-1413, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29910216

RESUMO

The aim of the present study was to investigate the protective effects of Shenfu injection (SFI) against myocardial ischemia-reperfusion injury (MIRI) in model rats and to explore its mechanism of action. Sprague-Dawley (SD) rats were pretreated with SFI and NG-nitro-L-arginine methyl ester (L-NAME) via tail vein injection and then rats were subjected to ischemia by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Left ventricular function was evaluated by echocardiography. Hemodynamic was measured by the Millar pressure-volume system; serum creatine kinase (CK), lactate dehydrogenase (LDH) and serum troponin (TNNI3) levels were determined. Myocardial infarct size was observed by 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) staining; p-Akt/Akt, and p-endothelial nitric oxide synthase (p-eNOS)/eNOS levels were assessed by Western blotting; nitric oxide (NO) content in serum was determined by the Griess reaction. SFI significantly decreased serum CK, LDH and TNNI3 levels in MIRI rats, while it significantly increased the level of left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), maximal rate of the increase of left ventricular pressure (+dp/dtmax), maximal rate of the decrease of left ventricular pressure (-dp/dtmax), left ventricle ejection fraction percentage (EF), and stroke volume (SV). In addition, SFI significantly reduced myocardial infarction area and activated the phosphorylation of eNOS via Akt. The phosphorylation of eNOS and the concurrent increase of NO production contributed significantly to the protective effects of SFI. These results demonstrate that SFI protects the rat heart against MIRI and that this effect is mediated in part by Akt/eNOS signaling.

20.
Zhongguo Zhong Yao Za Zhi ; 43(6): 1228-1234, 2018 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-29676133

RESUMO

This paper aimed to investigate whether psoralen inhibits the differentiation and bone resorption by regulating CD4+T cell differentiation in RANKL-induced osteoclastogenesis in RAW264.7 cells, and elucidate its mechanism for osteoporosis. CD4+T cells were isolated from spleen cells of Balb/c mice by immunomagnetic separation method. The cells were divided into blank control group and psoralen group. The cells were cultured in 24-well plates and cultured for 3 days, and then they were collected for co-culture experiments after 4 days. Co-culture experiments were divided into RAW264.7 cell group, psoralen+RAW264.7 cell group, without psoralen treatment of CD4+T cells+RAW264.7 cell group, psoralen treatment of CD4+T cells+RAW264.7 cell group. After 5 days of co-culture, TRAP staining was used to detect the number of osteoclasts, and after 8 days of co-culture, bone resorption was evaluated by toluidine blue staining. The expressions of RORγt, Foxp3, IL-17, TNF-α, TGF-ß and IL-10 in CD4+T cells and osteoclast differentiation-related genes MMP-9, TRAP and Cat-K were detected by Real-time polymerase chain reaction (RT-PCR); ELISA kit was used to detect IL-17, TNF-α, TGF-ß and IL-10 and other cytokines levels. Our data confirmed that the psoralen significantly promoted the expression of Foxp3, TGF-ß and IL-10 in CD4+T, and inhibited the expression of RORγt, IL-17 and TNF-α in CD4+T, the CD4+T cells without treatment by psoralen can significantly promote RANKL-induced differentiation of RAW264.7 to osteoclasts, and psoralen treatment of CD4+T can significantly inhibit RANKL-induced RAW264.7 osteoclast differentiation and bone resorption. Taken together, psoralen inhibits the differentiation and bone resorption of RAW264.7 into osteoclasts by promoting the development of CD4+ CD25+ Treg/Th17 balance in CD4+T cells to CD4+CD25+T.

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