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1.
Zhen Ci Yan Jiu ; 45(2): 87-92, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32144916

RESUMO

OBJECTIVE: To observe the effect of bone-edge electroacupuncture (EA) intervention on mechanical pain threshold (PT) and expression of G protein-coupled receptor kinase (GRK5), ß-arrestin 2, total and phosphorylated PKC alpha (p-PKCα) proteins in the locus coeruleus (LC) of rats with bone cancer pain induced morphine tolerance, so as to reveal its partial central mechanisms underlying pain relief. METHODS: Forty SD rats were randomly divided into 5 groups, namely sham bone cancer, bone cancer pain, morphine tolerance, bone-edge EA, and sham EA (n= 8 rats in each group). The bone cancer with morphine tolerance model was established by intramedullary injection of MRMT-1 cells into the tibial cavity, and then intraperitoneal injection of morphine hydrochloride injection. After successful establishment of morphine tolerance model, the bone-edge EA (2 Hz/100 Hz,0.5-1.5 mA) was applied to bilateral "Zusanli" (ST36) and "Kunlun" (BL60) for 30 min, once a day for 7 days, after inserting the needle-tip to the tibial bone surface. The ipsilateral mechanical paw withdrawal thresholds (PWTs) were detected dynamically. The expression levels of GRK5, ß-arrestin 2, PKCα and p-PKCα in the LC area were measured by Western blot. RESULTS: The PWTs of bone cancer pain rats were decreased on day 10 after inoculation of cancer cells (P<0.01). After i.p. of morphine for 11 days, no analgesic effect and pain tolerance appeared (P>0.05). The PWTs were significantly increased in the bone-edge EA intervention group (P<0.01), not in the sham EA group (P>0.05). In comparison with the sham bone cancer group, the expression of GRK5 protein in morphine tolerance group was significantly decreased (P<0.01); compared with morphine tolerance group, the expression of GRK5 protein in bone-edge EA group was increased(P<0.01). In comparison with the sham bone cancer group, the expression of ß-arrestin 2 and p-PKCα in bone cancer group significantly increased (P<0.01). After the intervention, the increased ß-arrestin 2 and p-PKCα expressions were reversed in the bone-edge EA group (P<0.01); compared with morphine tolerance group and sham EA group, the expression of PKCα protein was decreased(P<0.01). CONCLUSION: Bone-edge EA can effectively relieve morphine tolerance in bone cancer pain rats, which may be related to its functions in up-regulating GRK5 protein and down-regulating ß-arrestin 2, PKCα and p-PKCα proteins in LC. .


Assuntos
Neoplasias Ósseas , Dor do Câncer , Eletroacupuntura , Pontos de Acupuntura , Animais , Quinase 5 de Receptor Acoplado a Proteína G , Locus Cerúleo , Morfina , Proteína Quinase C-alfa , Ratos , Ratos Sprague-Dawley , beta-Arrestina 2
2.
Cancer Commun (Lond) ; 40(1): 3-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32125093

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp) catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penile squamous cell carcinoma (PSCC) and explored their clinical significance. METHODS: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn) were examined in 114 PSCC patients by immunohistonchemistry and solid-phase extraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were defined by principal component analysis. The correlativity was assessed by Pearson's correlation analysis. RESULTS: The expression level of IDO1 in PSCC cells was positively correlated with serum Kyn concentration and Kyn/Trp radio (KTR; both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 up-regulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008 and 0.032, respectively). High expression level of IDO1 in cancer cells and serum KTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926; 95% confidence interval [CI], 2.458-19.068; P < 0.001) and pathologic grade (HR, 2.194; 95% CI, 1.021-4.529; P = 0.038), only serum KTR (HR, 2.780; 95% CI, 1.066-7.215; P = 0.036) was an independent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-γ (IFNγ, P < 0.001) and immunosuppressive markers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2; all P < 0.05), and the infiltration of immune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells; all P < 0.001) in PSCC tissues. Furthermore, the expression of IDO1 was induced by IFNγ in a dose-dependent manner in PSCC cells. CONCLUSIONS: IFNγ-induced IDO1 plays a crucial role in immunoediting and immunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1 catabolic activity, can be utilized as an independent prognostic factor for PSCC.

3.
Mol Cancer Res ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169891

RESUMO

The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is not fully understood. The significant downregulation of protein tyrosine phosphatase non-receptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. Immunohistochemical analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 expression was an independent, favorable prognostic factor for overall survival (P = 0.0343) and distant metastasis-free survival (P = 0.0166) of patients. The ccRCC cell lines SN12C, 1932, ACHN and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. PTPN3 overexpression suppressed xenograft tumor growth and lung metastasis in vivo mice models. PTN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of ccRCC cells. Further, the inhibition of phospho-AKTThr308 and phospho-AKTSer473 reversed PTPN3 induced-silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in ccRCC patients. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. Implications: PTPN3 is an independent favorable prognostic factor for ccRCC patients and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.

4.
iScience ; 23(3): 100942, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32179471

RESUMO

Many animals, including humans, have evolved to live and move in groups. In humans, disrupted social interactions are a fundamental feature of many psychiatric disorders. However, we know little about how genes regulate social behavior. Zebrafish may serve as a powerful model to explore this question. By comparing the behavior of wild-type fish with 90 mutant lines, we show that mutations of genes associated with human psychiatric disorders can alter the collective behavior of adult zebrafish. We identify three categories of behavioral variation across mutants: "scattered," in which fish show reduced cohesion; "coordinated," in which fish swim more in aligned schools; and "huddled," in which fish form dense but disordered groups. Changes in individual interaction rules can explain these differences. This work demonstrates how emergent patterns in animal groups can be altered by genetic changes in individuals and establishes a framework for understanding the fundamentals of social information processing.

5.
Medicine (Baltimore) ; 99(12): e19276, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195932

RESUMO

This study aimed to investigate the efficacy and safety of drug-eluting beads (DEB) transarterial chemoembolization (TACE) treatment in Chinese intrahepatic cholangiocarcinoma (ICC) patients.37 ICC patients underwent DEB-TACE treatment in CTILC study (registered on clinicaltrials.gov with registry No. NCT03317483) were included in this present study. Treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Overall survival (OS) was calculated from the time of DEB-TACE operation until the date of death from any causes. Liver function change and adverse events (AEs) were recorded during and after DEB-TACE operation.3 (8.1%) patients achieved complete response (CR) and 22 (59.5%) patients achieved partial response (PR), with objective response rate (ORR) of 67.6%. After DEB-TACE treatment, mean OS was 376 days (95%CI: 341-412 days). Multivariate logistic regression analysis revealed that Bilobar disease (P = .040, OR: 0.105, 95% CI: 0.012-0.898) and portal vein invasion (P = .038, OR: 0.104, 95% CI: 0.012-0.881) could independently predict less possibility of ORR. Patients with ALB abnormal, TP abnormal, ALT abnormal and AST abnormal were increased at 1-week post DEB-TACE treatment (P = .034, P = .001, P < .001, P = .006, respectively), while returned to the levels at baseline after 1 to 3 months (all P > .050). Besides, most of the AEs were mild including pain, fever, vomiting, and nausea in this study.DEB-TACE was effective and well tolerated in treating ICC patients, and bilobar disease as well as portal vein invasion were independently correlated with less probability of ORR achievement.

6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 255-261, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027286

RESUMO

OBJECTIVE: To investigate the efficacy of bone marrow mesenchymal stem cells (BMMSC) on children with refractory graft-versus-host disease (GVHD) and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC, so as to provide a theoretical basis for clarifying the mechanism of BMMSC. METHODS: 17 children with refractory aGVHD including 7 of grade II, 6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled. All the children with aGVHD, who received routine immunosuppressive therapy, but the state of disease not improved, were treated with immunosuppressive drugs combined with BMMSC infusion. Study endpoints included safety of BMMSC infusion, response to BMMSC, and overall response of aGVHD. The serum levels of IL-2α, IL-6, IL-10, IL-8 and TNF-α in aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7, Day 14 after infusion of BMMSCs. RESULTS: The cumulative median dose of BMMSCs was 5.5 (3.4-11.1) × 106/kg for average of 3.7 times, and the median time of 16.5 (4-95) days for the first infusion of MSCs. In 17 cases of refractory GVHD, 14 responded to treatment, whereas 3 patients failed. The total effective rate was 82.4% and no adverse reactions occurred. Of the 14 survived cases (82.4%), the median follow-up time was 944 (559-1245) days from the first infusion of MSCs. The levels of TNF-α in children with grade II, III and IV GVHD before treatment were 9.5±4.3 pg/ml, 16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively. The difference between grade II and IV, III and IV was statistically significant (P<0.05). Compared with the ineffective group of BMMSC infusion, the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml (t=-3.901, P<0.05) before treatment. In the effective group of BMMSCs infusion, IL-10 20±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment (t=-2.850, P<0.05), while , the serum levels of IL-2α, IL-6, IL-8, TNF-α were not statistically significantly different (P>0.05). CONCLUSION: The infusion of BMMSC is safe and effective in the treatment of refractory GVHD in children. TNF-αlevel relates with the severity of GVHD. BMMSC may play an anti-GVHD role by up regulating the level of cytokine IL-10 in vivo.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Doença Aguda , Criança , Citocinas , Humanos , Transplante Homólogo
7.
J Thorac Oncol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007598

RESUMO

INTRODUCTION: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy. METHODS: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study. RESULTS: Between November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40-240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. CONCLUSIONS: Alflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.

8.
Cancer Lett ; 477: 131-143, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061950

RESUMO

Nasopharyngeal carcinoma (NPC) is one of the most malignant tumors in Southern China and southeast Asia, which is characterized by a dense lymphocyte infiltration and a poor prognosis. The emergence of single-cell sequencing represents a powerful tool to resolve tumor heterogeneity and delineate the complex communication among the tumor cells with neighboring stromal and immune cells in the tumor microenvironment (TME). Here, we performed single cell RNA-seq and analyzed tumor cells together with the infiltrating immune cells from three NPC tumor tissues. In our study, the malignant cells display the intra- and inter-tumoral heterogeneity among the individual patients. Analysis of the immune cells reveal the heterogeneous composition of the distinct immune cells and the various functional states of T cells in NPC tumors. Additionally, coupled with the reconstruct of the T cell receptor (TCR) sequences from immune cells full-length single-cell sequence data, we identify the diverse T cell clonotypes and expansion distribution in individual tumors. Overall, we firstly reveal the landscape of tumor and infiltrating immune cells in nasopharyngeal cancer. These results provide deeper insights on the mechanisms of tumor clearance by immune cells in the surrounding microenvironment, which will be helpful in improving the targeted and immune therapies for NPC.

9.
Zhongguo Zhen Jiu ; 40(2): 173-8, 2020 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-32100504

RESUMO

OBJECTIVE: To observe the expression of GABAA receptor mRNA in different brain regions of the central nervous system in chronic inflammatory pain rats and the intervention effect of electroacupuncture (EA). METHODS: A total of 48 SPF male SD rats were randomly divided into a blank control group, a model control group, an EA group and a sham EA group, 12 rats in each group. The model of chronic inflammatory pain was established by injecting Freund's complete adjuvant into the foot. The EA group was treated with EA 28 days after the model establishment. The "Housanli" (ST 36) and "Kunlun" (BL 60) were selected and treated with dilatational wave, 2 Hz/100 Hz in frequency, 0.5-1.5 mA for 30 min; EA was given only once. In the sham EA group, the same acupoints were selected but the needles were only inserted into subcutaneous area; EA was connected for 30 min without electrical stimulation. The behavior changes of mechanical pain threshold and thermal pain threshold before model establishment, 1 day, 3 days, 7 days, 14 days, 21 days and 28 days after the model establishment as well as emotional behavior 29 days after the model establishment were observed; the relative expressions of GABAA receptor mRNA in anterior cingulate cortex, amygdala and hypothalamus were observed. RESULTS: Compared with the blank control group, the change rates of mechanical pain threshold and thermal pain threshold in the model control group were decreased significantly 1 day, 3 days, 7 days, 14 days, 21 days, 28 days after model establishment (P<0.01); 29 days after model establishment, the movement distance and staying time in the central area of open field test in the model control group were decreased significantly (P<0.05). After EA intervention, compared with the model control group and the sham EA group, the change rates of mechanical pain threshold and thermal pain threshold, as well as the movement distance and the staying time of central area were significantly increased in the EA group (P<0.01, P<0.05). Twenty-nine days after model establishment, the expression of GABAA receptor mRNA in anterior cingulate cortex and hypothalamus was not significantly different among all groups (P>0.05). Compared with the blank control group, the expression of GABAA receptor mRNA in the amygdala was decreased significantly in the model control group (P<0.01); compared with the model control group and the sham EA group, the expression of GABAA receptor mRNA in amygdala was increased after intervention in the EA group (P<0.01). CONCLUSION: Single treatment of EA could significantly increase the mechanical pain threshold and thermal pain threshold, improve abnormal emotional behavior in rats with chronic inflammatory pain, which may be related to the increasing of expression of GABAA receptor mRNA in the amygdala.


Assuntos
Encéfalo/metabolismo , Eletroacupuntura , Inflamação/terapia , Dor , Receptores de GABA-A/metabolismo , Pontos de Acupuntura , Tonsila do Cerebelo , Animais , Masculino , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
10.
J Cancer Res Clin Oncol ; 146(4): 1011-1020, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31919567

RESUMO

PURPOSE: The impact of myeloid sarcoma (MS) on clinical outcome of pediatric acute myeloid leukemia (AML) patients remains controversial. Moreover, little is known about the role of stem cell transplantation (SCT) in such patients. METHODS: Clinical data of patients with AML under 18 years of age were retrieved from the TARGET dataset. We analyzed the prevalence, clinical profile, molecular characteristics, and prognosis of MS in these patients. RESULTS: Among 884 pediatric patients with AML, the frequency of MS was 12.3%. Pediatric AML with MS was associated with age under 1-year, abnormal cytogenetics, and KMT2A rearrangement. Moreover, MS was associated with a low complete remission rate, high induction death, poor 5-year EFS, and OS. KMT2A rearrangement had a negative impact on clinical outcome in AML patients with MS. In addition, SCT had no significant effect on the survival of AML patients with MS. Multivariate analysis revealed that MS was an unfavorable prognostic factor in pediatric AML in terms of EFS (Hazard ratio 1.670, P < 0.001) and OS (Hazard ratio 1.623, P = 0.004). CONCLUSIONS: The presence of MS at diagnosis of pediatric AML is associated with poor clinical outcomes, particularly when associated with KMT2A rearrangements. Moreover, pediatric patients with AML and MS may not benefit from SCT.

11.
Blood Cancer J ; 10(1): 1, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31915364

RESUMO

Studies on the clinical significance of Nucleophosmin (NPM1) mutations in pediatric AML in a large cohort are lacking. Moreover, the prognosis of patients with co-occurring NPM1 and FLT3/ITD mutations is controversial. Here, we analyzed the impact of NPM1 mutations on prognoses of 869 pediatric AML patients from the TAGET dataset. The frequency of NPM1 mutations was 7.6%. NPM1 mutations were significantly associated with older age (P < 0.001), normal cytogenetics (P < 0.001), FLT3/ITD mutations (P < 0.001), and high complete remission induction rates (P < 0.05). Overall, NPM1-mutated patients had a significantly better 5-year EFS (P = 0.001) and OS (P = 0.016) compared to NPM1 wild-type patients, and this favorable impact was maintained even in the presence of FLT3/ITD mutations. Stem cell transplantation had no significant effect on the survival of patients with both NPM1 and FLT3/ITD mutations. Multivariate analysis revealed that NPM1 mutations were independent predictors of better outcome in terms of EFS (P = 0.004) and OS (P = 0.012). Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in pediatric AML despite of FLT3/ITD mutations. In addition, pediatric AML patients with both NPM1 and FLT3/ITD mutations appear to have favorable prognoses and may not need hematopoietic stem cell transplantations.

12.
Biomaterials ; 230: 119648, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31791841

RESUMO

Implantable medical devices are now in regular use to treat or ameliorate medical conditions, including movement disorders, chronic pain, cardiac arrhythmias, and hearing or vision loss. Aside from offering alternatives to pharmaceuticals, one major advantage of device therapy is the potential to monitor treatment efficacy, disease progression, and perhaps begin to uncover elusive mechanisms of diseases pathology. In an ideal system, neural stimulation, neural recording, and electrochemical sensing would be conducted by the same electrode in the same anatomical region. Carbon fiber (CF) microelectrodes are the appropriate size to achieve this goal and have shown excellent performance, in vivo. Their electrochemical properties, however, are not suitable for neural stimulation and electrochemical sensing. Here, we present a method to deposit high surface area conducting diamond on CF microelectrodes. This unique hybrid microelectrode is capable of recording single-neuron action potentials, delivering effective electrical stimulation pulses, and exhibits excellent electrochemical dopamine detection. Such electrodes are needed for the next generation of miniaturized, closed-loop implants that can self-tune therapies by monitoring both electrophysiological and biochemical biomarkers.

13.
Lancet Respir Med ; 8(1): 45-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628085

RESUMO

BACKGROUND: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. METHODS: We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693. FINDINGS: Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). INTERPRETATION: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. FUNDING: Betta Pharmaceuticals.

14.
J Cell Physiol ; 235(4): 3438-3446, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31621076

RESUMO

High mobility group box (HMGB) consists primarily of HMGB1, HMGB2, and HMGB3 proteins. Although abnormal HMGB expression is associated with various tumors, the relationship with gastric cancer (GC) remains unclear. In this study, HMGB1, HMGB2, and HMGB3 expression was analyzed using the Oncomine and TCGA databases. Correlations between HMGB1, HMGB2, and HMGB3 and clinicopathological factors were analyzed. cBioPortal was used to analyze HMGB1, HMGB2, and HMGB3 genetic alterations and its gene regulation network in GC tissue. HMGB1, HMGB2, and HMGB3 expression was higher in tumor tissues than in normal tissues, especially in GC. High HMGB1, HMGB2, and HMGB3 expression may predict a poor prognosis among patients with GC (hazard ratios [HR] = 1.90; 95% confidence interval [CI]: [1.30-2.78]) and human digestive system neoplasm (HR = 1.85; 95% CI [1.64-2.10]). These findings suggest that HMGB1, HMGB2, and HMGB3 may be useful prognostic indicators for patients with GC.

15.
Oncol Res ; 28(1): 75-94, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31558180

RESUMO

The purpose of this study was to investigate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment in Chinese hepatocellular carcinoma (HCC) patients and the prognostic factors for treatment response as well as survival. A total of 275 HCC patients were included in this prospective study. Treatment response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST), and progression-free survival (PFS) as well as overall survival (OS) were determined. Liver function and adverse events (AEs) were assessed before and after DEB-TACE operation. Complete response (CR), partial response (PR), and objective response rate (ORR) were 22.9%, 60.7%, and 83.6%, respectively. The mean PFS was 362 (95% CI: 34.9-375) days, the 6-month PFS rate was 89.4 ± 2.1%, while the mean OS was 380 (95% CI: 370-389) days, and the 6-month OS rate was 94.4 ± 1.7%. Multivariate logistic regression revealed that portal vein invasion (p = 0.011) was an independent predictor of worse clinical response. Portal vein invasion (p = 0.040), previous cTACE treatment (p = 0.030), as well as abnormal serum creatinine level (BCr) (p = 0.017) were independent factors that predicted worse ORR. In terms of survival, higher Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.029) predicted for worse PFS, and abnormal albumin (ALB) (p = 0.011) and total serum bilirubin (TBIL) (p = 0.009) predicted for worse OS. The number of patients with abnormal albumin, total protein (TP), TBIL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were augmented at 1 week posttreatment and were similar at 1-3 months compared with baseline. The most common AEs were pain, fever, nausea, and vomiting, and no severe AEs were observed in this study. DEB-TACE was effective and tolerable in treating Chinese HCC patients, and portal vein invasion, previous cTACE treatment, abnormal BCr, ALB, and TBIL appear to be important factors that predict worse clinical outcome.

16.
J Pharm Biomed Anal ; 180: 113045, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31887668

RESUMO

Nintedanib is a promising tyrosine kinase inhibitor for clinically treating idiopathic pulmonary fibrosis (IPF). Some clinical cases reported that nintedanib treatment can cause hepatotoxicity and myocardial toxicity. U. S. FDA warns the potential drug-drug interaction when it is co-administrated with other drugs. In order to understand the potential toxicity of nintedanib and avoid drug-drug interaction, the metabolism of nintedanib was systematically investigated in human liver microsomes and mice using metabolomics approach, and the toxicity of metabolites was predicted by ADMET lab. Nineteen metabolites were detected in vivo and in vitro metabolism, and 8 of them were undescribed. Calculated partition coefficients (Clog P) were used to distinguish the isomers of nintedanib metabolites in this study. The major metabolic pathways of nintedanib majorly included hydroxylation, demethylation, glucuronidation, and acetylation reactions. The ADMET prediction indicated that nintedanib was a substrate of the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). And nintedanib and most of its metabolites might possess potential hepatotoxicity and cardiotoxicity. This study provided a global view of nintedanib metabolism, which could be used to understand the mechanism of adverse effects related to nintedanib and its potential drug-drug interaction.

17.
Anal Chim Acta ; 1094: 80-89, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761050

RESUMO

In this paper, a composite electrode of N,P-doped Mo2C@C/Prussian blue (PB)/graphite felt (N,P-Mo2C@C/PB/GF) was prepared by a simple method and used for sensitive and effective detection of dopamine (DA). N,P-doped Mo2C nanospheres were prepared by using phosphomolybdic acid (PMo12) as an initiator to promote the polymerization of polypyrrole. Such nanospheres were used to accelerate the deposition process of PB from K3[Fe(CN)6] and FeCl3 in solution. The N,P-Mo2C@C/PB nanohybrid was then anchored to GF in order to obtain the electrochemical sensor. Two linear ranges were extrapolated for dopamine detection: from 0.18 to 30 µmol L-1 with a sensitivity of 0.268 µA µmol-1, and from 30 to 280 µmol L-1 with a sensitivity of 0.045 µA µmol-1. The device showed a detection limit as low as 0.011 µmol L-1, an excellent selectivity to DA over common interfering analytes, and a favorable long-time stability. Finally, the sensor was used for quantitative analysis of DA in the 10-fold dilution of human serum (10%) and exhibited a satisfactory recovery.


Assuntos
Carbono/química , Dopamina/sangue , Ferrocianetos/química , Grafite/química , Molibdênio/química , Nanocompostos/química , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Ferrocianetos/síntese química , Humanos , Limite de Detecção , Nitrogênio/química , Fósforo/química , Reprodutibilidade dos Testes
18.
Surg Laparosc Endosc Percutan Tech ; 30(1): 22-25, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31855923

RESUMO

OBJECTIVE: To compare the trauma of 3 different surgical approaches and provide a reference for clinicians in choosing the operative procedure. PATIENTS AND METHODS: A total of 150 patients were divided into the total endoscopic thyroidectomy (TET), endoscopic-assisted thyroidectomy (EAT), and conventional open thyroidectomy (COT) groups, with 50 patients in each group. The peripheral blood C-reactive protein (CRP) levels at different postoperative time points, operative time, intraoperative blood loss, postoperative drainage volume, postoperative pain, degree of satisfaction with the incision appearance, postoperative extubation time, and swallowing discomfort 3 months after surgery were compared among the groups that received different surgical approaches. RESULTS: The operative time of TET was longer than that of COT and EAT. The intraoperative blood loss was significantly lower in the TET and EAT groups than in the COT group. The postoperative drainage volume was lowest after EAT and highest after TET. The extubation time was significantly shorter after EAT than after TET and COT. The 6-hour CRP level was significantly higher after TET than after EAT and COT, and the 24-hour CRP level was better in the EAT group than in the other 2 groups. The CRP levels at 72 hours postoperatively were lowest in the EAT group and highest in the TET group. Postoperative pain was significantly lower after EAT than after TET and COT. Cosmetic satisfaction was highest in the TET group and lowest in the COT group. Swallowing discomfort was lowest in the EAT group and highest in the TET group. There was a positive correlation between the drainage volume on the first postoperative day, the drainage tube removal time, dysphagia, and the CRP level in each period. There was a positive correlation between pain, cosmetic satisfaction and CRP in 2 of the time periods. CONCLUSIONS: All 3 types of thyroidectomy are safe and reliable in benign tumor resection. Therefore, in clinical practice, the age, sex, and cosmetic needs of the patients, and the oncological safety should all be considered to provide patients with the most appropriate recommendations. In view of oncological safety, TET should be carefully selected for malignant tumor resection.

19.
J Hazard Mater ; 381: 120947, 2020 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394395

RESUMO

Organic-inorganic nanoflower is a new type of functional material that can effectively immobilize a wide range of enzymes to form flower-like structures for various enzymatic applications with enhanced catalytic performance and stability. In order to avoid the processing inconvenience and flower structure damage caused by the particular form of these hybrid nanoflowers during material fabrication and catalytic application, different substrates have been used to carry out supported growth of hybrid nanoflowers. However, all previously used substrates have only 2-dimensional feature and only incorporate hybrid nanoflowers on surface with limited nanoflower loading. In this study, three-dimensional (3D) hierarchically porous nanofibrous PVA-co-PE membranes (HPNM) are prepared by a simple template method for effectively immobilizing laccase-Cu2(PO4)3•3H2O hybrid nanoflowers. Compared with dense nanofibre membrane with only small sized pores (<1 micron), the coexistence of both small and large sized (30-80 microns) pores of HPNM could significantly increase the nanoflower density and allow the penetrated growth of hybrid nanoflowers into the inner structure of the membrane. The hybrid nanoflower containing hierarchically porous nanofibrous membranes (HNF-HPNM) show excellent catalytic performance in degrading different types of textile dyes (reactive blue 2, acid blue 25, acid yellow 76 and indigo carmine), with a degradation efficiency of ˜99.5% for indigo carmine. In addition, the HNF-HPNM could be reused at least 14 times for indigo carmine degradation, with a negligible degradation efficiency drop from 99.48% to 98.52%. These results indicate that hierarchically porous nanofibrous membrane can be a promising type of materials for supported hybrid nanoflower growth for practical applications such as waste water treatment, dye degradation and biosensing.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31831448

RESUMO

This article solves the event-triggered exponential synchronization problem for a class of complex-valued memristive neural networks with time-varying delays. The drive-response complex-valued memristive neural networks are translated into two real-valued memristive neural networks through the method of separating the complex-valued memristive neural networks into real and imaginary parts. In order to reduce the information exchange frequency between the sensor and the controller, a novel event-triggered mechanism with the event-triggering functions is introduced in wireless communication networks. Some sufficient conditions are established to achieve the event-triggered exponential synchronization for drive-response complex-valued memristive neural networks with time-varying delays. In addition, to guarantee that the Zeno behavior cannot occur, a positive lower bound for the interevent times is explicitly derived. Finally, numerical simulations are provided to illustrate the effectiveness and superiority of the obtained theoretical results.

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