ABSTRACT
A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Subject(s)
Female , Male , Humans , Cisplatin/pharmacology , Disulfiram/pharmacology , Testicular Neoplasms/drug therapy , Fanconi Anemia/drug therapy , Alcoholism/drug therapy , Drug Resistance, Neoplasm , Cell Line, Tumor , Substance Withdrawal Syndrome/drug therapy , Apoptosis , Antineoplastic Agents/therapeutic use , Cell ProliferationABSTRACT
Objective: To review the advances in utilizing paracrine effect of stem cells in knee osteoarthritis (OA) treatment. Methods: The researches in applying stem cells derived conditioned medium, extracellular matrix, exosomes, and microvesicles in knee OA treatment and cartilage repair were reviewed and analyzed. Results: The satisfying outcomes of using different products of stem cells paracrine effect in knee OA condition as well as cartilage defect is revealed in studies in vitro and in vivo. The mechanism including suppressing the intraarticular inflammation, the apoptosis of chondrocytes, and the degradation of cartilage matrix, while enhancing the synthesis of cartilage matrix, the differentiation of in-situ stem cells into chondrocytes and the migration to the affected area. The effectiveness can be further improved supplemented with the tissue engineering methods or gene modification. Conclusion: Compared with the traditional stem cell therapy, applying the products from paracrine effect of stem cells in knee OA treatment is more economical and safer, presenting great potential in clinical practice.
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Objective To investigate the application value of intravoxel incoherent motion (IVIM) MRI for evaluating the sensitivity of chemoradiotherapy on nasopharyngeal carcinoma (NPC). Methods Sixty eight consecutive patients newly diagnosed with NPC in the stage of T3 (30 patients) or T4 (38 patients) were retrospectively enrolled. They were divided into effective group (45 patients) and poor?effective group (23 patients) clinically after a standard chemoradiotherapy according to the RECIST criteria. IVIM with 13 b?values (range,0 to 800 s/mm2) and general MRI were performed at 3.0 T MR scanner before and after chemoradiotherapy. Two radiologists major in MRI diagnose analyzed all images independently and placed regions of interest (ROIs). Intraclass correlation coefficient (ICC) was used to evaluate intra?observer and inter?observer agreement. And Mann?Whitney test was used to assess the differences between the two groups. Results The reproducibility between intra?observer and inter?observer was relatively good. Statistically,D [(0.69±0.06)×10?3 mm2/s vs. (0.52±0.10)×10?3 mm2/s; U=51.5,P<0.01)] and D* [(161.33 ± 11.50)×10-3 mm2/s vs. (126.96 ± 10.27)×10-3 mm2/s; U=18.0, P<0.01] were significantly higher in effective group than those in poor?effective group, whereas the difference of f (16.68 ± 1.94% vs. 16.40±1.11%, U=434.5, P=0.282) and ADC (1.23±0.11)×10?3 mm2/s vs. (1.25±0.10)×10?3 mm2/s,U=427.0,P=0.240) could not reach statistical significance between the 2 groups (P>0.05). Conclusions IVIM may be potentially useful in assessing the chemoradiotherapy on NPC. The higher D value combined with higher D*value might indicate the chemoradiotherapy on NPC is more sensitive,and the higher D*value might reflect increased blood vessel generation and parenchymal perfusion in NPC.
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<p><b>OBJECTIVE</b>To investigate the changes in brain regional homogeneity in first-onset major depressive disorders (MDDs) using resting-state functional magnetic resonance imaging (fMRI).</p><p><b>METHODS</b>Eighteen patients with first-onset MDDs and twenty gender- and age-matched healthy controls underwent resting-state fMRI scans to compare the regional homogeneities of the brain regions.</p><p><b>RESULTS</b>Compared with the normal controls, the patients with MDDs showed significantly decreased regional homogeneity in the left posterior cingulated gyrus, bilateral inferior temporal gyrus, bilateral superior temporal gyrus, left inferior frontal gyrus, left hippocampa gyrus, left posterior central gyrus, left angular gyrus, right amygdala, right orbital frontal gyrus, right supplementary motor area, and right cerebellar lobe.</p><p><b>CONCLUSION</b>Patients with first-onset MDDs have dysfunctions in the brain regions closed related with cognition and emotional control.</p>
Subject(s)
Humans , Amygdala , Brain , Case-Control Studies , Cerebellum , Cognition , Depressive Disorder, Major , Diagnosis , Emotions , Frontal Lobe , Magnetic Resonance Imaging , Temporal LobeABSTRACT
Objective To investigate the expression level of miR-21, miR-146a and miR-224 and their clinical significances in cervical cancer .Methods miR-21, miR-146a and miR-224 were extracted from the normal cervical tissues and cervical cancer tissues , and their expression levels were quantified by real-time quan-titative polymerase chain reaction analysis .t test was used to analyze the expression difference of the two tissues and examine the associations between miR expression and the clinicopathological characters .The overall survival was analyzed by log-rank test, and survival curves were plotted according to Kaplan-Meier.Results miR-21 ex-pression levels of cervical cancer tissues and normal cervical tissues were 11.02 ±4.83 and 10.36 ±4.79, and miR-146a expression levels were 24.68 ±7.92 and 22.43 ±7.25, and there was no significant difference for both miR-21 and miR-146a expression between groups (P>0.05).miR-224 expression levels were 5.78 ±1.03 and 3.35 ±0.93 in cervical cancer tissues and normal cervical tissues , and the difference had statistical significance (P<0.001).For cervical cancer tissues, the miR-224 levels were significantly higher in tumors less differentia-ted, in advanced FIGO stage and with lymph nodes metastasis (P<0.05).miR-224 levels showed obvious corre-lation with survival time and the median survival time was shorter in patients with higher expression level of miR -224(P <0.05).COX multivariate analysis showed miR-224 expression level was an independent factor in patients'survival and prognosis ( P<0.05 ) .Conclusion miR-224 is independent predictor for aggressive pro-gression and poor prognosis in cervical cancer , and it might serve as a biomarker for predicting clinical outcome of cervical cancer patients .
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Objective To investigate the feasibility of diffusion-weighted(DWI) MRI on basis of the intravoxel incoherent motion (IVIM) in nasopharyngeal carcinoma (NPC),and the diagnostic value of pure molecular diffusion coefficient (D),perfusion-related diffusion coefficient (D *) and perfusion fraction (f) in first onset NPC.Methods From December 2011 to January 2013,40 consecutive patients (26 men,14 women; median age,52 years) with suspected NPC were examined on a 3.0 T MR scanner.DW imaging was performed by using a single-shot echo-planar sequence with 13 b-values (0,10,20,30,50,80,100,150,200,300,400,600,800 s/mm2).MR imaging was compared with endoscopy and biopsy for the detection of NPC.Mean interval time between MR imaging examination and subsequent nasopharyngeal biopsy was 3 days (range,0-11 days).The subjects were divided into 2 groups according to the pathological results,group A was subjects with NPC (17 men,9 women; median age,35) and group B was ones with nasopharyngeal chronic hyperplastic inflammation(NPH) (9 men,5 women; median age,35).The D,D * and f were measured and compared in patients with first onset NPC and nasopharyngeal hyperplasia (Mann-Whitney test).Results IVIM DWI was successful in 24/26 with NPC and 12/14 with NPH.D value was significantly lower in A group compared with B group [mean,(0.70 ± 0.13) ×10-3 mm2/s vs (0.78 ± 0.05) × 10-3 mm2/s ; U =2.05,P ＜ 0.05],as was f value [mean,(16.25 ±1.46) ％ vs (26.20 ± 3.90) ％ ; U =11.16,P ＜ 0.01].However,D* value was significantly higher in Agroupas compared with B group[mean,(161.8 ±23.56) × 10-3 mm2/s vs (55.28 ± 17.05) × 10-3 mm2/s; U =13.90,P ＜0.01].Conclusions IVIM DWI is a feasible technique for investigating first onset NPC and D value has a certain value in differentiating NPC and NPH.D* value has an important potential value in distinguishing benign and malignant NPC.
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Objective To evaluate the clinical application value of susceptibility weighted imaging (SWI) in neonatal hy-poxic ischemic encephalopathy (HIE). Methods Thirty-six neonates with HIE were collected and scanned by GE 3.0 T supercon-ducting MR scanner. Routine axial T1WI, T2WI, FLAIR scan and axial SWI scan were conducted. SWI sequence was compared with conventional head MRI sequences in detection rate of distribution and quantity of intracranial hemorrhage. Meanwhile, the display condition of the dilated cerebral deep veins and cortical veins was observed on SWI image and the performance of HIE in different clinical classification on SWI was compared. Results A total of 97 intracranial hemorrhages were detected by SWI in 27 cases. Only 41, 27 and 51 hemorrhages were found by TIWI, T2WI and FLAIR sequences, respectively. SWI were significantly superior to T1WI, T2WI and FLAIR in displaying the size, scope and boundary definition of hemorrhage. A total of 50 dilated ce-rebral deep veins and cortical veins were detected by SWI in 22 cases which were not found by conventional head sequences. The detection rates of intracranial hemorrhage and intracranial hemorrhage in addition of dilated cerebral veins on SWI sequence were the lowest in mild HIE group, and highest in severe group. There was significant difference among the mild, medium and severe groups (P<0.05). Conclusions SWI sequence has higher sensitivity than conventional MRI sequence in detecting intracranial hemorrhage and dilated vein in HIE, and is useful for early diagnosis of HIE.
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Objective To investigate the effects on self-renewal of pancreatic cancer stem cells by inhibiting hedgehog signaling pathway through cyclopamine. Methods PANC1 stem cells, PANC1 adherent cells and immortalized pancreatic ductal epithelial H6C7 cells were treated with 0.5, 1, 2, 5, 10 mol/L of cyclopamine for 24, 48, 72 h. The expression of Smo mRNA and Gli1 mRNA were detected by real-time PCR.Cell growth viability was measured by CCK 8. Cell cycle and apoptosis were determined by flow cytometry.Results Seventy-two hours after cyclopamine treatment, the Smo mRNA expressions of PANC1 stem cells,PANC1 adherent cells and H6C7 cells were 1,0.83 and 2.61; the expressions of Gli mRNA were 57.27,26.35,1; the inhibitory rates were ( 37.85 ± 13.69 ) %, ( 8.53 ± 4.43 ) %, (43.55 ± 28.98 ) %. Compared with PANC1, the expressions of Smo mRNA, Gli1 mRNA and the inhibitory rate of PANC1 stem cells significantly increased ( P ＜ 0.05 ). The proportion of G1 stage of PANC1 stem cells significantly decreased from (67.41 ±6.35)% to (36.53 ±6.03)% (P ＜0.05), and the apoptosis decreased from (10.95 ±5.68) % to ( 5.73 ± 1.42 ) % ( P ＞ 0.05 ). The proportion of G1 stage of PANC1 cells significantly decreased from ( 67.64 ± 6.88 ) % to ( 53.13 ± 1.10 ) % ( P ＜ 0.05 ); the apoptosis decreased from ( 12.08 ±4.12)% to (5.66 ± 1.33)% (P ＞0.05). While both the proportion of G1 stage and apoptosis of H6C7 cells was not significantly different. Conclusions Cyclopamine can inhibit the proliferation of PANC1 stem cells via blocking hedgehog signal pathway, and the mechanism may not be associated with cell apoptosis.
ABSTRACT
MicroRNAs(miRNAs) are small non-coding RNAs that regulate gene expression at posttranscription. Its abnormality expression could be one of the main mechanisms on development of pancreatic neoplasm. It also offers new candidate targsts for diagnostic and therapeutic strategies of pancreatic neoplasm.