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Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.
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Objective:To study the role of corticotropin-releasing hormone (CRH) system in locus ceruleus (LC) in irritable bowel syndrome (IBS) and to explore its molecular mechanism.Methods:The IBS rat was established by maternal separation following with postnatal stress. The tissues sample of LC was obtained by micropunched nuclei. The expression of c- Fos, CRH and its receptors including corticotropin-releasing hormone receptor (CRHR) 1 and CRHR2 of rats’ LC tissues of control group and IBS group was detected by quantitative polymerase chain reaction(PCR). The expression of DNA methyltransferase ( DNTM) 1, DNMT3a and DNMT3b at the mRNA level were also measured. In addition, the expression of histone methyltransferase ASH2-like protein (ASH2L) and SET and MYND domain containing 2 (SMYD2) was determined by Western blotting. T test was used for statistical analysis. Results:The rectal pneumatic pressure of IBS group was lower than that of control group ((69.82±5.47) mmHg vs. (86.86±5.98) mmHg; 1 mmHg=0.133 kPa), however compared with that of control group, the expression of c- Fos at the mRNA level increased (2.11±0.44 vs.1.00±0.19), and the differences were statistically significant ( t=6.215 and 2.321, P<0.01 and 0.05). In addition, compared with that of control group, the expression of CRH at the mRNA level increased (1.99±0.35 vs.1.00±0.13), and the difference was statistically significant ( t= 2.797, P<0.05). Compared with that of control group, the expression of SMYD2 at the protein level up-regulated (1.04±0.21 vs. 0.61±0.12), and the difference was statistically significant ( t=4.451, P<0.01). However, there were no statistically significant differences in the expression of CRHR-1, CRHR2, DNMT1, DNMT3a, DNMT3b at the mRNA level, and the expression of ASH2L between IBS group and control group (0.96±0.13 vs. 1.00±0.26, 1.35±0.63 vs. 1.00±0.43, 1.40±0.61 vs.1.00±0.19, 1.39±0.58 vs. 1.00±0.21, 1.45±0.71vs.1.00±0.39 and 0.80±0.19 vs. 1.05±0.26, respectively; all P>0.05). Conclusions:Maternal separation combined with postnatal stress affect the transcription of Crh gene in LC and cause the activation of the stress regulation network CRH and norepinephrine system, resulting in the increase of the visceral sensitivity of rats. The abnormal transcription of Crh gene may be related with SMYD2-mediated histone H3K36 methylation, but not related with the modification of DNA methylation.
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Objective@#To study the role of corticotropin-releasing hormone (CRH) system in locus ceruleus (LC) in irritable bowel syndrome (IBS) and to explore its molecular mechanism.@*Methods@#The IBS rat was established by maternal separation following with postnatal stress. The tissues sample of LC was obtained by micropunched nuclei. The expression of c-Fos, CRH and its receptors including corticotropin-releasing hormone receptor (CRHR) 1 and CRHR2 of rats’ LC tissues of control group and IBS group was detected by quantitative polymerase chain reaction(PCR). The expression of DNA methyltransferase (DNTM) 1, DNMT3a and DNMT3b at the mRNA level were also measured. In addition, the expression of histone methyltransferase ASH2-like protein (ASH2L) and SET and MYND domain containing 2 (SMYD2) was determined by Western blotting. T test was used for statistical analysis.@*Results@#The rectal pneumatic pressure of IBS group was lower than that of control group ((69.82±5.47) mmHg vs. (86.86±5.98) mmHg; 1 mmHg=0.133 kPa), however compared with that of control group, the expression of c-Fos at the mRNA level increased (2.11±0.44 vs.1.00±0.19), and the differences were statistically significant (t=6.215 and 2.321, P<0.01 and 0.05). In addition, compared with that of control group, the expression of CRH at the mRNA level increased (1.99±0.35 vs.1.00±0.13), and the difference was statistically significant (t= 2.797, P<0.05). Compared with that of control group, the expression of SMYD2 at the protein level up-regulated (1.04±0.21 vs. 0.61±0.12), and the difference was statistically significant (t=4.451, P<0.01). However, there were no statistically significant differences in the expression of CRHR-1, CRHR2, DNMT1, DNMT3a, DNMT3b at the mRNA level, and the expression of ASH2L between IBS group and control group (0.96±0.13 vs. 1.00±0.26, 1.35±0.63 vs. 1.00±0.43, 1.40±0.61 vs.1.00±0.19, 1.39±0.58 vs. 1.00±0.21, 1.45±0.71vs.1.00±0.39 and 0.80±0.19 vs. 1.05±0.26, respectively; all P>0.05).@*Conclusions@#Maternal separation combined with postnatal stress affect the transcription of Crh gene in LC and cause the activation of the stress regulation network CRH and norepinephrine system, resulting in the increase of the visceral sensitivity of rats. The abnormal transcription of Crh gene may be related with SMYD2-mediated histone H3K36 methylation, but not related with the modification of DNA methylation.
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Objective To investigate the significance of an accessory hepatic vein (AHV) in the interventional treatment of Budd-Chiari syndrome (BCS).Methods From Mar.2011 to Jun.2013,35 patients with BCS who also had an AHV were included into this study.The patients were divided into two groups according to whether the AHV was obstructive:21 patients had obstruction to the inferior vena cava (IVC) and to the 3 hepatic veins (HV),but the AHV was open; 14 patients had obstruction to the AHV and the 3 HVs.In 13 of these patients the IVC was open,but 1 patient had obstruction to the IVC.During treatment,the patients in the AHV open group underwent balloon dilation or stent insertion of IVC ; patients in the AHV obstruction group underwent balloon dilation or stent insertion of AHV.The patient with obstruction to the IVC underwent balloon dilation of IVC first.Results All patients were successfully treated without any procedure-related complications.In the AHV open group,the average pressure of the AHV decreased from (28.81 ± 6.23) cmH2 O (1 cmH2O =0.098 kPa) before treatment to (18.62 ± 5.06) cmH2O after treatment (P ＜ 0.01) ; the average serum TBIL decreased from (23.24 ± 6.41) μmol/L before treatment to (19.52 ± 4.31) μmol/L after treatment (P ＜ 0.01) ; the average serum albumin changed from (33.76 ± 3.74) g/L before treatment to (34.05 ± 3.62) g/L after treatment (P =0.485).In the AHV obstruction group,the average pressure of the AHV decreased from (36.29 ± 11.65) cmH2O before treatment to (22.07 ± 7.67) cmH2O after treatment (P ＜ 0.01) ; the average serum TBIL decreased from (31.24 ± 9.54) μmol/L before treatment to (20.93 ±7.26) μmol/L after treatment (P ＜0.01) ; the average serum albumin changed from (32.14 ± 4.55) g/L before treatment to (32.11 ± 4.47) g/L after treatment (P =0.861).During follow-up,no patients experienced recurrence of symptoms in the AHV open group; one patient experienced recurrence of symptoms 5 months after treatment in the AHV obstruction group.This patient received a second balloon dilation of the AHV.Conclusions For patients with BCS with IVC and the 3 HVs obstruction,if the AHV was open,we could only treat the IVC.For patients with BCS with AHV and the 3 HVs obstruction,AHV dilation followed by recanalization of AHV was also effective.
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Objective To discuss the ventilatory catheter-assisted airway stenting under local anesthesia for airway stenosis.Methods From May 2008 to January 2013,25 consecutive patients with airway stenosis underwent the treatment of ventilatory catheter-assisted airway stenting under local anesthesia.The dyspnea score was grade Ⅱ in 3 patients,grade Ⅲ in 18 patients and grade Ⅳ in 4 patients.During the treatment,a 4 F VER catheter was placed into one of the main bronchi as a ventilatory catheter for oxygen supply in advance,the oxygen flow was set at 2 to 4 L/rmin according to the patients' condition,then the airway stenting was performed,after release of the stent,the ventilatory catheter was removed smoothly.Data on technical success,clinical outcome and follow-up were collected and analyzed respectively.The paired t test was performed to compare variables before and after tracheal stenting.Results Ventilatory catheter-assisted airway stenting under local anesthesia was technically successful in all patients.A total of 25 stents were placed in 25 patients.The stents included I-shaped stents (n=19) and Y-shaped stents (n=6).After the oxygen supply,the patients' SaO2 was increased to 94％ to 97％ rapidly.When the stent introducer sheaths were passing through the stenotic site,the SaO2 could be maintained at 92％ to 97％.The improvement of the respiratory difficulty was achieved in 100％ of our patients.The hypoxia symptom was relieved immediately after stents placement,the dyspnea score decreased to grade 0 in 2 patients,to grade Ⅰ in 19 patients and to grade Ⅱ in 4 patients.Respiratory rate and SaO2 improved from (30.0±2.1) times/min and (6.0±3.8)％ before stenting to (19.7±1.6) times/min (t=23.33,P＜0.01) and (93.0± 1.7)％ (t=23.50,P＜0.01) after stenting,respectively.Through the follow-up,3 patients suffered the stent-related complications after discharge,the complications included re-stenosis (n=2) and fracture(n=1).Conclusion Ventilatory catheter-assisted airway stenting under local anesthesia can be an effective,simple and safe method for airway stenosis.