Objective:To analyze the risk factors of first-episode hematogenous metastasis in patients with thoracic esophageal squamous cell carcinoma (ESCC) who received non-surgical treatment after radiotherapy and chemotherapy, and its impact on survival and prognosis.Methods:The clinical data of 230 ESCC patients who met the inclusion criteria and received radical radiotherapy in Tengzhou Central People′s Hospital and Affiliated Hospital of Xuzhou Medical University from January 2011 to October 2018 were retrospectively analyzed.Logistic regression analysis and survival were used to analyze the risk factors and prognosis of blood group metastasis after treatment.Results:In 230 patients with thoracic esophageal cancer, 70 cases (30.4%) developed hematogenous metastasis for the first time.Compared with patients without hematogenous metastasis, the median overall survival was 15 months and 20 months (χ 2=7.249, P=0.007), and the median progression free survival was 9 months and 13 months (95% CI was 7.2-10.8 months and 10.8-15.2 months, respectively χ 2=21.664, P<0.001). Logistic multivariate analysis showed that there was significant difference in the occurrence of hematogenous metastasis among different N stages (χ 2=30.764, P<0.001). N stage was an independent factor for judging hematogenous metastasis, and the increased N stage increased the risk of hematogenous metastasis (OR value were 6.000, 12.629 and 48.167, respectively; 95% CI were 1.712-21.025, 3.546-44.976 and 10.848-213.858, respectively; all P<0.05). The overall survival time of patients with concurrent chemoradiotherapy before hematogenous metastasis was longer than that of patients with sequential chemoradiotherapy and radiotherapy alone (χ 2=10.002, P=0.007). Stratified analysis showed that adjuvant chemotherapy after concurrent chemoradiotherapy could prolong the overall survival of patients with N2 and N3 (χ 2=11.025, P=0.001). Conclusion:N staging is an independent factor to judge the hematogenous metastasis.ESCC patients with hematogenous metastasis after chemoradiotherapy have poor prognosis.N2, N3 patients with concurrent chemoradiotherapy after adjuvant chemotherapy have clinical benefits.

Objective To explore the expression of Ras-related protein 11(Rab11)in hypoxia, the effect of Rab11 on the invasion and migration of cervical cancer cell line SiHa and its possible mechanism. Methods SiHa cells were divided into 4 groups, the normoxic blank group (normal culture in normoxia), the hypoxic blank group (normal culture in hypoxia), the negative control group [transfection of negative control small interfering RNA(siRNA)in hypoxia], the Rab11-siRNA group (transfection of Rab11 siRNA in hypoxia). Western blot was used to examine the expression of Rab11, integrin α5, integrin β3, phosphorylated focal adhesion kinase(p-FAK), phosphorylated phosphatidylinositol 3 kinase(p-PI3K) protein, together with the expression of Ras correlative C3 creotoxin substrate 1(Rac1), which was critical in regulating cell invasion. The mRNA expression of Rab11 in the 4 groups was detected by realtime-qPCR. The cell invasion was detected by matrigel assay, while the cell migration was detected by transwell assay. Immunofluorescence was used to identify intracellular location of Rac1 in SiHa cell. Results (1) The expression of Rab11, intergrin α5, intergrin β3, p-FAK, p-PI3K and Rac1 in the normoxic blank group were 0.56±0.04, 0.33±0.03, 0.32±0.03, 0.36±0.03, 0.35±0.03 and 0.47±0.03, respectively. In the hypoxic blank group, they were 0.73±0.03, 0.74±0.03, 0.61±0.03, 0.62±0.03, 0.60±0.03 and 0.73±0.03, respectively. In the negative control group, their expressions were 0.72±0.03, 0.73±0.03, 0.59±0.03, 0.61±0.03, 0.59±0.03 and 0.72±0.03, respectively. While in the Rab11-siRNA group, they were 0.44±0.03, 0.30±0.03, 0.29±0.03, 0.30±0.03, 0.30±0.03 and 0.34±0.04, respectively. The expressions of Rab11, α5, β3, p-FAK, p-PI3K and Rac1 were significantly higher in the hypoxic blank group than in the normoxic blank group(P<0.05), and were significantly lower in the Rab11-siRNA group than in the hypoxic blank group and the negative control group(P<0.05). (2) The expressions of Rab11-mRNA were 1.000±0.000, 1.454±0.114, 1.442±0.101, 0.570± 0.046 in the normoxic blank group, the hypoxic blank group, the negative control group and the Rab11- siRNA group, respectively. It was significantly higher in the hypoxic blank group than in the normoxic blank group(P<0.05), and was significantly lower in the Rab11-siRNA group than in the hypoxic blank group and the negative control group(P<0.05). (3) By Matrigel, the invasion cell number in the normoxic blank group, the hypoxic blank group,the negative control group and the Rab11-siRNA group were 65±12, 106±16, 104± 17 and 50±11, respectively. The invasion capacity was significantly higher in the hypoxic blank group than in the normoxic blank group(P<0.05), and was significantly lower in the Rab11- siRNA group than in the hypoxic blank group and the negative control group(P<0.05). (4) By transwell assay, the migration cells in the normoxic blank group, the hypoxic blank group, the negative control group and the Rab11-siRNA group were 127±12, 169±15, 161±13 and 77±13, respectively. The capacity of invasion was significantly higher in the hypoxic blank group than in the normoxic blank group(P<0.05), and was significantly lower in the Rab11- siRNA group than in the hypoxic blank group and the negative control group(P<0.05). (5) The immunofluorescence showed that the red fluorescence intensity around nucleus was significantly increased in the normoxic blank group, the hypoxic blank group and the negative control group than in the Rab11- siRNA group. Conclusions Hypoxia could promote the invasion and migration of SiHa cells. In hypoxia, the down regulation of Rab11 expression could inhibit the invasion and migration of SiHa cells. This might be due to the decreased expression of the intergrin α5, intergrin β3, p-FAK, p-PI3K and Rac1 protein.

Objective To study the clinical efficiency and adverse reactions of simultaneous modulated accelerated radiotherapy (SMART)and intensity-modulated radiation therapy (IMRT)in advanced cervical cancer. Methods Sixty patients with advanced cervical cancer were collected from April 2011 to April 2017 in our hospital. The 60 patients were randomly divided into experimental group (30 cases)and control group (30 cases)by using stratified randomization method. The two groups were given intracavitary irradiation and concur-rent chemotherapy. The patients in experimental group were treated with SMART and the patients in control group were treated with IMRT. 95％ planned target volume was 50. 4 Gy/ 28 F in the two groups and the dose for IMRT with simultaneous integrated boost was 64. 4 Gy/ 28 F to the planning target volume. Disease progres-sion,survival time and adverse reactions of the two groups were compared. Results At the end of radiothe-rapy,the experimental group had 23 patients with complete response (CR),4 patients with partial response (PR),2 patients with unaltered stable disease (SD),1 patient with progressive disease (PD),and the control group had 22 patients with CR,3 patients with PR,3 patients with SD,2 patients with PD. The overall effi-ciency of the experimental group was slightly higher than that of the control group (90. 0％ vs. 83. 3％),but the difference was not statistically significant (χ2 = 0. 144,P = 0. 704). After 3 months of radiotherapy,the experimental group had 28 patients with CR,1 patient with PR,1 patient with PD,and the control group had 22 patients with CR,2 patients with PR,3 patients with SD,3 patients with PD. The overall efficiency of the experimental group (96. 7％)was higher than that of the control group (96. 7％ vs. 80. 0％),but the diffe-rence was not statistically significant (χ2 = 2. 588,P = 0. 108). The median overall survival time of the experi-mental group and control group were 43 months and 38 months,and the difference was statistically significant (χ2 = 7. 087,P = 0. 008). The 1-year survival rates of the two groups were 96. 6％ and 85. 7％,and the 3-year survival rates were 86. 2％ and 60. 7％,respectively. There were no significant differences in the inci-dences of gastrointestinal reaction (66. 7％ vs. 63. 3％,χ2 = 0. 073,P = 0. 787),urinary system reaction (33. 3％ vs. 30. 0％,χ2 = 0. 077,P = 0. 781)and bone marrow suppression (83. 3％ vs. 86. 7％,χ2 =0. 000,P = 1. 000)between the two groups. Conclusion The efficiency of advanced cervical cancer patient treated with SMART is better than IMRT,and the adverse reactions are tolerable,which is worthy of clinical promotion.

Objective To investigate the improvement of endoplasmic reticulum stress mediated by microRNA (miR)-34a-5p/transmembrane fusion protein 1(Notch1) signaling axis on hypoxia/reoxygenation (H/R) human cardiomyocytes.Methods Human cardiomyocytes were randomly divided into Control group, H/R group, mimic NC group, mimic group, inhibitor NC group and inhibitor group.Except the Control group, H/R injury model was established in other groups.The expression levels of miR-34a-5p and Notch1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) , cell survival rate was detected by thiazolyl blue (MTT) , cell apopto-sis rate was detected by flow cytometry, and the targeting relationship between miR-34a-5p and Notch1 was detec-ted by dual luciferase gene reporting method.The expressions of transcriptional activator 6 (ATF6), inositol demand enzyme 1 (IRE 1), protein kinase - like endoplasmic reticulum kinase (PERK) and glucose regulatory protein 78 (GRP78) were detected by Western blot.Results miR-34a-5p targeted Notch1 (P<0.05); compared with Con-trol group, the expression level of miR-34a-5p, apoptosis rate and protein expressions of ATF6, IRE1, PERK and GRP78 in H/R group increased, while the cell survival rate and Notch1 mRNA and protein expressions decreased (P<0.05).Compared with H/R group and mimic NC group, miR-34a-5p expression, apoptosis rate, and protein expressions of ATF6, IRE1, PERK and GRP78 in mimic group increased, while cell survival rate and Notch1 mR-NA and protein expressions decreased (P<0.05).Compared with H/R group and inhibitor NC group, the expres-sion of miR-34a-5p, apoptosis rate and protein expressions of ATF6, IRE1, PERK and GRP78 decreased in inhibi-tor group, while cell survival rate and Notch1 mRNA and protein expressions increased (P<0.05).Conclusion miR-34a-5p can inhibit the apoptosis of H/R human cardiomyocytes, possibly through the targeted inhibition of Notch1-mediated endoplasmic reticulum stress.

Objective:To introduce and validate the Pediatric Nausea Assessment Tool (PeNAT) and the Baxter Retching Faces Scale (BARF) in the assessment of chemotherapy induced nausea in Chinese children with malignant neoplasms, and to explore the cut-off value for rescue antiemetic.Methods:A prospective descriptive study was conducted, 244 children in Sun Yat-sen University Cancer Center with malignant neoplasms who received chemotherapy were selected by convenience sampling from July to August 2021. PeNAT, BARF, Visual Analogue Scale (VAS) and the Faces Pain Scale-Revised(FPS-R) were used to assess the severity of nausea and pain before and after chemotherapy, before and 30-60 minutes after the use of rescue antiemetic or analgesic. After chemotherapy, the children also were asked the changes of nausea severity and whether antiemetic was needed.Results:A test-retest reliability was conducted on the patients with the same severity of nausea before and after chemotherapy, and the intraclass correlation coefficient of the PeNAT and BARF were 0.940 (both P<0.05). After chemotherapy, the PeNAT and BARF were 1.5(1.0, 2.0) and 2.0(0, 2.0) points, which were significantly higher than the 1.0(1.0, 1.0) and 0(0, 0) points before chemotherapy ( Z = - 9.19, - 9.09, both P<0.01). The PeNAT and BARF of 11 cases receiving antiemetic before medication were 4.0 (4.0, 6.0) and 3.0(2.0, 4.0) points, which were higher than the 0(0, 2.0) and 1.0(1.0, 2.0) points without antiemetic ( Z = - 4.03, - 3.86, both P<0.05). After chemotherapy, the correlation coefficients between PeNAT or BARF and VAS-nausea were r = 0.933, 0.957 (both P<0.01), and FPS-R were r = 0.192, 0.189 (both P<0.05). After using antiemetic, PeNAT and BARF were 2.0(2.0, 3.0) and 2.5(2.0, 4.0) points, which were significant different than the 3.0(3.0, 3.8) and 4.0(4.0, 8.0) points before using antiemetic ( Z = - 2.97, - 2.83, both P<0.05). According ROC curves and cut-off values, it was determined that PeNAT≥3 and BARF≥4 had clinical significance and require clinical intervention. Conclusions:PeNAT and BARF have excellent reliability and validity in the assessment of chemotherapy induced nausea in children with malignant neoplasms, they can effectively identify the requirement of rescue antiemetic, and evaluate the efficacy of antiemetic.

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.
Humans ; Morphine/pharmacology* ; Hyperalgesia/metabolism* ; Analgesics, Opioid/pharmacology* ; Neurons/metabolism* ; Signal Transduction

Mechanical allodynia (MA), including punctate and dynamic forms, is a common and debilitating symptom suffered by millions of chronic pain patients. Some peripheral injuries result in the development of bilateral MA, while most injuries usually led to unilateral MA. To date, the control of such laterality remains poorly understood. Here, to study the role of microglia in the control of MA laterality, we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice. Surprisingly, the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA. Moreover, in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons. Consistent with behavioral results, microglial depletion did not prevent the opening of bilateral gates for Aβ pathways in the superficial dorsal horn. This study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.
Mice ; Animals ; Hyperalgesia/metabolism* ; Microglia/metabolism* ; Disease Models, Animal ; Spinal Cord/metabolism* ; Spinal Cord Dorsal Horn/metabolism* ; Ganglia, Spinal/metabolism*