[Abstract] Objective: To investigate the effect of miR-383-5p on the proliferation and invasion of medulloblastoma (MB) by targeting DNA mismatch repair MSH6 gene. Methods: A total of 15 pairs of tumor tissues and corresponding adjacent tissues from MB patients, who were surgically treated and pathologically confirmed in the Department of Oncology of the Second Affiliated Hospital of Hainan Medical College from July 2014 to May 2017, were collected for this study. qPCR was applied to detect the expression of miR-383-5p in MB tissues and cell lines. The experimental cells were divided into control group (NC group), miR-383-3p overexpression group (miR-383-5p group), MSH6 knockdown group (si-MSH6 group) and miR-383-5p inhibitor+si-MSH6 group. CCK-8 assay was used to detect the proliferation of UW473 cells. Transwell assay was used to examine the invasion and migration of UW473 cells, the targeting relationship between miR-383-5p and MSH6 was verified by Dual-luciferase reporter gene assay, and Western blotting (WB) was performed to detect the protein expression of MSH6. Results: The expression level of miR-383-5p was significantly down-regulated in MB tissues and cell lines compared with para-cancer tissues (all P<0.05 or P<0.01). Overexpression of miR-383-5p significantly inhibited the proliferation, migration and invasion of UW473 cells (all P<0.05 or P<0.01), and down-regulated the expression level of MSH6 (all P<0.01). Dual-luciferase reporter gene assay demonstrated that miR-383-5p could targetedly bind to the 3'UTR of MSH6. Knockdown of MSH6 could inhibit the proliferation, invasion and migration of UW473 cells (all P<0.01). Further experiments showed that simultaneous knockdown of miR-383-5p and MSH6 could attenuate the inhibition of MSH6 silence on the proliferation, invasion and migration of UW473 cells. Conclusion: miR-383-5p expression is down-regulated in MB tissues and cell lines, and miR-383-5p suppresses the proliferation, migration and invasion of UW473 cells via targetedly down-regulating MSH6.

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
Animals ; Bicuculline ; pharmacology ; Disease Models, Animal ; Glycine ; metabolism ; Hyperalgesia ; drug therapy ; etiology ; metabolism ; Imidazoles ; pharmacology ; Inhibitory Postsynaptic Potentials ; drug effects ; physiology ; Male ; Mice, Inbred C57BL ; Neurons ; drug effects ; metabolism ; Neurotransmitter Agents ; pharmacology ; Peripheral Nerve Injuries ; drug therapy ; metabolism ; Phenanthrolines ; pharmacology ; Potassium Channels, Inwardly Rectifying ; antagonists & inhibitors ; metabolism ; Receptors, GABA-A ; metabolism ; Receptors, Glycine ; metabolism ; Strychnine ; pharmacology ; Synaptic Transmission ; drug effects ; physiology ; Tissue Culture Techniques ; Touch

BACKGROUND On March 2022, the United States Food and Drug Administration(FDA) announced the approval of radiolabeled drug lutetium Lu 177 vipivotide tetraxetan for treatment of adult patients with prostate specific membrane antigen(PSMA)-positive metastatic castration-resistant prostate cancer who have been treated with androgen-receptor pathway inhibition and taxane-based chemotherapy. As PSMA is barely expressed on non-prostatic tissue, it has a very low background accumulation in healthy tissue, consequently, avoiding severe adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan. A multicenter phase Ⅲ VISION study(NCT 03511664) showed that about 30% of patients with evaluable disease at baseline demonstrated an overall response with lutetium Lu 177 vipivotide tetraxetan plus standard care, compared to only 2% in the control arm. The high efficacy and mild adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan cause opportunities for the healthcare systems and represent an important next step towards novel oncotherapy, but also cause great challenges in its clinical use due to lack of practical experience. Currently, data on the large sample and real-world comprehensive safety of lutetium Lu 177 vipivotide tetraxetan are still limited. Therefore, it is necessary to employ data mining algorithms to seek out the potential adverse event signals of lutetium Lu 177 vipivotide tetraxetan by post-marketing monitoring. METHODS FDA Adverse Event Reporting System(FAERS) is a publicly available, voluntary, and spontaneous reporting database. In the present study, the adverse events reported from the second quarter of 2022 to the fourth quarter of 2022 with lutetium Lu 177 vipivotide tetraxetan from FAERS were retrospectively analyzed. Seven types of datasets, including patient demographic and administrative information(DEMO), drug information(DRUG), therapy start dates and end dates for reported drugs(THER), adverse event results(OUTC), adverse event sources(PRSP), coded for the adverse events(REAC), and indications for use/diagnosis(INDI) were used. The reports of lutetium Lu 177 vipivotide tetraxetan were identified using generic name(LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN in prod_ai column) and trade name(PLUVICTO in drug name column) in the DRUG dataset. The adverse event reports with the role_cod as the primary suspected(PS) were chose. Next, the report characteristics, demographic characteristics and onset time of lutetium Lu 177 vipivotide tetraxetan-associated adverse events were analyzed. The adverse events were coded using preferred terms(PT) derived from the standardized Medical Dictionary for Regulatory Activities 25.1(MedDRA), which contained 27 system organ classes(SOCs). Four algorithms, including reporting odds ratio(ROR), proportional reporting ratio(PRR), Bayesian confidence propagation neural network(BCPNN) and multi-item gamma Poisson shrinker(MGPS) were used to detect the signals. All the four data mining algorithms were based on the disproportionality analysis. An adverse event signal was detected only when it conformed to all of the four algorithms criteria simultaneously. RESULTS A total of 634 reports associated with lutetium Lu 177 vipivotide tetraxetan were considered. As a whole, the number of reports had increased gradually month-on-month, and 568(89.6%) reports occurred in the United States. The most common age and body weight groups were 61-80 years(75.4%) and 61-80 kg(50.9%), respectively. Most reports occurred within 30 d after administration of lutetium Lu 177 vipivotide tetraxetan, accounting for 41.5%. Based on 4 algorithms of ROR, PRR, BCPNN and MGPS, six effective signals at the PT level were detected, including anaemia(PT: 10002034), thrombocytopenia(PT: 10043554), laboratory test abnormal(PT: 10023547), platelet count decreased(PT: 10035528), full blood count decreased(PT: 10017413) and dry mouth(PT: 10013781). CONCLUSION When using lutetium Lu 177 vipivotide tetraxetan, it is important to strengthen clinical monitoring within one month and pay attentions to laboratory results including complete blood cell and platelet count. This study might provide powerful support for clinical monitoring of lutetium Lu 177 vipivotide tetraxetan.

Background:The current World Health Organization (WHO) classiifcation of nasopharyngeal carcinoma (NPC) con?veys little prognostic information. This study aimed to propose an NPC histopathologic classiifcation that can poten?tially be used to predict prognosis and treatment response. Methods:We initially developed a histopathologic classiifcation based on the morphologic traits and cell differentia?tion of tumors of 2716 NPC patients who were identiifed at Sun Yat?sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classiifcation was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The effcacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% conifdence intervals (CI) for overall survival (OS). Results:The 5?year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid?epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P<0.001). In mul?tivariate models, patients with MSEC had a shorter OS than patients with EC (HR=1.44, 95% CI=1.27–1.62), SC (HR=2.00, 95% CI=1.76–2.28), or SCC (HR=4.23, 95% CI=3.34–5.38). Radiochemotherapy signiifcantly improved survival compared with radiotherapy alone for patients with EC (HR=0.67, 95% CI=0.56–0.80), MSEC (HR=0.58, 95% CI=0.49–0.75), and possibly for those with SCC (HR=0.63; 95% CI=0.40–0.98), but not for patients with SC (HR=0.97, 95% CI=0.74–1.28). Conclusions:The proposed classiifcation offers more information for the prediction of NPC prognosis compared with the WHO classiifcation and might be a valuable tool to guide treatment decisions for subtypes that are associ?ated with a poor prognosis.