Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.

Objective:To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy. Method:Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022. Organoids were cultured and tumor tissue were passaged. In vitro hyperthermic perfusion experiments were performed on organoids with good viability. Firstly, 10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations: 1 000, 250, 62.5, 15.6, 3.9, and 0.98 μmol/L. The organoids were exposed to oxaliplatin at 42℃ for 30 minutes and to lobaplatin at 42℃ for 60 minutes. Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated. Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids. This testing revealed oxaliplatin was effective at 579 μmol/L at a hyperthermic perfusion temperature of 42℃ for 30 min and lobaplatin was effective at 240 μmol/L at a hyperthermic perfusion temperature of 42℃ for 60 minutes. Result:Thirty-two tumor organoids were cultured from samples of colorectal cancer. The median concentration required for oxaliplatin to eliminate 50% of tumor cells (IC50) was 577.45 μmol/L (IQR: 1846.09 μmol/L). The median IC50 for lobaplatin was 85.04 μmol/L (IQR: 305.01 μmol/L).The difference between the two groups was not statistically significant ( Z=1.784, P=0.084). In seven of 10 organoids, lobaplatin showed a greater IC50 after in vitro hyperthermic perfusion than did oxaliplatin. Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6% (95%CI: 32.1%?47.0%), whereas the average rate of inhibition for lobaplatin was 89.7% (95%CI: 87.0%?92.3%): this difference is statistically significant ( t=?15.282, P<0.001). Conclusion:The rate of inhibition achieved by hyperthermic perfusion of lobaplatin in vitro is better than that achieved by hyperthermic perfusion with oxaliplatin. Lobaplatin is more effective than oxaliplatin when administered by hyperthermic intraperitoneal perfusion and therefore has the potential to replace oxaliplatin in this setting.

Objective:To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy. Method:Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022. Organoids were cultured and tumor tissue were passaged. In vitro hyperthermic perfusion experiments were performed on organoids with good viability. Firstly, 10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations: 1 000, 250, 62.5, 15.6, 3.9, and 0.98 μmol/L. The organoids were exposed to oxaliplatin at 42℃ for 30 minutes and to lobaplatin at 42℃ for 60 minutes. Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated. Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids. This testing revealed oxaliplatin was effective at 579 μmol/L at a hyperthermic perfusion temperature of 42℃ for 30 min and lobaplatin was effective at 240 μmol/L at a hyperthermic perfusion temperature of 42℃ for 60 minutes. Result:Thirty-two tumor organoids were cultured from samples of colorectal cancer. The median concentration required for oxaliplatin to eliminate 50% of tumor cells (IC50) was 577.45 μmol/L (IQR: 1846.09 μmol/L). The median IC50 for lobaplatin was 85.04 μmol/L (IQR: 305.01 μmol/L).The difference between the two groups was not statistically significant ( Z=1.784, P=0.084). In seven of 10 organoids, lobaplatin showed a greater IC50 after in vitro hyperthermic perfusion than did oxaliplatin. Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6% (95%CI: 32.1%?47.0%), whereas the average rate of inhibition for lobaplatin was 89.7% (95%CI: 87.0%?92.3%): this difference is statistically significant ( t=?15.282, P<0.001). Conclusion:The rate of inhibition achieved by hyperthermic perfusion of lobaplatin in vitro is better than that achieved by hyperthermic perfusion with oxaliplatin. Lobaplatin is more effective than oxaliplatin when administered by hyperthermic intraperitoneal perfusion and therefore has the potential to replace oxaliplatin in this setting.

Disorders of gastrointestinal motility (DGIM) are very common diseases in the department of gastroenterology and the prevalence is increasing gradually. The pathogenesis of DGIM is complex and closely related to Cajal interstitial cells of gastrointestinal tract, brain-intestinal axis and intestinal microecology. So far, a variety of diagnostic techniques have emerged, including esophageal 24 h pH monitoring and impedance analysis, electrogastrography, radionuclide scanning, ultrasound, 13C gastric emptying breath test, hydrogen breath test, defecation contrast, X-ray marker method, high resolution manometry and wireless motility capsules. According to the different pathogenesis of DGIM, treatment methods emerge in an endless stream, such as adjustment of lifestyle, drugs and surgical treatment and so on. Individual treatment should be provided clinically for different patients.

Objective:To investigate the risk factors for organoid culture failure in colorectal cancer.Methods:This was a retrospective observational study. Tumor specimens were obtained from 1130 patients with colorectal cancer who had undergone surgery or biopsy and had no other concurrent malignancies at Nanfang Hospital of Southern Medical University from December 2021 to November 2022. Organoid culture was performed on 1231 tumor tissue samples. Univariate analysis and multivariate logistic regression were used to analyze the factors that might have influenced the rate of successful organoid culture of colorectal cancer tissue samples.Results:The median (range) duration of organoid culture was 7 (3–12) days. The overall rate of successful culture was 76.3% (939/1231). The rate of successful organoid cultures varied according to the sampling site, malignant ascites having the highest success rate (96.4%, 27/28), followed by liver metastases (83.1%, 54/65), lung metastases (8/10), primary tumors (76.0%, 816/1074), omental metastases (10/14), peritoneal metastases (61.5%, 16/26), ovarian metastases (3/5), and lymph node metastases (5/9). The difference in rates of successful organoid culture between primary tumors and malignant ascites was statistically significant ( P=0.012), whereas none of the other rates of successful organoid culture success differed significantly (all P>0.05). The rate of successful organoid culture was 96.4% (27/28) for malignant ascites obtained by abdominal puncture, 76.5% (864/1130) for surgical specimens, and 65.8% (48/73) for endoscopic biopsies; these differences are statistically significant (χ 2=10.773, P=0.005). The rate of successful organoid culture was 62.5% (40/64) in the neoadjuvant chemoradiotherapy group, which is significantly lower than in the non-adjuvant (76.9%, 787/1023) and chemotherapy groups (77.8%, 112/144) (χ 2=7.134, P=0.028). Multivariate logistic regression analysis revealed that endoscopic biopsy (OR=0.557, 95%CI: 0.335–0.924, P=0.024) and neoadjuvant chemoradiotherapy (OR=0.483, 95%CI: 0.285–0.820, P=0.007) were independent risk factors for failure of organoid culture of colorectal cancer samples. Malignant ascites (OR=8.537, 95%CI:1.154–63.131, P=0.036) and abdominal puncture (OR=8.294, 95% CI: 1.112–61.882, P=0.039) were identified as independent protective factors. Conclusions:The rate of successful organoid culture was influenced by the sampling site, sampling method, and chemoradiotherapy. The rate of successful organoid culture was lower for endoscopic biopsies and in patients receiving preoperative neoadjuvant chemoradiotherapy, and higher for malignant ascites. We consider that culture of malignant ascites is preferable when peritoneal metastases are suspected.

Objective:To investigate the risk factors for organoid culture failure in colorectal cancer.Methods:This was a retrospective observational study. Tumor specimens were obtained from 1130 patients with colorectal cancer who had undergone surgery or biopsy and had no other concurrent malignancies at Nanfang Hospital of Southern Medical University from December 2021 to November 2022. Organoid culture was performed on 1231 tumor tissue samples. Univariate analysis and multivariate logistic regression were used to analyze the factors that might have influenced the rate of successful organoid culture of colorectal cancer tissue samples.Results:The median (range) duration of organoid culture was 7 (3–12) days. The overall rate of successful culture was 76.3% (939/1231). The rate of successful organoid cultures varied according to the sampling site, malignant ascites having the highest success rate (96.4%, 27/28), followed by liver metastases (83.1%, 54/65), lung metastases (8/10), primary tumors (76.0%, 816/1074), omental metastases (10/14), peritoneal metastases (61.5%, 16/26), ovarian metastases (3/5), and lymph node metastases (5/9). The difference in rates of successful organoid culture between primary tumors and malignant ascites was statistically significant ( P=0.012), whereas none of the other rates of successful organoid culture success differed significantly (all P>0.05). The rate of successful organoid culture was 96.4% (27/28) for malignant ascites obtained by abdominal puncture, 76.5% (864/1130) for surgical specimens, and 65.8% (48/73) for endoscopic biopsies; these differences are statistically significant (χ 2=10.773, P=0.005). The rate of successful organoid culture was 62.5% (40/64) in the neoadjuvant chemoradiotherapy group, which is significantly lower than in the non-adjuvant (76.9%, 787/1023) and chemotherapy groups (77.8%, 112/144) (χ 2=7.134, P=0.028). Multivariate logistic regression analysis revealed that endoscopic biopsy (OR=0.557, 95%CI: 0.335–0.924, P=0.024) and neoadjuvant chemoradiotherapy (OR=0.483, 95%CI: 0.285–0.820, P=0.007) were independent risk factors for failure of organoid culture of colorectal cancer samples. Malignant ascites (OR=8.537, 95%CI:1.154–63.131, P=0.036) and abdominal puncture (OR=8.294, 95% CI: 1.112–61.882, P=0.039) were identified as independent protective factors. Conclusions:The rate of successful organoid culture was influenced by the sampling site, sampling method, and chemoradiotherapy. The rate of successful organoid culture was lower for endoscopic biopsies and in patients receiving preoperative neoadjuvant chemoradiotherapy, and higher for malignant ascites. We consider that culture of malignant ascites is preferable when peritoneal metastases are suspected.

Objective: To evaluate the disinfection efficacy of peracetic acid disinfectant (type Ⅲ ) on gastrointestinal endoscopy. Methods: Endoscopes were disinfected respectively by 2% glutaraldehyde (GA group) and peracetic acid disinfectant (type Ⅲ ) (PAA group) according to the process by the 2016 version of "Regulation for cleaning and disinfection technique of flexible endoscope" , and then samples were collected through biopsy channel at the specified steps. The bacterial count and pathogenic bacteria of these samples were detected. Hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody and Treponemia pallidum antibody (TP-Ab) were detected by chemiluminesent microparticle immunoassay (CMIA) in the PAA group. The PAA group were continuously sampled for 5 days. Results: A total of 56 gastroscopes and 16 colonoscopes were disinfected in the GA group, and 46 gastroscopes and 15 colonoscopes were disinfected in the PAA group. Compared with pre-disinfection, the bacterial count was both significantly reduced in the two groups after disinfection (P<0.05). The qualified rate of gastroscopes disinfection and total qualified rate of the PAA group were higher than those of the GA group [the qualified rate of gastroscopes: 97.83% (45/46) VS 92.86% (52/56), P>0.05; total qualified rate: 98.36% (60/61) VS 94.44% (68/72), P>0.05]. The qualified rate of colonoscopes in the two groups were both 100.00% (15/15, 16/16). After disinfecting by peracetic acid disinfectant (Type Ⅲ), HBsAg, anti-HCV and TP-Ab were negative. There were no significant differences on colonies number at different steps in a 5-day continuous sampling (P>0.05). Conclusion Peracetic acid disinfectant (type Ⅲ) can provide a satisfied disinfectant effect, and be applied in clinic to meet the requests of high-level disinfection for gastrointestinal endoscopy.

Objective: To investigate the clinicopathologic and molecular features of the rare cribriform morular variant of papillary thyroid carcinoma (CMV-PTC). Methods: The clinicopathologic data of 10 patients with CMV-PTC were retrospectively reviewed. Immunohistochemical (IHC) staining was done using LSAB method. DNA sequencing for APC were applied using Sanger method. BRAF V600E mutation was examined using ARMS method. The cytological, morphological, IHC and molecular features were analyzed. Results: All patients were female at an average age of 27 years old. The tumors were mostly located in the right lobe of thyroid. Fine needle aspiration cytology was performed in three patients; two were diagnosed as suspicious for PTC and one as PTC. Nine tumors presented as solitary nodule and two as multiple nodules in both lobes. Infiltration was demonstrated in three cases. The average size was 2.6 cm. The neoplastic cells were arranged in papillary, cribriform, solid and glandular patterns, with rare or without colloid inside the lumen. The number of morula varied, ranging from zero to many. The neoplastic cells were variably enlarged, showing round, oval or spindle shape. Nuclear irregularity was identified as irregular membrane, nuclear grooves or pseudoinclusion, but no typical ground glass feature. Peculiar nuclear clearing could be observed in the morular cells. IHC staining showed the neoplastic cells were negative for thyroglobulin and p63, but positive for TTF1, cytokeratin 19 and estrogen receptor. Diffuse staining with cytokeratin was seen in the neoplastic cells and the morula. Specific cytoplasmic and nuclear staining of β-catenin was seen in the neoplastic cells but not the morula. Ki-67 proliferation index was 1%-30%. No recurrence or metastasis was observed. One patient was demonstrated to harbor both somatic and germline mutations of the APC gene, who was found to have adenomatous polyposis and her mother died of colonic carcinoma. No BRAF V600E mutation was detected. Conclusions CMV-PTC is rare and shows atypical cytological and clinicopathological features, and it is easily misdiagnosed.TG, TTF1, ER and β-catenin are specific IHC markers for CMV-PTC. The morula is negative for cytokeratin 19, in contrast to squamous metaplasia. Although CMV-PTC has indolent clinical behavior, a definite diagnosis is necessary to rule out the possibility of APC gene mutation and related extra-thyroidal neoplasm, such as FAP and Gardner syndrome.

Objective To study the incidence and risk factors ofdefecatory dysfunction in acute minorischemic strokepatientsandexplore the influence of the risk factors onprognosis.Methods Clinical data of 274 patients with acute minor ischemic strokewere reviewed and analyzed retrospectively.According to the presence of poststroke defecatorydysfunction,they were divided into defecatory dysfunction group and non-defecatory dysfunction group.The factors associated withdefecatory dysfunctionwere analyzed by univariate analysis and multivariatelogisticanalysis respectively,followed by investigating their effects on the prognosis.Results 74 patients of them with acute minor ischemic stroke had defecatory dysfunction.The univariate analysis indicated that4 factors including baseline NIHSS scorewere the risk factors.Multivariate logistic analysis showed that female,age,diabetes mellitus and baseline NIHSS score were independent risk factors for defecatory dysfunction.The scores of modified Rankin Scale (mRS) after 3 months in minor stroke patients with defecatory dysfunction wassignificantly higher(P ＜ 0.05).Baseline NIHSS score was a predictive factor for the prognosis of post-stroke defecatorydysfunctionpatients.Conclusions Defecatory dysfunction in acute minor stroke patients may increase the risk of poor prognosis.The female,elderlypatients as well those with diabetes mellitus and serious neurologicalfunction deficits are more likely to suffer post-stroke defecatory dysfunction.

[ ABSTRACT] AIM:To investigate the role of ATP-sensitive potassium ( KATP ) channels in the inhibitory effect of hydrogen sulfide ( H2 S) on high glucose ( HG)-induced inflammation mediated by necroptosis in H 9c2 cardiac cells. METHODS:The expression levels of receptor-interacting protein 3 ( RIP3; an indicator of necroptosis ) and cyclooxyge-nase-2 (COX-2) were determined by Western blot.The levels of interleukin-1β(IL-1β) and tumor necrosis factor-α( TNF-α) were detected by ELISA .RESULTS:After H9c2 cardiac cells were treated with 35 mmol/L glucose ( HG) for 24 h, the expression of RIP3 was significantly increased .Pre-treatment of the cells with 100 μmol/L diazoxide ( DZ; a KATP channel opener) or 400 μmol/L NaHS (a donor of H2S) for 30 min considerably blocked the up-regulation of RIP3 induced by HG.Moreover, pre-treatment of the cells with 100 μmol/L 5-hydroxydecanoic acid (5-HD; a KATP channel
blocker) attenuated the inhibitory effect of NaHS on HG-induced up-regulation of RIP3.On the other hand, co-treatment of the cells with 100μmol/L necrostatin-1 ( a specific inhibitor of necroptosis ) or pre-treatment of the cells with 100 μmol/L DZ or 400 μmol/L NaHS attenuated HG-induced inflammatory responses , evidenced by decreases in the expression of COX-2 and secretion levels of IL-1βand TNF-α.However , pre-treatment of the cells with 100 μmol/L 5-HD significantly attenuated the above anti-inflammatory effects of NaHS.CONCLUSION:KATP channels play an important role in the inhib-itory effect of H2 S on HG-induced inflammation mediated by necroptosis in H 9c2 cardiac cells.