Neuropathic pain, often featuring allodynia, imposes significant physical and psychological burdens on patients, with limited treatments due to unclear central mechanisms. Addressing this challenge remains a crucial unsolved issue in pain medicine. Our previous study, using protein kinase C gamma (PKCγ)-tdTomato mice, highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia. However, the regulatory mechanisms governing this circuit necessitate further elucidation. We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin (5-HT) facilitation system on spinal PKCγ neurons. Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_2C receptors, disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia. Inhibiting spinal 5-HT_2C receptors restored the feedforward inhibitory circuit, effectively preventing neuropathic allodynia. These insights offer promising therapeutic targets for neuropathic allodynia management, emphasizing the potential of spinal 5-HT_2C receptors as a novel avenue for intervention.
Animals ; Neuralgia/physiopathology* ; Protein Kinase C/metabolism* ; Receptor, Serotonin, 5-HT2C/metabolism* ; Hyperalgesia/physiopathology* ; Mice, Transgenic ; Mice ; Spinal Cord/metabolism* ; Serotonin/metabolism* ; Male ; Neurons/metabolism* ; Mice, Inbred C57BL

Orodispersible films (oral dispersible films), a novel form of oral solid dosage forms, are widely used for patients with dysphagia and those with uncontrollable autonomic behavior. In this study, suvorexant orodispersible film was prepared by hot melt extrusion technology, and the disintegration time, mechanical properties, in vitro dissolution and pharmacokinetics were evaluated, compared with other orodispersible films and commercially available tablets Belsomra. All experiments were approved by the Committee on the Management and Use of Laboratory Animals of Academy of Military Medical Sciences (IACUC-DWZX-2024-504). The results showed that the dissolution rate of suvorexant orodispersible film was faster and the mechanical strength was better than that of other commercially available orodispersible film, which could meet the needs of storage and transportation. Differential scanning calorimetry and X-ray diffraction results showed that suvorexant was dispersed within the orodispersible film in an amorphous state. The in vitro dissolution of the film was observed to be four times faster than that of the commercial tablets, achieving complete dissolution within five minutes. Pharmacokinetic evaluations in Beagle dogs revealed that the self-formulated orodispersible film exhibited no significant differences in the area under the blood concentration-time curve when compared with Belsomra. However, the film showed a faster onset of action, with a peak time that was twice as rapid, and a maximum blood concentration that was twice as high as that of Belsomra. Leveraging hot melt extrusion technology, the suvorexant orodispersible film offers a straightforward, continuous production process with consistent quality. It serves as an excellent platform for the development of solvent-free film preparations tailored for patients with special needs.

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R&D and shorten the R&D cycle of solid dispersions prepared by hot melt extrusion.

The pregnane X receptor (PXR) is a crucial regulator of cytochrome P-450 (CYP450) expression. It is involved in oxidative stress, steroid and bile acid metabolism, inflammatory response, apoptosis, cell proliferation and other biological behaviors, and also participates in the metabolism, transport and clearance of chemotherapy drugs. After activation, PXR can affect chemotherapy drug resistance of breast cancer through genetic variation and epigenetic modification, regulation of apoptosis, and participation in phosphorylation/dephosphorylation. It may be a potential therapeutic target for patients with breast cancer resistance.

Objective:To compare the short-term efficacy of Kamikawa anastomosis and double-tract reconstruction (DTR) after proximal gastrectomy.Methods:This was a propensity score matched, retrospective, cohort study. Inclusion criteria comprised age 20–70 years, diagnosis of gastric cancer by pathological examination of preoperative endoscopic biopsies, tumor diameter ≤4 cm, and location in the upper 1/3 of the stomach (including the gastroesophageal junction), and TNM stage IA, IB, or IIA. The study cohort comprised 73 patients who had undergone laparoscopic proximal gastric cancer radical surgery in the Department of Gastroenterology, Tangdu Hospital, Air Force Medical University between June 2020 and February 2023, 19 of whom were in the Kamikawa group and 54 in the DTR group. After using R language to match the baseline characteristics of patients in a ratio of 1:2, there were 17 patients in the Kamikawa group and 34 in the DTR group. Surgery-related conditions, postoperative quality of life, and postoperative complications were compared between the two groups.Results:After propensity score matching, there were no statistically significant differences in baseline data between the two groups ( P>0.05). Compared with the DTR group, the Kamikawa group had longer operative times (321.5±15.7 minutes vs. 296.8±26.1 minutes, t=32.056, P<0.001), longer anastomosis times (93.0±6.8 minutes vs. 45.3±7.7 minutes, t=56.303, P<0.001), and less bleeding (76 [54~103] mL vs.112 [82~148) mL, Z=71.536, P<0.001); these differences are statistically significant. There were no statistically significant differences between the two groups in tumor size, time to first postoperative passage of gas, postoperative hospital stay, number of lymph nodes removed, duration of lymph node dissection, or total hospitalization cost (all P>0.05). The median follow-up time was 6.1 ± 1.8 months. As to postoperative quality of life, the Kamikawa group had a lower rate of upper gastrointestinal contrast reflux than did the DTR group (0 vs. 29.4% [10/34], χ 2=6.220, P=0.013); this difference is statistically significant. However, differences between the two groups in quality of life score on follow-up of 3 months and 6 months on the Gastroesophageal Reflux Disease (GERD) scale were not statistically significant (all P>0.05). The incidence of postoperative complications was 2/17 in the Kamikawa group, which is significantly lower than the 41.2% (14/34) in the DTR group (χ 2=4.554, P=0.033). Conclusion:Kamikawa anastomosis and DTR are equally safe and effective procedures for reconstructing the digestive tract after proximal gastric surgery. Although Kamikawa anastomosis takes slightly longer and places higher demands on the surgical team, it is more effective at preventing postoperative reflux.

Objective To establish the reference intervals of neutrophil to lymphocyte ratio(NLR),mono-cyte to lymphocyte ratio(MLR)and platelet to lymphocyte ratio(PLR)in different genders and age groups in northern Chinese adults.Methods The data were analyzed according to the Clinical and Laboratory Stand-ards Institute C28-A3.Outliers were checked and judged according to the Dixon method.Subgroups were di-vided according to gender or age factors,and reference intervals were established for different subgroups.Ref-erence intervals were expressed as two-sided 95％percentiles.Results The reference intervals of NLR,MLR and PLR were 0.90-3.82,0.09-0.33 and 71.20-246.87,respectively.The results showed that NLR and PLR in men were lower than those in women(P＜0.001),while MLR in men was significantly higher than that in women(P＜0.001).Linear trend plots showed that NLR,MLR and PLR changed significantly in dif-ferent genders and age groups.In men,NLR and MLR increased with age,while PLR gradually increased and reached the peak before 50 years old,and gradually decreased after 50 years old.In women,NLR and MLR showed the lowest values at 50-＜60 years old,while PLR reached the peak at about 50 years old.The refer-ence intervals established by the model set were verified,and the percentages beyond the reference intervals were less than 10％in different genders and age groups.Conclusion The reference intervals of NLR,MLR and PLR in different genders and age groups of healthy adults in northern China are established in the study.

Objective:To compare the short-term efficacy of Kamikawa anastomosis and double-tract reconstruction (DTR) after proximal gastrectomy.Methods:This was a propensity score matched, retrospective, cohort study. Inclusion criteria comprised age 20–70 years, diagnosis of gastric cancer by pathological examination of preoperative endoscopic biopsies, tumor diameter ≤4 cm, and location in the upper 1/3 of the stomach (including the gastroesophageal junction), and TNM stage IA, IB, or IIA. The study cohort comprised 73 patients who had undergone laparoscopic proximal gastric cancer radical surgery in the Department of Gastroenterology, Tangdu Hospital, Air Force Medical University between June 2020 and February 2023, 19 of whom were in the Kamikawa group and 54 in the DTR group. After using R language to match the baseline characteristics of patients in a ratio of 1:2, there were 17 patients in the Kamikawa group and 34 in the DTR group. Surgery-related conditions, postoperative quality of life, and postoperative complications were compared between the two groups.Results:After propensity score matching, there were no statistically significant differences in baseline data between the two groups ( P>0.05). Compared with the DTR group, the Kamikawa group had longer operative times (321.5±15.7 minutes vs. 296.8±26.1 minutes, t=32.056, P<0.001), longer anastomosis times (93.0±6.8 minutes vs. 45.3±7.7 minutes, t=56.303, P<0.001), and less bleeding (76 [54~103] mL vs.112 [82~148) mL, Z=71.536, P<0.001); these differences are statistically significant. There were no statistically significant differences between the two groups in tumor size, time to first postoperative passage of gas, postoperative hospital stay, number of lymph nodes removed, duration of lymph node dissection, or total hospitalization cost (all P>0.05). The median follow-up time was 6.1 ± 1.8 months. As to postoperative quality of life, the Kamikawa group had a lower rate of upper gastrointestinal contrast reflux than did the DTR group (0 vs. 29.4% [10/34], χ 2=6.220, P=0.013); this difference is statistically significant. However, differences between the two groups in quality of life score on follow-up of 3 months and 6 months on the Gastroesophageal Reflux Disease (GERD) scale were not statistically significant (all P>0.05). The incidence of postoperative complications was 2/17 in the Kamikawa group, which is significantly lower than the 41.2% (14/34) in the DTR group (χ 2=4.554, P=0.033). Conclusion:Kamikawa anastomosis and DTR are equally safe and effective procedures for reconstructing the digestive tract after proximal gastric surgery. Although Kamikawa anastomosis takes slightly longer and places higher demands on the surgical team, it is more effective at preventing postoperative reflux.

Objective:To investigate the effect of neoadjuvant chemotherapy on the safety of laparoscopic D 2 radical resection and prognosis of patients with locally advanced gastric cancer. Methods:The propensity score matching and retrospective cohort study was conducted. The clinicopathological data of 351 patients with locally advanced gastric cancer who underwent laparos-copic D 2 radical resection in the Second Affiliated Hospital of Air Force Medical University from December 2016 to December 2021 were collected. There were 256 males and 95 females, aged (58±9)years. Of the 351 patients, 124 cases undergoing neoadjuvant chemotherapy were divided into the neoadjuvant chemotherapy group, 227 patients undergoing postoperative adjuvant chemotherapy were divided into the adjuvant chemotherapy group. Observation indicators: (1) propensity score matching and comparison of general data of patients between the two groups after matching; (2) effect evaluation of neoadjuvant chemotherapy; (3) intraoperative and postoperative situations; (4) postoperative histopathological examinations; (5) follow-up. Propensity score matching was done by the 1∶1 nearest neighbor matching method. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measure-ment data with skewed distribution were represented as M(range) or M( Q1, Q3), and comparison between groups was conducted using the rank sum test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to draw survival curves, and the Log-Rank test was used for survival analysis. Results:(1) Propensity score matching conditions and comparison of general data of patients between the two groups of patients after matching. Of 351 patients, 154 cases were successfully matched, including 77 cases in the neoadjuvant chemotherapy group and 77 cases in the adjuvant chemotherapy group. The elimination of gender, age, preoperative body mass index, clinical T staging and clinical N staging confounding bias ensured comparability between the two groups after propensity score matching. (2) Effect evaluation of neoadjuvant chemotherapy. Of the 77 patients receiving neoadjuvant chemotherapy, none of patient achieved complete response, 26 patients achieved partial response, 46 patients showed stable disease, 5 patients had progression of disease, showing the objective response rate as 33.8%(26/77) and the disease control rate as 93.5%(72/77). There were 15 males and 11 females sensitive to neoadjuvant chemotherapy, while 46 males and 5 females not sensitive, showing a significant difference between them ( χ2=11.05, P<0.05). (3) Intra-operative and postoperative situations. The operation time, volume of intraoperative blood loss, cases with intraoperative blood transfusion, time to postoperative first flatus, time to postoperative first liquid food intake, duration of postoperative hospital stay, cases with postoperative immediate complications, cost of hospital stay were (308±71)minutes, 100(range, 20?600)mL, 5, 3.0(range, 2.0?10.0)days, 4.0(range, 2.0?12.0)days, 9.0(range, 4.0?31.0)days, 7, 7.96(7.37,8.58) ten thousand yuan in patients of the neoadjuvant chemotherapy group, versus (296±67)minutes, 100(range, 20?500)mL, 4, 3.5(range, 1.0?14.0)days, 4.0(range, 2.0?15.0)days, 8.0(range, 5.0?45.0)days, 11, 8.18(7.52,9.19) ten thousand yuan in patients of the adjuvant chemotherapy group, showing no signifi-cant difference in the above indicators between the two groups ( t=1.13, Z=?0.37, χ2=0.12, Z=?1.26, ?0.33, ?0.70, χ2=1.01, Z=?1.04, P>0.05). (4) Postoperative histopathological examinations. Results of postoperative histopatho-logical examinations showed that all 154 patients achieving R 0 resection. Cases with pathological T staging as stage T1, stage T2, stage T3, stage T4, cases with pathological N staging as stage N0, stage N1, stage N2, stage N3, number of positive lymph nodes, cases with human epidermal growth factor receptor 2 (negative, positive) were 3, 7, 5, 62, 27, 19, 19, 12, 1(range, 0?28), 59, 18 in patients of the neoadjuvant chemotherapy group, versus 0, 0, 2, 75, 17, 15, 21, 24, 3(range, 0?31), 44, 33 in patients of the adjuvant chemotherapy group, showing significant differences in the above indicators between the two groups ( Z=?3.39, ?2.55, ?3.12, χ2=6.60, P<0.05). (5) Follow-up. Of the 154 patients, 143 patients were followed up for 37(range, 5?69)months. The 3-year overall survival rate and 3-year disease-free survival rate was 72.1% and 70.0%, respectively, in patients of the neoadjuvant chemotherapy group, versus 74.8% and 76.6% in patients of the adjuvant chemo-therapy group, showing no significant difference in the above indicators between the two groups ( χ2=0.14, 0.60, P>0.05). Conclusions:Compared to postoperative adjuvant chemotherapy, neoadjuvant chemotherapy does not bring additional surgical risks, but can reduce the tumor stage of patients who underwent laparoscopic D 2 radical resection for locally advanced gastric cancer. However, it does not show any advantage in improving survival of patients.

Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients, which often results in patients suffering from severe hyperalgesia and allodynia. Up to now, the clinical therapeutic effect of DPN is still unsatisfactory. Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades. Studies have shown that metformin can improve pain caused by DPN, but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN, and the mechanism for improving DPN are not clear. Therefore, the STZ-induced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN, and to preliminarily explore its mechanism in this study. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). After the model was established successfully, STZ diabetic rats were randomly divided into a model group and a metformin treatment group, and 10 normal SD rats were selected as the normal control group, and the rats were intragastrically administered for 12 weeks. The results showed that metformin significantly reduced blood glucose, glycosylated hemoglobin, food consumption and water consumption in STZ rats. Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold, prolonged the hot plate latency threshold, and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats. In addition, metformin increased the content of glutathione (GSH), enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced the content of malondialdehyde (MDA) in serum and sciatic nerve of STZ diabetic rats, as well as regulating the expression of genes related to oxidative stress in the sciatic nerve. Metformin obviously reduced the levels of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the serum in STZ rats, and inhibited the gene expression of these inflammatory factors in the sciatic nerve. In summary, metformin significantly increased nerve conduction velocity, improved sciatic nerve morphological abnormalities and pain in DPN rats, which may be related to its effect in improving oxidative stress and reducing inflammation.