High glucose level, bacterial infection, and persistent inflammation within the microenvironment are key factors contributing to the delay of diabetic ulcers healing, while traditional therapeutic methods generally fail to address these issues simultaneously. Here, we present a spatiotemporally responsive cascade bilayer microneedle (MN) patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide (NO) release for long-term antibacterial and anti-inflammatory effects. The MN patch (G/AZ-MNs) possesses a degradable tip layer loading glucose oxidase (GOx), as well as a dissolvable base layer encapsulating l-arginine (Arg)-loaded nanoparticles (NPs). After wound administration, the base part rapidly dissolved, resulting in prompt separation of the MN tip within the wound tissue, which subsequently responded to the overexpressed matrix metalloproteinase-9 (MMP-9) in diabetic lesions, leading to the responsive release of GOx. The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide (H₂O₂), which not only reduced glucose level within the diabetic wound, but also initiated the cascade reaction between H₂O₂ with the Arg that was released from NPs, thereby achieving continuous production of NO for 7 days. Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.

Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Objective:To compare oxytocin combined with ergometrine with oxytocin alone in terms of primary prophylaxis for postpartum hemorrhage (PPH) at the time of cesarean section (CS).Methods:This was a multicenter double-blind randomized controlled interventional study comparing ergometrine combined with oxytocin and oxytocin alone administered at CS. From December 2018 to November 2019, a total of 298 parturients were enrolled in 16 hospitals nationwide. They were randomly divided into experimental group (ergometrine intra-myometrial injection following oxytocin intravenously; 148 cases) and control group (oxytocin intra-myometrial injection following oxytocin intravenously; 150 cases) according to 1∶1 random allocation. The following indexes were compared between the two groups: (1) main index: blood loss 2 hours (h) after delivery; (2) secondary indicators: postpartum blood loss at 6 h and 24 h, placental retention time, incidence of PPH, the proportion of additional use of uterine contraction drugs, hemostatic drugs or other hemostatic measures at 2 h and 24 h after delivery, the proportion requiring blood transfusion, and the proportion of prolonged hospital stay due to poor uterine involution; (3) safety indicators: nausea, vomiting, dizziness and other adverse reactions, and blood pressure at each time point of administration.Results:(1) The blood loss at 2 h after delivery in the experimental group [(402±18) ml] was less than that in the control group [(505±18) ml], and the difference was statistically significant ( P<0.05). (2) The blood loss at 6 h and 24 h after delivery in the experimental group were less than those in the control group, and the differences were statistically significant (all P<0.05). There were no significant differences between the two groups in the incidence of PPH, the proportion of additional use of uterine contraction drugs, hemostatic drugs or other hemostatic measures at 2 h and 24 h after delivery, the proportion requiring blood transfusion, and the proportion of prolonged hospital stay due to poor uterine involution (all P>0.05). (3) Adverse reactions occurred in 2 cases (1.4%, 2/148) in the experimental group and 1 case (0.7%, 1/150) in the control group. There was no significant difference between the two groups ( P>0.05). The systolic blood pressure within 2.0 h and diastolic blood pressure within 1.5 h of drug administration in the experimental group were higher than those in the control group, and the differences were statistically significant ( P<0.05), but the blood pressure of the two groups were in the normal range. Conclusion:The use of ergometrine injection in CS could reduce the amount of PPH, which is safe and feasible.

Objective:To explore CT imaging features related to disease-free survival (DFS) for gastric cancer (GC) patients with no clinical lymph node metastasis (cN0).Methods:From January 2005 to December 2018, 298 patients with GC were collected retrospectively in Peking University People′s Hospital. All the patients performed CT scanning before operation, and cT1-4N0M0 was defined by CT images. The clinical tumor stage (cT), extramural vessel invasion (EMVI), tumor morphological type, location and size were defined and recorded based on preoperative contrast-enhanced CT images. According to the pathological results, the patients were divided into pT1-2, pT3-4, pN0, and pN1-3 subgroups, with 148, 150, 135, and 163 cases, respectively. Progressive events and corresponding time were recorded during follow-up. DFS was defined as the time from radical operation to progressive events; if no progressive events occurred, DFS was defined as the time from radical operation to the last follow-up. The Kaplan-Meier curve and log-rank test were used to analyze the differences in cumulative DFS among patients with different CT imaging features, and Cox survival analysis was used to explore the independent CT imaging risk factors affecting DFS of cN0 patients. The log-rank test was used to test the effect of independent risk factors on cumulative DFS in different subgroups.Results:The follow-up time of enrolled patients was 36.0 (14.9, 59.3) months. The 3-year cumulative DFS rates of cT3-4 and cT1-2 GC patients were 61.2% and 85.6%, respectively, and the difference of DFS was statistically significant (χ 2=22.72, P<0.001). The 3-year cumulative DFS rate of EMVI-positive patients was 46.3%, which was lower than that of EMVI-negative patients (77.1%), and the difference was statistically significant (χ 2=21.34, P<0.001). There was no significant difference in 3-year cumulative DFS between different tumor locations and morphological types (χ 2=1.75, 1.73, P=0.189, 0.196). The difference in 3-year cumulative DFS between the tumor maximal diameter ≥3.4 cm and <3.4 cm groups was statistically significant (χ 2=17.58, P<0.001). On Cox survival analysis, cT (HR=5.203, P=0.001) and EMVI (HR=1.971, P=0.025) were independent risk factors for 3-year DFS in patients with cN0 GC. The results of subgroup analysis showed that the effect of EMVI on the 3-year DFS in pN0, pN1-3, pT1-2 and pT3-4 subgroups was statistically significant ( P<0.05). The effect of cT on the 3-year DFS was statistically significant in pN0, pN1-3, and pT1-2 subgroups ( P<0.05), but not in pT3-4 group (χ 2=2.58, P=0.108). Conclusion:cT and EMVI defined on preoperative CT examination are independently prognostic factors of 3-year DFS for patients with cN0 GC.

Objectives:To investigate the value of histopathological growth patterns (HGP) in predicting the 3-year progression free survival (PFS) after resection the liver metastasis from patients with colorectal cancer.Methods:The clinicopathological data of the 111 patients with liver metastasis of colorectal cancer diagnosed at Peking University People′s Hospital, Beijing, China from January 2007 to January 2017 were analyzed. After excluding the patients who did not meet the inclusion criteria, a total of 80 patients were analyzed. According to the international expert consensus on HGP, the HGP types of liver metastasis were evaluated. The correlation between HGP and other clinicopathological factors was analyzed using χ 2 or Fisher test. Kaplan-Meier survival curve was used to examine 3-year PFS in the patients with liver metastasis of colorectal cancer by HGP. The independent risk factors of 3-year post-resection PFS were determined using univariable and multivariable analyses. Results:A total of 80 cases were analyzed, including 43 cases of desmoplastic type (54%), 32 cases of replacement type (40%), 3 cases of pushing type (4%), and 2 cases of mixed type (2%). There was no correlation of HGP with age, gender, time of metastasis, tumor burden, histological grade, mucous differentiation or microsatellite instability. The 3-year post-resection PFS of the patients with desmoplastic type was significantly longer than that of patients with replacement type. The univariable and multivariable analyses showed that HGP was an independent prognostic factor.Conclusions:The HGP of colorectal cancer metastases to the liver mainly present as desmoplastic and replacement types. HGP is an independent prognostic factor for the patients with liver metastasis of colorectal cancer after resection of the metastasis. Therefore, HGP should be clearly indicated in the pathological report to help guide clinical treatments.