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Abstract Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Abstract Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò–Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

Abstract In recent years, the development of photocatalysts based on noncovalent strategies has shown an important role in medical and organic materials. Herein, an organic fluorescent dye benzothiazole derivative (2‐(N,N‐diethylanilin‐4‐yl)‐4,6‐bis(3‐methylpyrazol‐1‐yl)‐1,3,5‐triazine [MPBT]) was designed and synthesized. It was encapsulated in the cavity of cucurbit[8]uril (CB[8]) to form a supramolecular dimer through host–guest interaction, which converted the dye into a highly efficient photocatalyst. With the formation of 2MPBT‐CB[8] supramolecular dimer, the emergence of host‐enhanced charge transfer interactions could significantly facilitate singlet to triplet through intersystem crossing. At the same time, the alternating structure of 2MPBT‐CB[8] facilitated the triplet states for further energy transfer and electron transfer. In addition, the electron transfer process with electron donor generated cationic free radical and photocatalyst negative ion free radical (PC⋅−), which in turn reacted with oxygen (O2) to form superoxide anion radical (O2⋅−). The generated O2⋅− could be used to catalyze the oxidative hydroxylation of aryl boronic acid. Therefore, the 2MPBT‐CB[8] had become a highly efficient photocatalyst for the oxidative hydroxylation of aryl boronic acid. This strategy of supramolecular dimerization provides a new strategy for the development of new photocatalysts based on noncovalent interactions.

ObjectiveTo observe the efficacy and safety of pelvic floor magnetic stimulation (PFMS) combined with mirabegron in female patients with refractory overactive bladder (OAB) symptoms.Patients and methodsA total of 160 female patients with refractory OAB symptoms were prospectively randomized into two groups. Eighty cases in the combination group accepted PFMS and mirabegron therapy and 80 cases as control only accepted mirabegron therapy (The clinical trial registry number: ChiCTR2200070171). The lower urinary tract symptoms, OAB questionnaire (OAB-q) health-related quality of life (HRQol), symptom bother score and OABSS between two groups were compared at the 1st, 2nd and 4th week ends.ResultsAll of 160 patients were randomly assigned to two groups, of which 80 patients were included in the combination group and 80 in the mirabegron group. The incidences of LUTS, including urgency, frequent urination, and incontinence episodes, in the 2nd week and the 4th week after combination treatment were significantly lower than those in the mirabegron group (p 0.05). With respect to secondary variables, the OAB-q HRQol score in the combination group was statistically superior in comparison with that in the mirabegron group between the 2nd week and the 4th week (p

Abstract Background Uterine tumors resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm of unknown etiology and has undetermined malignant potential. The emergence of recurrent UTROSCT case reports has led to its initial identification as a tumor of low malignancy potential. Owing to its low incidence, we currently lack any in-depth studies regarding the subset of UTROSCTs that may be aggressive in nature. Here, we sought to identify unique characteristics in aggressive UTROSCT. Methods 19 cases of UTROSCT were collected. Their histologic and tumor immune microenvironment were evaluated by three gynecologic pathologists. The gene alteration was also detected by RNA sequencing. For later analyses regarding differences between benign and malignant tumors, we supplemented our 19 included cases with additional reports from the literature. Results Interestingly, we found PD-L1 expression in stromal tumor-infiltrating immune cells (stromal PD-L1) was markedly higher in aggressive UTROSCT. Patients with high stromal PD-L1 (≥ 22.5 cells/mm2) had worse prognosis. When our cases were added with previous cases identified in the literature, we discovered that aggressive UTROSCT was more likely to have significant mitotic activity and NCOA2 gene alterations than benign UTROSCT. Consistence with those results, patients with significant mitotic activity and gene alteration of NCOA2 had worse prognoses. Conclusions Collectively, high expression of stromal PD-L1, significant mitotic activity, and gene alteration of NCOA2 may be useful markers to predict aggressive UTROSCT.

Transetherifications between ethers and alcohols are fundamental organic reactions that are frequently used for the preparations of unsymmetrical ethers. In this article, the authors challenge the fundamental tenets of the traditional transetherification mechanism via systematic experimental and computational investigations of a Re2O7-mediated annulation.

Context Ursolic acid (UA) and acteoside (ATS) are important active components that have been used to treat Alzheimer’s disease (AD) because of their neuroprotective effects, but the exact mechanism is still unclear.Objective Network pharmacology was used to explore the mechanism of UA + ATS in treating AD, and cell experiments were used to verify the mechanism.Materials and methods UA + ATS targets and AD-related genes were retrieved from TCMSP, STITCH, SwissTargetPrediction, GeneCards, DisGeNET and GEO. Key targets were obtained by constructing protein interaction network through STRING. The neuroprotective effects of UA + ATS were verified in H2O2-treated PC12 cells. The subsequent experiments were divided into Normal, Model (H2O2 pre-treatment for 4 h), Control (H2O2+ solvent pre-treatment), UA (5 μM), ATS (40 μM), UA (5 μM) + ATS (40 μM). Then apoptosis, mitochondrial membrane potential, caspase-3 activity, ATG5, Beclin-1 protein expression and Akt, mTOR phosphorylation levels were detected.Results The key targets of UA + ATS-AD network were mainly enriched in Akt/mTOR pathway. Cell experiments showed that UA (ED50: 5 μM) + ATS (ED50: 40 μM) could protect H2O2-induced (IC50: 250 μM) nerve damage by enhancing cells viability, combating apoptosis, restoring MMP, reducing the activation of caspase-3, lessening the phosphorylation of Akt and mTOR, and increasing the expression of ATG5 and Beclin-1.Conclusions ATS and UA regulates multiple targets, bioprocesses and signal pathways against AD pathogenesis. ATS and UA synergistically protects H2O2-induced neurotrosis by regulation of AKT/mTOR signalling.

Abstract To observe the efficacy and safety of solifenacin and/or mirabegron as a medical expulsive therapy (MET) in patients with double-J stent-related overactive bladder (OAB) symptoms. A total of 219 patients with double-J stent-related OAB symptoms were prospectively randomized into two groups. One-hundred and nine cases in the combination group accepted mirabegron and solifenacin therapy and 110 cases as control only accepted solifenacin therapy. The lower urinary tract symptoms and overactive bladder questionnaire (OAB-q) health-related quality of life (HRQol) and symptom bother score between two groups were compared at the 1st, 2nd and 4th week ends. All of 219 patients were randomly assigned to two groups, of which 109 patients were included in the combination group and 110 in the solifenacin group. The incidences of LUTS, including urgency, frequent urination, and incontinence episodes, in the 2nd week (44.9% vs. 64.5%, P = 0.028; 48.6% vs. 62.7%, P = 0.036; and 40.4% vs. 56.4%, P = 0.018) and the 4th week (14.7% vs. 30.9%, P = 0.004; 16.5% vs. 33.6%, P = 0.003; and 11.9% vs. 26.4%, P = 0.007) after combination treatment were significantly lower than those in the solifenacin group. The incidence of drug-related adverse events in the solifenacin group was higher than that in the combination group, but there was no statistically significant difference (P > 0.05). In terms of secondary variables, the OAB-q HRQol score in the combination group was statistically superior in comparison with that in the solifenacin group between the second and fourth week (77.9 vs. 76.4, P = 0.020; and 87.9 vs. 85.6, P = 0.001). The OAB-q symptom bother score was higher in the solifenacin group than in the combination group (37.6 vs. 36.4, P = 0.016; and 26.2 vs. 24.8, P = 0.003). Combination therapy of solifenacin and mirabegron demonstrated significant improvements over solifenacin monotherapy in reducing OAB symptoms associated with double-J stents, and providing a higher quality of life without increasing bothersome adverse effects.

Objective Tan lambs (n = 36, 3 mo old, 19.1±0.53 kg) were used to assess effects of dietary guanidinoacetic acid (GAA) and rumen-protected methionine (RPM) on growth performance, carcass traits, meat quality, and serum parameters. Methods Lambs were randomly assigned to three treatment groups, with 6 pens per group and 2 lambs per pen. Dietary treatments were: basal diet alone (I); basal diet supplemented with 0.08% GAA+0.06% RPM (II); and basal diet supplemented with 0.08% GAA+0.08% RPM (III). Diets were provided three times a day for 90 d. Intake per pen was recorded daily and individual lamb body weight (BW) was measured monthly. Carcass traits were measured after slaughter and meat quality at the end of the experiment, blood samples were taken on a subgroup of lambs for analysis of indicators mostly related to protein metabolism. Results Final BW and average daily gain for the first and second month, and for the entire experiment were greater in Treatment II compared to Treatment I (p

ObjectiveTo observe the efficacy and safety of retrograde intrarenal surgery combined with vacuum-assisted ureteral access sheath (V-UAS) and minimally invasive percutaneous nephrolithotomy (MPCNL) in patients with 1–2 cm infectious upper ureteral stone.Patients and methodsA total of 173 patients with 1–2 cm infectious upper ureteral stone were prospectively randomized into two groups. Eighty-six in the V-UAS group and 87 cases as control in the MPCNL group. The SFRs at different times (Postoperative 1 day, 2nd week and 4th week) was considered as the primary outcome of the study. The secondary end points were operative time, postoperative hospital stay and operative complications.ResultsThere was no obvious difference between two groups in patients' demographics and preoperative clinical characteristics (all P > 0.05). Postoperative data showed that the SFR at postoperative 1 day in the V-UAS group was significantly lower than that in the MPCNL group (73.2% vs. 86.2%, P = 0.034). However, there was no statistical significance between two groups in SFRs during postoperative 2 weeks and 4 weeks (All P > 0.05). The levels of WBC, CRP and PCT were all significant lower in the V-UAS group than those in the MPCNL group at the postoperative 24 h and 48 h (all P