Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

[Effects of electroacupuncture on BNDF/mTORC1 signaling pathway and synaptic plasticity in prefrontal cortex of rats exposed to chronic unpredictable mild stress].

OBJECTIVE: To investigate the effects of electroacupuncture (EA) on the expression of related proteins in the brain-derived neurotrophic factor (BDNF)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and synapse-associated proteins and the density of dendrite spines in the prefrontal cortex (PFC) of depression model rats, and to reveal the underlying mechanism by which EA regulates the synaptic plasticity to improve depressive symptoms. METHODS: Thirty-six healthy male Sprague-Dawley (SD) rats were randomly divided into normal group, model group, EA group, and scopolamine (SCOP) group, with 9 in each group. The depression model was established by exposing rats to chronic unpredictable mild stress (CUMS) combined with isolated feeding. Rats in the EA group were treated with EA (2 Hz/100 Hz, 1-1.2 mA) at "Baihui" (GV20), "Yintang" (EX-HN3), "Hegu" (LI4), and "Taichong" (LR3), 20 min each time, once per day, for 14 d, while those in the SCOP group treated with intraperitoneal injection of 25 µg/kg SCOP, once every 16 h, for 14 d. The sucrose preference and feeding latency of rats in each group were observed in the sucrose preference test (SPT) and novelty-suppressed feeding test. The expression levels of proteins in the BDNF/mTORC1 signaling pathway and synapse-associated proteins PSD95, Synapsin Ⅰ, and GluR1 were assayed by Western blot. Golgi-Cox staining was conducted for exploring the total density of dendritic spines on the apical dendrites of layer Ⅴ pyramidal neurons in PFC as well as the densities of mature, immature, and filopodial-like dendritic spines. RESULTS: Compared with the normal group, the model group exhibited significantly decreased sucrose preference (P<0.001), prolonged feeding latency (P<0.001), down-regulated BDNF, mTORC1, phosphorylated mTORC1 (p-mTORC1), PSD95, Synapsin Ⅰ, and GluR1 expression (P<0.001，P<0.01), and diminished total, mature, and immature spine dendritic densities (P<0.001). Compared with the model group, both EA and SCOP remarkably increased the sucrose preference (P<0.001), shortened the feeding latency (P<0.001), up-regulated the BDNF, mTORC1, p-mTORC1, PSD95, Synapsin Ⅰ, and GluR1 expression in PFC(P<0.05，P<0.01，P<0.001), and elevated the total and immature spine dendritic densities (P<0.001,P<0.01). The density of filopodial-like dendritic spine in the EA group was obviously enhanced (P<0.01), whereas the mature dendritic spine density in the SCOP group rose sharply (P<0.001). However, there were no significant differences between the EA group and SCOP group (P>0.05). CONCLUSION: EA alleviates the depressive symptoms of CUMS model rats possibly by up-regulating the expression of proteins in the BDNF/mTORC1 signaling pathway and synapse-asso-ciated proteins PSD95, Synapsin Ⅰ, and GluR1, increasing the dendritic spine density, and enhancing the synaptic plasticity in PFC.

[Characteristics of acidification and the distribution of available phosphorus along soil depths in heavy clay soils in southern Henan Province, China]. / è±«å—é»æ¿åœŸå£¤åˆ†å±‚é ¸åŒ–å’Œè€•å±‚é€Ÿæ•ˆç£·åˆ†å¸ƒç‰¹å¾.

The acidification of agricultural soil in the southern part of the North China Plain has become more obvious, which is particularly true for the heavy clay soil types, such as yellow-cinnamon and lime concretion black soils. To understand the spatial variability of the pH value and nutrients on the vertical agricultural soil profile of heavy clay soils in this area, we measured pH values and available phosphorus (AP) in 63 farmland sample points from Xiping County in the southern Henan Province. Geostatistical methods and ArcGIS technology were used to map soil pH values along three soil depths (0-10, 10-20, and 20-30 cm) and the spatial distribution of soil AP in the tillage layer (0-20 cm). Furthermore, the correlation between pH and AP was analyzed. The results showed that mean pH values of typical yellow-cinnamon and typical fluvo-aquic soils from three soil layers were 4.98, 4.93, 5.31, and 5.46, 5.81, 6.26, respectively, which gradually increased with soil depths. However, there was no significant difference among the three soil layers. Mean pH values of typical lime concretion black soil from the three soil layers were 5.23, 5.43 and 6.03, respectively, and that of the 20-30 cm soil layer was significantly higher than that of the 0-10 cm (by 0.8-1 pH unit) and the 10-20 cm layers. The pH of the 20-30 cm soil layer of the calcareous lime concretion black and moist soils were also significantly higher than that of the 0-10 and 10-20 cm soil layers. The AP contents of the typical yellow-cinnamon, typical lime concretion black, moist, typical fluvo-aquic and calcareous lime concretion black soils in 0-20 cm soil layer were 8.85-54.75, 4.27-37.49, 8.22-51.80, 6.07-34.82, and 13.22-22.85 mg·kg-1, respectively. The results of the map indicated that the areas with low AP were distributed in the middle of the study area in blocks, and the areas with high AP were distributed around the study area in dots and flakes. The pH values of the typical yellow-cinnamon, typical lime concretion black, and moist soils positively correlated with the content of AP in the 0-20 cm soil layer. In conclusion, the heavy clay soil in southern Henan Province became stratified acidification, which slowed down along the soil depth. Soil AP contents in the tillage layer were distributed unevenly in the study area, and were affected by soil types and soil pH. These results would be useful for the improvement of heavy clay soil acidification in the southern part of the North China Plain.

Antibacterial Activity Prediction Model of Traditional Chinese Medicine Based on Combined Data-Driven Approach and Machine Learning Algorithm: Constructed and Validated.

Traditional Chinese medicines (TCMs), as a unique natural medicine resource, were used to prevent and treat bacterial diseases in China with a long history. To provide a prediction model of screening antibacterial TCMs for the design and discovery of novel antibacterial agents, the literature about antibacterial TCMs in the China National Knowledge Infrastructure (CNKI) and Web of Science database was retrieved. The data were extracted and standardized. A total of 28,786 pieces of data from 904 antibacterial TCMs were collected. The data of plant medicine were the most numerous. The result of association rules mining showed a high correlation between antibacterial activity with cold nature, bitter and sour tastes, hemostatic, and purging fire efficacies. Moreover, TCMs with antibacterial activity showed a specific aggregation in the phylogenetic tree; 92% of them came from Tracheophyta, of which 74% were mainly concentrated in rosids, asterids, Liliopsida, and Ranunculales. The prediction models of anti-Escherichia coli and anti-Staphylococcus aureus activity, with AUC values (the area under the ROC curve) of 77.5 and 80.0%, respectively, were constructed by the Neural Networks (NN) algorithm after Bagged Classification and Regression Tree (Bagged CART) and Linear Discriminant Analysis (LDA) selection. The in vitro experimental results showed the prediction accuracy of these two models was 75 and 60%, respectively. Four TCMs (Cirsii Japonici Herba Carbonisata, Changii Radix, Swertiae Herba, Callicarpae Formosanae Folium) were proposed for the first time to show antibacterial activity against E. coli and/or S. aureus. The results implied that the prediction model of antibacterial activity of TCMs based on properties and families showed certain prediction ability, which was of great significance to the screening of antibacterial TCMs and can be used to discover novel antibacterial agents.

[Professor FU Wen-bin's experience in treatment of mental disorder with acupuncture and moxibustion from perspective of "psychosomatic medicine"].

The paper summarizes the ideas and characteristics of acupoint selection in treatment of mental disorder with acupuncture and moxibustion by professor FU Wen-bin. Professor FU believes that mental disorder is manifested as the simultaneous illness of "heart" and "body". On the base of "holism" for the unity of body and mind, professor FU proposes the treating idea as "soothing the liver, regulating the mind and focusing on the heart and the gallbladder in treatment". In clinical practice, the acupoint prescription on specifically regulating and harmonizing yin and yang is composed to calm down the mind. The eight confluent points and back-shu points of five zang organs are selected to regulate zangfu functions. The "ghost" points, the points on the second line of bladder meridian and the acupoints with specific effect are used to tranquilize the mind, open the orifices and consolidate therapeutic effect. Meanwhile, the complicated symptoms are also considered in treatment. The integrative and holistic pattern of acupuncture and moxibustion therapy as "acupuncture at the top priority, followed by moxibustion, and consolidation at the end" achieves the co-regulation of qi and blood and tranquilization for both the mental and the physical.