Mechanism of EGFR inhibitor AG1478 combined with oxaliplatin in inhibiting PI3K/AKT pathway and promoting autophagy in HI 975 cells / 中国药理学通报

Aim To explore the effect of oxaliplatin combined with epidermal growth factor receptor tyrosine kinase inhibitor AG1478 on autophagy in non-small cell lung cancer H1975 cells. Methods H1975 cells were cultured in vitro using gradient concentrations of AG1478 (0, 5, 10, 15, 20, 25, 30, 35, 40 jjimol • IT

Evaluation of Animal Model of Autism Spectrum Disorders Based on Characteristics of Clinical Symptoms of Traditional Chinese and Western Medicine / 中国实验方剂学杂志

ObjectiveBased on the new method of animal model evaluation， this paper summarized and analyzed the characteristics of traditional Chinese medicine（TCM） and Western medicine syndromes in existing autism spectrum disorder（ASD） animal models， and put forward suggestions for improvement. MethodRelevant literature on ASD animal models in China National Knowledge Infrastructure（CNKI） and PubMed were searched. According to the diagnostic standards of traditional Chinese and western medicine， core symptoms and accompanying symptoms were assigned values， and the clinical consistency of the models was comprehensively evaluated. ResultMost ASD model experimental animals were rodents， and the modeling methods included genetic and non-genetic. Domestic research focused on biochemical induction， while foreign research used genetic models more commonly. Among all models， valproic acid induction had the highest clinical consistency， followed by the neuroligin 4（NLGN4） and contactin associated protein like 2（CNTNAP2） gene knockout models. Most modeling methods could meet the characteristics of surface validity and structural validity， but did not clearly distinguish TCM syndromes. Currently， there is no model that has a high degree of clinical agreement between TCM and western medicine at the same time. ConclusionThe existing ASD animal models are mostly constructed under the guidance of western medicine， which lacks the characteristics of TCM syndromes. And the selection of evaluation indicators of western medicine is relatively single， without specifying the types of TCM syndromes. It is recommended to apply TCM intervention factors during the process of model preparation， to improve the evaluation indicators of traditional Chinese and western medicine， and to emphasize the study of on non-human primates， so as to lay a solid foundation for future experiments.

Clinical Analysis of Colistin Sulfate in the Treatment of Hematonosis Infected by Multidrug-Resistant Gram-Negative Bacteria / 中国实验血液学杂志

OBJECTIVE@#To investigate the efficacy and safety of colistin sulfate in the treatment of hematonosis patients infected by multidrug-resistant (MDR) gram-negative bacteria (GNB), and discuss the possible factors that affect the efficacy of colistin sulfate.@*METHODS@#The clinical data of 85 hematologic patients infected with MDR GNB in the Soochow Hopes Hematonosis Hospital from April 2022 to November 2022 were collected and divided into clinically effective group with 71 cases and ineffective group with 14 cases according to the therapeutic efficacy of colistin sulfate. The age, gender, type of hematologic disease, status of hematopoietic stem cell transplantation, infection sites, type of pathogen, timing of administration, daily dose and duration of colistin sulfate, and combination with other antibacterial agents of patients in two groups were compared. Logistic regression was used to analyze on the meaningful variables to study the influencing factors of colistin sulfate. The adverse reactions of colistin sulfate were also evaluated.@*RESULTS@#There were no significant differences in age, gender, type of hematologic disease, hematopoietic stem cell transplantation status, infection sites and pathogen type between the effective group and the ineffective group (P>0.05). Compared with the medication time more than 7 days, meropenem used within 7 days in the clinical effective group, and timely replacement with colistin sulfate could obtain better efficacy, the difference was statistically significant (P=0.018). The duration of tigacycline before colistin sulfate did not affect the efficacy, and there was no significant difference in efficacy between the effective and ineffective groups. The therapeutic effect of colistin sulfate at daily dose of 500 000 U q8h was better than that of 500 000 U q12h, the difference was statistically significant (P=0.035). The time of colistin sulfate use in the clinically effective group was longer than that in the ineffective group, which had a statistical difference (P=0.003). Compared with the clinical ineffective group, the efficacy of combination regimens with colistin sulfate was better than that of colistin sulfate monotherapy, and the difference was statistically significant (P=0.013). Multivariate logistic regression analysis was performed on the indicators with statistical differences in the two groups of patients, which suggested that the use time of colistin sulfate (B: 2.358; OR: 10.573; CI: 1.567-71.361; P=0.015) and the combination of colistin sulfate (B: 1.720; OR: 5.586; CI: 1.210-25.787; P=0.028) were influential factors in the efficacy of colistin sulfate. During the treatment, the incidence of nephrotoxicity, hepatotoxicity and peripheral neurotoxicity were 5.9%, 1.2% and 1.2%, respectively.@*CONCLUSION@#The use of colistin sulfate improves the clinical efficacy of MDR GNB infections in hematological patients, and the timing of colistin sulfate administration and the combination of drugs are independent factors affecting its clinical efficacy, and the safety during treatment is high.

Constructed "ashi point" / 中国针灸

Ashi point is one of the three major categories of acupoint in acupuncture-moxibustion theory nowadays. It is originally recorded in Beiji Qianjin Yaofang (Important Formulas Worth a Thousand Gold Pieces for Emergency) as one of the effective folk methods. The theoretic development of ashi point goes through the innovation period of contemporary and modern acupuncture-moxibustion theory, specifically in three aspects, definition, property and status. Through the analysis of historical data, it is found that the bias of ashi point theory results from the misunderstanding of connotation, the distortion of application techniques, the misinterpretation of semantics and the gradual promotion of status. All of these are generally caused by the reform of acupuncture-moxibustion theory in Japan, which covers the essence of ashi point, limits its connotation and clouds the concept of acupoint. It is necessary to re-understand the literal sense and theoretic construction of ashi point and timely update the knowledge system of acupuncture-moxibustion in association with the results of theoretical researches.

Advances in conditioning regimens for allogeneic hematopoietic stem cell transplantation in elderly patients with acute myeloid leukemia / 中华器官移植杂志

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a sole viable treatment for acute myeloid leukemia (AML). As the median age of AML is approaching 68 years and the global population is aging, allo-HSCT for is becoming more vital for elderly AML patients (60 years and over). Conditioning regimen is important in determining the clinical outcomes of post-allo-HSCT patients.This review summarized the classic and latest conditioning regimens and evaluated their respective clinical outcomes.Clinicians may appreciate the advantages of each conditioning regimen and formulate optimal options for elderly AML patients.

Humanized anti-CD25 monoclonal antibody as a salvage therapy for steroid-refractory acute graft-versus-host disease after hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To investigate the efficacy of humanized anti-CD25 monoclonal antibody for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: A total of 64 patients with SR-aGVHD between June 2019 and October 2020 in Suchow Hopes Hematology Hospital were enrolled in this study. Humanized anti-CD25 monoclonal antibodies 1 mg·kg(-1)·d(-1) were administered on days 1, 3, and 8, and then once per week according to the disease progression. Efficacy was assessed at days 7, 14, and 28 after humanized anti-CD 25 treatment. Results: Of the 64 patients with a median age of 31 (15-63) years, 38 (59.4%) were male and 26 (40.6%) were female. The overall response (OR) rate of the humanized CD25 monoclonal antibody in 64 patients with SR-aGVHD on days 7, 14, and 28 were 48.4% (31/64), 53.1% (34/64), and 79.7% (51/64), respectively. Liver involvement is an independent risk factor for poor efficacy of humanized CD25 monoclonal antibody for SR-aGVHD at day 28 (OR=9.588, 95% CI 0.004-0.291, P=0.002). The median follow-up time for all patients was 17.1 (0.2-50.8) months from the start of humanized CD25 monoclonal antibody therapy. The 1- and 2-year OS rates were 63.2% (95% CI 57.1% -69.3%) and 52.6% (95% CI 46.1% -59.1%), respectively. The 1- and 2-year DFS rates were 58.4% (95% CI 52.1% -64.7%) and 49.8% (95% CI 43.4% -56.2%), respectively. The 1- and 2-year NRM rates were 28.8% (95% CI 23.1% -34.5%) and 32.9% (95% CI 26.8% -39.0%), respectively. The results of the multifactorial analysis showed that liver involvement (OR=0.308, 95% CI 0.108-0.876, P=0.027) and GVHD grade Ⅲ/Ⅳ (OR=9.438, 95% CI 1.211-73.577, P=0.032) were independent risk factors for OS. Conclusion: Humanized CD25 monoclonal antibody has good efficacy and safety for SR-aGVHD. This study shows that SR-aGVHD with pretreatment grade Ⅲ/Ⅳ GVHD and GVHD involving the liver has poor efficacy and prognosis and requires early intervention.

Effect of down-regulation of let-7c/g on triggering a double-negative feedback loop and promoting restenosis / 中华医学杂志(英文版)

BACKGROUND@#Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are the main causes of restenosis (RS) in diabetic lower extremity arterial disease (LEAD). However, the relevant pathogenic mechanisms are poorly understood.@*METHODS@#In this study, we introduced a "two-step injury protocol" rat RS model, which started with the induction of atherosclerosis (AS) and was followed by percutaneous transluminal angioplasty (PTA). Hematoxylin-eosin (HE) staining and immunohistochemistry staining were used to verify the form of RS. Two-step transfection was performed, with the first transfection of Lin28a followed by a second transfection of let-7c and let-7g, to explore the possible mechanism by which Lin28a exerted effects. 5-ethynyl-2΄-deoxyuridine (EdU) and Transwell assay were performed to evaluate the ability of proliferation and migration of VSMCs. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to detect the expression of Lin28a protein and let-7 family members.@*RESULTS@#Using a combination of in vitro and in vivo experiments, we discovered that let-7c, let-7g, and microRNA98 (miR98) were downstream targets of Lin28a. More importantly, decreased expression of let-7c/let-7g increased Lin28a, leading to further inhibition of let-7c/let-7g. We also found an increased level of let-7d in the RS pathological condition, suggesting that it may function as a protective regulator of the Lin28a/let-7 loop by inhibiting the proliferation and migration of VSMCs.@*CONCLUSION@#These findings indicated the presence of a double-negative feedback loop consisting of Lin28a and let-7c/let-7g, which may be responsible for the vicious behavior of VSMCs in RS.

Scientific, transparent and applicable rankings of Chinese guidelines and consensus of rehabilitation medicine published in medical journals in 2022 / 中国康复理论与实践

ObjectiveTo evaluate the Chinese guidelines and consensus of rehabilitation medicine published in the medical journals in 2022 using Scientific, Transparent and Applicable Rankings (STAR). MethodsGuidelines and consensus which were developed by Chinese institutions or led by Chinese scholars were retrieved in databases of CNKI, Wanfang Data, CBM, Chinese Medical Journal Network, PubMed and Web of Science, in 2022, followed by screening for rehabilitation medicine field. The literature were rated with STAR. ResultsSeven guidelines and eleven consensuses were included. The STAR scores ranged from 11.7 to 69.6, with a median score of 25.9 and mean score of 28.3. There was a significant difference in the total score between guidelines and consensus (U = 12.000, P = 0.014). The score ratio was high in the domains of recommendations (73.6%), evidence (39.5%) and others (33.3%), while it was low in the domains of protocol (1.4%), clinical questions (12.5%) and conflicts of interest (13.9%). The score ratio was high in the items of listing the institutional affiliations of all individuals involved in developing the guideline (94.4%), identifying the references for evidence supporting the main recommendations (94.4%), indicating the considerations (e.g., adverse effects) in clinical practice when implementing the recommendations (88.9%), and making the recommendations clearly identifiable, e.g., in a table, or using enlarged or bold fonts (75%); and it was low in the items of describing the role of funder(s) in the guideline development (0), indicating information about the evaluation and management of conflicts of interest (0), providing tailored editions of the guidelines for different groups of target users (0), presenting the guideline or recommendations visually, such as with figures or videos (0), providing details of the guideline protocol (2.8%), assessing the risk of bias or methodological quality of the included studies (2.8%), describing the responsibilities of all individuals or sub-groups involved in developing the guideline (5.6%), indicating how the clinical questions were selected and sorted (5.6%), formating clinical questions in PICO or other formats (5.6%), making the guideline accessible through multiple platforms (5.6%), and declaring that the funder(s) did not influence the guideline's recommendations (8.3%). ConclusionThe quality of current clinical practice guidelines and consensus of rehabilitation medicine is poor, which should be developed in accordance with the relevant standards.

Hot water washing processing technology of Euodiae Fructus based on change laws of active components and tastes / 中国中药杂志

In order to establish the standardized processing technology of the hot water washing of Euodiae Fructus, this study, based on the traditional processing method of hot water washing of Euodiae Fructus recorded in ancient works and modern processing specifications of traditional Chinese medicine decoction pieces, took the yield of decoction pieces and the content of main components as the indicators and optimized the processing conditions by orthogonal test based on the results of single factor investigation. At the same time, electronic tongue technology was used to analyze the change law of the taste index of Euodiae Fructus during the hot water washing. The results of the single factor investigation showed that the content of the main components in Euodiae Fructus showed some regular changes during the processing. Specifically, the content of chlorogenic acid, hyperin, isorhamnetin-3-O-rutinoside, isorhamnetin-3-O-galactoside, and dehydroevodiamine decreased significantly, with average decreases of-23.75%,-27.80%,-14.04%,-14.03%, and-13.11%, respectively. The content of limonin increased significantly with an average increase of 19.83%. The content of evodiamine, rutaecarpine, evocarpine, and dihydroevocarpine showed fluctuating changes and generally increased, with average variation amplitudes of 0.54%,-3.78%, 2.69%, and 5.13%, respectively. The orthogonal test results showed that the optimum processing parameters for the hot water washing of Euodiae Fructus were as follows: washing time of 2 min, the solid-to-liquid ratio of 1∶10 g·mL~(-1), washing temperature of 80 ℃, washing once, and drying at 50 ℃. After the hot water washing processing, the average yield of Euodiae Fructus pieces was 94.80%. The content of limonin, evodiamine, and rutaecarpine was higher than those of raw pro-ducts, and the average transfer rates were 102.56%, 103.15%, and 105.16%, respectively. The content of dehydroevodiamine was lower than that of the raw products, and the average transfer rate was 83.04%. The results of taste analysis showed that the hot water washing could significantly reduce the salty, astringent, and bitter tastes of Euodiae Fructus. This study revealed the influence of the hot water washing on the content of main components and taste of Euodiae Fructus, and the processing technology of the hot water was-hing of Euodiae Fructus established in this study was stable, feasible, and suitable for industrial production, which laid a foundation for clarifying its processing principle and improving the quality standard and clinical application value of decoction pieces.

Clinical risk factors for fracture risk prediction in patients with type 2 diabetes using adjusted FRAX / 中华内分泌外科杂志

Objective:To study the clinical risk factors for osteoporotic fracture (OF) risk prediction in patients with type 2 diabetes mellitus (T2DM) using adjusted fracture risk assessment tool (FRAX) .Methods:A cross-sectional study of 429 patients with T2DM who were hospitalized in the Department of Endocrinology and Geriatrics of the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University from Sep. 2019 to Sep. 2020 was conducted. Participants were divided into OF low-risk group and OF high-risk group. Participant characteristics (age, gender, height, weight, waist, blood pressure, history of drug treatment, serum glucose, glycosylated hemoglobin, total cholesterol, low-density lipoprotein cholesterol (LDL-C) , high-density lipoprotein cholesterol (HDL-C) , triglyceride, serum uric acid, alkaline phosphatase, and thyroid stimulating hormone levels, urine protein/creatinine ratio, urea, creatinine and TPOAB) and dual energy x-ray absorptiometry results were obtained and analyzed. Logistic regression model was used to investigate the relationship between the OF risk of T2DM assessed by adjusted FRAX and clinical risk factors.Results:Patients in the OF high-risk group accounted for 9.09% of the subjects. After adjustment for other variables, the duration of diabetes was still positively associated with significantly elevated risk of OF assessed by adjusted FRAX ( OR 7.660, 95% CI 1.661-35.334, P=0.009) , whereas the blood uric acid was negatively associated with significantly elevated risk of OF assessed by adjusted FRAX ( OR 0.345, 95 % CI 0.128-0.928, P=0.035) .Likewise, LDL-C levels decreased the odds of the risk of OF assessed by adjusted FRAX ( OR 0.316, 95 % CI 0.114-0.881, P=0.028) . There was no significant relationship between alkaline phosphatase ( OR 1.902, 95 % CI 0.904-4.004, P=0.090) as well as total cholesterol ( OR 0.297, 95% CI 0.056~1.560, P=0.151) levels and the elevated risk of OF assessed by adjusted FRAX. Conclusion:Diabetes duration could be a risk factor for OF risk prediction in patients with T2DM using adjusted FRAX, and serum uric acid and LDL-C could be protective factors for OF risk prediction in patients with T2DM using adjusted FRAX.

Vegetarian diet and vitamin B 12 level in Chinese pregnant women / 中华围产医学杂志

Objective:To explore the relationship between vegetarian diets and vitamin B 12 levels in Chinese pregnant women. Methods:A cross-sectional survey was used to explore the relationship between vegetarian diets and vitamin B 12 levels in Chinese pregnant women based on data from the Chinese National Nutrition and Health Surveillance (2015-2017). Maternal serum vitamin B 12 concentration was determined by electrochemiluminescence. Background and diet information of all subjects were collected using general and food frequency questionnaires. General Linear Model was used to analyze the difference in serum vitamin B 12 levels between vegetarian and non-vegetarian pregnant women and multivariate logistic regression for examining the relationship between vegetarian diets and vitamin B 12 deficiency (vitamin B 12<150 pmol/L) in pregnant women. Results:A total of 8 366 pregnant women were included in the analysis, and vegetarians accounted for 1.2% (102/8 366). The median serum vitamin B 12 concentrations were 155.8(93.6-212.4) pmol/L and 187.2(127.4-267.6) pmol/L ( Z=－4.22, P<0.001), and the vitamin B 12 deficiency rates were 48.0% (49/102) and 35.0% (2 896/8 264) in vegetarian and non-vegetarian women, respectively. The vitamin B 12 deficiency rate in vegetarian women was 0.89-fold higher than in non-vegetarians (95% CI: 1.24-2.89). Among the vegetarian and non-vegetarian pregnant women, vitamin B 12 deficiency rates during the first, second, and third trimesters were 34.8%(16/46), 54.3%(19/35), 66.7%(14/21), and 20.4%(521/2 559), 32.6%(941/2 886), 50.9%(1 430/2 807), noting for an increasing trend ( Z=23.54 and 2.57, P=0.010 and P<0.001). Conclusions:Vegetarian pregnant women are at high risk of vitamin B 12 deficiency. Compared with non-vegetarian women, vegetarian pregnant women in China have lower vitamin B 12 levels and a higher risk of vitamin B 12 deficiency. Moreover, the risk of vitamin B 12 deficiency will gradually increase during pregnancy.

Influence of eye movement on precision of corneal ablation and refraction status in SMILE / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the influence of slight eye movement during laser scanning on femtosecond laser precision of corneal ablation and postoperative refractive status in small incision lenticule extraction(SMILE). METHODS: Totally 32 patients(62 eyes)who underwent SMILE surgery in our hospital from January 2019 to March 2021 were included and divided into the movement group and the fixation group according to whether the eyeballs were slightly moved during the operation, and select patients with slightly moved monocular eyeballs for binocular pairing. The actual difference of absolute value of corneal absolute cutting error(ACE), astigmatism error(AE), absolute refractive error(ARE)and absolute visual error(AVE)was compared between the movement group and the fixation group and the two eyes of the patients with slight ocular movement in one eye at 1mo after surgery, and the surgical images were quantified to analyze the correlation between the amplitude of ocular movement and AE, and to compare the effects of the area, layer and direction of slight eye movement on ACE.RESULTS: There were no differences in all observed results between movement group and fixation group(P&#x003E;0.05). Patients with slight movement of one eye had a difference in binocular AE(0.57±0.31D vs 0.33±0.27D, P&#x003C;0.05), and the amplitude of movement was positively correlated with AE at 1mo after surgery(r=0.564, P&#x003C;0.05). There was no statistical differences in ACE at 1mo after surgery in patients with slight ocular movement in different regions(central/peripheral), layers(upper/lower lens)and direction(nasal/temporal)(all P&#x003E;0.05).CONCLUSION:The slight eye movement during laser scanning in SMILE has no significant influence on precision of corneal ablation. It mainly causes decentered ablation and the changes of corneal astigmatism, which has little effect on the spherical equivalent and visual acuity.

Qingre Xiaoyanning inhibits emotional stress-induced reactivation of latent herpes simplex virus type 1 in mice / 药学学报

In this study, according to TCM theory of "liver qi stagnation forming fire", emotional stress mice model was employed to evaluate the protective effects of Qingre Xiaoyanning on herpes simplex virus type 1 (HSV-1) induced reactivation. The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Jinan University, in compliance with the Institutional Animal Care Guidelines. BALB/c mice were divided into six groups, including mock group, HSV-1 latency group, HSV-1 reactivation group (HSV-1 latency + stress), low (0.658 g·kg-1·day-1) and high dose (1.316 g·kg-1·day-1) of Qingre Xiaoyanning groups and positive control group (acyclovir, 0.206 g·kg-1·day-1). Except for the normal group and HSV-1 latency group, all mice in other groups received a daily 12-h restraint stress for 4 days. After 7-day treatment of drugs, body weight and recurrent eye infections of mice were recorded. Brain tissues were harvested to monitor HSV-1 antigen distribution by immunohistochemical staining and detect virus titer by plaque assay. In the meantime, the mRNA and protein levels of infected cell polypeptide (ICP27) and glycoprotein B (gB) in the brain tissues were detected by RT-PCR and Western blot, respectively. The level of 4-hydroxynonenal (4-HNE) and expressions of ferroptosis-related proteins were measured by Western blot. The evaluation of malondialdehyde (MDA) content in the brain tissues was conducted by MDA assay commercial kit. The results showed that Qingre Xiaoyanning significantly retarded the decline of body weight of mice induced by HSV-1 reactivation, reduced the activation rate of HSV-1 and recurrent eye infections, declined virus titer of HSV-1, down-regulated gene and protein expressions of ICP27 and gB, and hindered the distribution of HSV-1 antigen in the brain of mice. Meanwhile, Qingre Xiaoyanning also decreased the protein expression of ferroptosis-related proteins, including DMT1, TFR1 and ALOX15 in the brain tissue of HSV-1 reactivated mice. The levels of lipid peroxidation products, 4-HNE and MDA, were also reduced by Qingre Xiaoyanning treatment. All the above results indicate that Qingre Xiaoyanning significantly inhibited HSV-1 reactivation by restraint stress, which might be related to the regulation of ferroptosis. Our findings provide a theoretical basis for the application of "clearing liver-fire" TCM on treatmenting HSV-1 reactivation-related symptoms.

Captopril related kidney damage: renal afferent arteriolar responses to angiotensin II and inflammatory signaling / 生理学报

Captopril can have nephrotoxic effects, which are largely attributed to accumulated renin and "escaped" angiotensin II (Ang II). Here we test whether angiotensin converting enzyme-1 (ACE1) inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang II and inflammatory signaling. C57Bl/6 mice were given vehicle or captopril (60 mg/kg per day) for four weeks. Hypertension was obtained by minipump supplying Ang II (400 ng/kg per min) during the second 2 weeks. We assessed kidney histology by periodic acid-Schiff (PAS) and Masson staining, glomerular filtration rate (GFR) by FITC-labeled inulin clearance, and responses to Ang II assessed in afferent arterioles in vitro. Moreover, arteriolar H2O2 and catalase, plasma renin were assayed by commercial kits, and mRNAs of renin receptor, transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) in the renal cortex, mRNAs of angiotensin receptor-1 (AT1R) and AT2R in the preglomerular arterioles were detected by RT-qPCR. The results showed that, compared to vehicle, mice given captopril showed lowered blood pressure, reduced GFR, increased plasma renin, renal interstitial fibrosis and tubular epithelial vacuolar degeneration, increased expression of mRNAs of renal TGF-β and COX-2, decreased production of H2O2 and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang II contractions. The latter were blunted by incubation with H2O2. The mRNAs of renal microvascular AT1R and AT2R remained unaffected by captopril. Ang II-infused mice showed increased blood pressure and reduced afferent arteriolar Ang II responses. Administration of captopril to the Ang II-infused mice normalized blood pressure, but not arteriolar Ang II responses. We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang II and may enhance important inflammatory pathways.

Pathological features related to onco-immunity and their clinical significance of pancreatic ductal adenocarcinoma / 中华病理学杂志

Objective: To investigate the tumor immunity-related pathologic features and clinical significance in pancreatic ductal adenocarcinoma (PDAC). Methods: All pathologic materials and clinical information of 192 PDAC patients from the Cancer Hospital of the University of Chinese Academy of Sciences from January 2010 to December 2020 were collected. The onco-immune microenvironment associated morphologic features were evaluated, and MHC-Ⅰ, PD-L1, CD3, and CD8 expression were detected by immunohistochemistry (IHC). Then the correlation between the factors and their influence on prognosis was analyzed. Results: There were 163 cases of non-specific adenocarcinoma (163/192, 84.90%), 18 cases of adeno-squamous carcinoma (18/192, 9.37%), and 11 cases of other rare subtypes (11/192, 5.73%). Perineural invasion was observed in 110 cases (110/192, 57.29%) and vascular invasion in 86 cases (86/192, 44.79%). There were 84 cases (84/182, 46.15%) with severe chronic inflammation. Tumor infiltrating immune cell numbers (TII-N) were increased in 52 cases (52/192, 27.08%). Lymphocytes and plasma cells were the main infiltrating immune cells in 60 cases (60/192, 31.25%), whereas in 34 cases (34/192, 17.71%) the tumors were mainly infiltrated by granulocytes, and 98 cases (98/192, 51.04%) showed mixed infiltration. CD3+T cells were deficient in 124 cases (124/192, 66.31%). CD8+T cells were deficient in 152 cases (152/192, 79.58%). MHC-Ⅰ expression was down-regulated in 156 cases (156/192, 81.25%), and PD-L1 was positive (CPS≥1) in 46 cases (46/192, 23.96%). Statistical analysis showed that TII-N was negatively correlated with vascular invasion (P=0.035), perineural invasion (P=0.002), stage (P=0.004) and long-term alcohol consumption (P=0.039). The type of immune cells correlated positively with chronic pancreatic inflammation (P=0.002), and negatively with tumor differentiation (P=0.024). CD8+T cells were positively correlated with CD3+T cells (P=0.032), MHC-Ⅰ expression (P<0.001) and PD-L1 expression (P=0.001), and negatively correlated with long-term smoking (P=0.016). Univariate analysis showed that histological nonspecific type (P=0.013) and TII-N (P<0.001) were the factors for good prognosis. Vascular invasion (P=0.032), perineural invasion (P=0.001), high stage (P=0.003) and long-term alcohol consumption (P=0.004) were adverse prognostic factors. COX multivariate risk analysis found that TII-N was an independent favorable factor for PDAC, while perineural invasion was an independent adverse risk factor. Conclusions: TII-N is an independent superior prognostic factor for PDAC, and significantly correlated with many factors; chronic alcohol consumption and smoking may inhibit onco-immunity in PDAC patients.

Herbal Textual Research on Zingiberis Rhizoma Recens in Famous Classical Formulas and Its Quality Evaluation / 中国实验方剂学杂志

ObjectiveTo provide references for the selection of Zingiberis Rhizoma Recens on the research of famous classical formulas and the reasonable uses for medicines and foods through herbal textural research and quality analysis of Zingiberis Rhizoma Recens from main producing areas in China. MethodBy consulting the ancient and modern literature， the name， origin， producing areas， harvest time， processing methods of Zingiberis Rhizoma Recens were summarized. According to the 2020 edition of Chinese Pharmacopoeia， the contents of 6-gingerol， 8-gingerol， 10-gingerol， and volatile oil in Zingiberis Rhizoma Recens samples were determined. ResultHerbal textural research indicated that medicinal Zingiberis Rhizoma Recens originated from the fresh rhizome of Zingiber officinale. Before Tang dynasty， Zingiberis Rhizoma Recens produced in Sichuan was the best. In the Song dynasty， Zingiberis Rhizoma Recens produced in Sichuan， Zhejiang， and Anhui was of excellent quality. The cultivation of Zingiberis Rhizoma Recens in Shandong developed during the Ming and Qing dynasties. From ancient times to the present， the harvest period extended from the autumnal equinox to the winter solstice. Quality evaluation standards of Zingiberis Rhizoma Recens were essentially the same in ancient and present documents， as those with little gluten or gluten-free and strong pungency were preferred. After determination， the contents of 6-gingerol， 8-gingerol， and 10-gingerol in 44 samples were qualified in 27 samples， with a qualified rate of 61.4%. Among them， 17 samples were unqualified in the total contents of 8-gingerol and 10-gingerol. Among these qualified samples， the content of 6-gingerol ranged from 0.067% to 0.255%， and the total contents of 8-gingerol and 10-gingerol ranged from 0.040% to 0.131%. The content of volatile oil in 36 samples were qualified in 33 samples， with a qualified rate of 91.7%. Among the qualified samples， the content of volatile oil ranged from 0.175% to 0.410%. ConclusionZingiberis Rhizoma Recens has been used as medicines and foods since ancient times， and the genuine producing areas are consistent in ancient and present times， while the quality of the products， especially the medicinal Zingiberis Rhizoma Recens， should be monitored. Medicinal Zingiberis Rhizoma Recens planted in Leshan city of Sichuan province contains high contents of effective components， followed by Qujing and Wenshan cities of Yunnan province. Zingiberis Rhizoma Recens planted in Shandong and other places is mostly edible.

Analysis on Indications and Medication Regularities of Famous Classical Formula Wuzhuyu Tang Based on Modern Clinical Literature / 中国实验方剂学杂志

Wuzhuyu Tang （WZYT）， a classical traditional Chinese medicine （TCM） formula， was first recorded in Treatise on Cold Damage by the prestigious physician ZHANG Zhong-jing in the Eastern Han Dynasty， and included in Catalogue of Ancient Classical Formulas （First Batch）. WZYT is composed of four medcinals： Euodiae Fructus， Ginseng Radix et Rhizoma， Zingiberis Rhizoma Recens， and Jujubae Fructus， which has the effects of warming the middle and tonifying deficiency， dissipating cold and descending adverse qi. Based on data mining， this paper analyzes the modern clinical research literature on WZYT， which is expected to lay a basis for clarifying the "disease-symptom-prescription-medicinal" relationship of WZYT， as well as its modern clinical indications and clinical dosage. With the search term "Wuzhuyu Tang"， 253 complete medical records were retrieved from CNKI， VIP， and Wanfang （2000-2020）， involving 292 TCM prescriptions. Microsoft Excel 2019 was employed to establish the medical record database and the main clinical indications were statistically analyzed. Moreover， the syndromes， incidence law， and medication regularity were summed up. The result indicates WZYT has a wide range of modern clinical applications， mainly including the treatment of headache， dizziness， vomiting， diarrhea， dysmenorrhea， morning sickness， and other diseases， and the "deficiency， cold， and reversal" symptoms， mainly manifested as nausea and vomiting， headache， fatigue and lack of strength， reversal cold of hands and feet， poor appetite， gloomy complexion， dizziness， aversion to wind and cold， abdominal pain， sloppy diarrhea， abdominal distension， poor sleep， pale tongue， white coating， and deep thread wiry pulse. These diseases and symptoms mainly occur in women and middle-aged people. In most cases， medicinals are added or subtracted according to the symptoms， and the common doses of Euodiae Fructus， Zingiberis Rhizoma Recens， Codonopsis Radix or Ginseng Radix et Rhizoma， and Jujubae Fructus in the original prescription are 6-15 g， 10-15 g， 10-15 g or 9-12 g， and 4-6， respectively. The added medicinals are in the descending order of Pinelliae Rhizoma， Atractylodis Macrocephalae Rhizoma， Poria， Glycyrrhize Radix et Rhizoma， and Chuanxiong Rhizoma according to the frequency.

Clinical Efficacy of Tiandan Tongluo Capsule Against Cerebral Infarction in Convalescence Corresponding to Stoke Due to Wind-Phlegm-Static Blood Obstructing Vessels / 中国实验方剂学杂志

Objective:To evaluate the safety and effectiveness of Tiandan Tongluo capsule in the treatment of cerebral infarction （CI） in convalescence （stoke involving meridians and collaterals due to wind-phlegm-static blood obstructing vessels）， with Naoshuantong capsule as a control. Method:A total of 352 convalescent patients with CI differentiated into stoke involving meridians and collaterals due to wind-phlegm-static blood obstructing vessels in traditional Chinese medicine （TCM） were included in this multi-center， randomized， double-blind， single-simulated， Naoshuantong capsule-controlled clinical trial， which lasted from 28 December， 2016 to 12 April， 2019. After being randomized into an experimental group and a control group at a ratio of 3∶1， patients in the experimental group were provided with oral Tiandan Tongluo capsule， five capsules per time， three times per day， whereas those in the control group received both Naoshuantong capsule simulator， two capsules per time， three times per day， and Naoshuantong capsule， three capsules per time， three times per day， for 12 successive weeks. The patients were followed up until 180 days after onset. The Barthel activities of daily living （ADL） index （BI） score was used as the primary outcome， and the secondary outcomes included neurological deficit score ［assessed with National Institutes of Health Stroke Scale （NIHSS）］， modified Rankin scale （mRS）， TCM syndrome score， and proportion of patients with new vascular events. The changes in laboratory indexes and the incidence of adverse reactions during treatment were observed. Result:Among the 389 cases enrolled， 30 dropped out， with the drop-out rate being 7.71%. There were 374 cases included in the full analysis set and 377 in the safety set. The comparison with the control group revealed that the total BI score and the percentage of BI score ≥ 75 in the experimental group were increased， but the difference was not statistically significant. The percentage of mRS score ≤ 2 within 180 days after onset in the experimental group obviously elevated in contrast to that of the control group （<italic>P</italic><0.05）. As demonstrated by TCM syndrome score analysis， the markedly effective rate in the experimental group was significantly higher than that in the control group （<italic>P</italic><0.05）. During the trial， the incidence rates of new vascular events in the experimental group and the control group were 0.00% and 1.09% （one case）， respectively， exhibiting no statistically significant difference between the two groups. Conclusion:Tiandan Tongluo capsule and Naoshuantong capsule both produce definite therapeutic effects in the treatment of CI in convalescence （stoke involving meridians and collaterals due to wind-phlegm-static blood obstructing vessels）. Compared with Naoshuantong capsule， Tiandan Tongluo capsule better alleviates neurological deficit， promotes neural functional recovery， and improves TCM syndrome score， without inducing severe adverse reactions.

Effect of Danggui Shaoyaosan on Diminished Ovarian Reserve in Model Rats： An Exploration Based on TGF-β1/ Smads Signaling Pathway / 中国实验方剂学杂志

Objective:To observe the improving effect of Danggui Shaoyaosan on diminished ovarian reserve （DOR） in rats triggered by Tripterygia wilfordii polyglycoside tablet combined with stress， and to explore the role of transforming growth factor-<italic>β</italic>₁（TGF-<italic>β</italic>₁）/Smads signaling pathway in such improvement. Method:Forty-eight female SD rats with normal sexual cycle were selected and randomly divided into a normal group （<italic>n</italic>=8） and a modeling group （<italic>n</italic>=40）， and the ones in the modeling group were given Tripterygium wilfordii polyglycoside tablets （50 mg·kg^-1） combined with random stress for 15 d. After successful modeling， the rats were randomized into the model group， low-， medium-， and high-dose （3.96， 7.92， 15.84 g·kg^-1） Danggui Shaoyaosan groups， and estradiol valerate group （0.09 mg·kg^-1）， with eight in each group. Under the premise of stress exposure， they were separately gavaged with the normal saline， low-， medium- and high-dose Danggui Shaoyaosan， and estradiol valerate for 15 successive days. The estrous cycle of rats in each group was observed daily. After intervention， the rats were sacrificed and the ovarian visceral index was calculated. The pathological changes in ovarian tissues were observed by hematoxylin eosin （HE） staining. The protein expression levels of TGF-<italic>β</italic>₁ and TGF-<italic>β</italic>₁receptor （TGF-<italic>β</italic>₁R） in the ovarian tissues of rats were measured by immunohistochemistry （IHC）， and the mRNA expression levels of Smad2， Smad3， and Smad7 in the ovarian tissues by real-time polymerase chain reaction （Real-time PCR）. Result:Compared with the normal group， the model group exhibited disordered estrus cycle （<italic>P</italic><0.05）， reduced visceral index （<italic>P</italic><0.01）， and down-regulated TGF-<italic>β</italic>₁ and TGF-<italic>β</italic>₁R protein and Smad2 and Smad3 mRNA expression in the ovarian tissues （<italic>P</italic><0.01）， and up-regulated Smad7 mRNA expression （<italic>P</italic><0.01）. Compared with the model group， Danggui Shaoyaosan at the low， medium， and high doses and estradiol valerate improved the estrus cycle of rats to varying degrees （<italic>P</italic><0.05） and increased the visceral index， with better effects observed in the medium-group and high-dose Danggui Shaoyaosan groups （<italic>P</italic><0.05，<italic>P</italic><0.01）. Besides， the protein expression levels of TGF-<italic>β</italic>₁ and TGF-<italic>β</italic>₁R and the mRNA expression levels of Smad2 and Smad3 in the ovarian tissues were elevated to varying degrees （<italic>P</italic><0.01）， and the Smad7 mRNA expression declined （<italic>P</italic><0.01）. The improvements in TGF-<italic>β</italic>₁ and TGF-<italic>β</italic>₁R protein expression of the medium-dose Danggui Shaoyaosan group and estradiol valerate group were more obvious. Conclusion:Danggui Shaoyaosan significantly improves ovarian reserve in DOR rats， which is closely related to the regulation of TGF-<italic>β</italic>₁/Smads signaling pathway.

Clinical Significance of Detection of ZIC1 Promoter Methylation in Peripheral Blood and Cancer Tissues of Non-small Cell Lung Cancer Patients / 肿瘤防治研究

Objective To investigate the methylation status of ZIC1 gene in peripheral blood and lung cancer tissues of NSCLC patients and its prognostic significance. Methods We took the peripheral blood, cancer tissues and adjacent tissues of 95 NSCLC patients. The peripheral blood of 95 healthy people was taken as control group. MSP was used to compare the detection rate of ZIC1 methylation between peripheral blood and cancer tissues. And we analyzed the correlation of ZIC1 methylation in peripheral blood and cancer tissues with the clinicopathological factors of NSCLC patients. Results The methylation detection rates of ZIC1 in peripheral blood and lung cancer tissues in NSCLC patients were significantly higher than those in peripheral blood of healthy people and adjacent tissues of NSCLC patients (P < 0.05), and the sensitivity and specificity of ZIC1 methylation in the diagnosis of tumor tissues were higher. The positive rate of ZIC1 gene methylation in peripheral blood and tumor tissues of NSCLC patients was significantly correlated with tumor diameter, metastasis, stage and pleural effusion (P < 0.05). Conclusion The methylation of ZIC1 gene is related to the occurrence, development, metastasis and stage of NSCLC. It may be used as a diagnostic and prognostic indicator of NSCLC.