Clinical value of circadian clock related biomarkers for the diagnosis of chronic pancreatitis with pancreatic exocrine insufficiency / 中华胰腺病杂志

Objective:To examine the expression of core clock genes in the peripheral blood mononuclear cells (PBMCs) and the level of circadian disturbance-related proteins in the serum of chronic pancreatitis (CP) patients with pancreatic exocrine insufficiency (PEI), and explore their potential diagnostic value in clinical practice.Methods:The peripheral blood samples and related clinical data from 68 patients diagnosed with CP in Shanghai General Hospital from Jan 2015 to Jan 2022 were collected. Peripheral blood samples from 30 healthy individuals were used for control. The M-ANNHEIM classification system was used to stratify the clinical stages of patients with CP. The mRNA expression of the core clock genes, including Clock, Bmal1, Per1/2/3 and Cry1/2 in PBMCs was analyzed using realtime qPCR, and the expression of circadian disturbance-related proteins like TrkB, CD 36 and Rbp in serum was measured with ELISA. The receiver operating characteristic curve(ROC) and the area under curve (AUC) was used to test the efficiency for diagnozing PEI. Results:The mRNA expression of Per1 in CP patients was significantly decreased (0.76 vs 1, P<0.05), and the AUC for diagnozing PEI was 0.744 (95% CI 0.628-0.860), with a cut-off value of 0.72; and the sensitivity and specificity was 84.8% and 57.1%, respectively. The protein abundance of serum CD 36 was significantly increased in CP patients (33.85±19.74ng/ml vs 24.71±11.53 ng/ml, P<0.05); the AUC for diagnozing PEI was 0.834 (95% CI 0.735-0.932), with a cut-off value of 29.75 pg/ml; and the sensitivity and specificity was 74.3% and 84.8%, respectively. The expression of CD 36 was increased with the increase of CP clinical stage, and there were statistically significant differences between either two stages (all P value <0.05). The mRNA expression of Per1 in patients with CP in Stage Ⅰ was significantly higher than that in patients with CP in Stage Ⅱ or Ⅲ, and the differences were statistically significant ( P<0.05), but no statistical difference was found between Stage Ⅱ and Stage Ⅲ. Conclusions:The decreased expression of Per1 mRNA in PBMCs and increased level of CD 36 in serum are significantly related to the occurrence of PEI in CP, suggesting that they may have potential value for diagnozing PEI and guiding the clinical practice.

Update on salivary gland transplantation in severe dry eye / 中华实验眼科杂志

As a chronic eye disease caused by multiple factors, the treatment of dry eye disease (DED) should be individualized according to the cause and severity of the disease.In patients with severe DED who have lost lacrimal secretion but have not suffered severe damage to the salivary glands, autologous salivary gland transplantation may help bring hope to these patients if conventional treatments are not effective enough.According to the literature, the three major salivary glands and the minor salivary glands have been used as lacrimal gland replacements.Studies have shown that submandibular glands not only have a high gland survival rate after transplantation, but also maintain secretory activity after transplantation and therefore successfully serve as lacrimal gland replacement.During the up to 180-month follow-up period, the subjective symptoms and signs of DED such as dryness, foreign body sensation, and other objective indicators related to DED such as visual acuity and tear film break-up time are effectively improved.Among the minor salivary glands, the labial glands have been proven to maintain secretory function during the up to ten-year follow-up period after transplantation according to the literature, and have therefore become an alternative lacrimal gland replacement.This review summarized the indications, surgical techniques, efficacy evaluation, modulation of salivary flow and complications of the surgery, involving three major salivary glands, parotid, submandibular and sublingual glands, and minor salivary glands among which labial glands are most commonly used.

Development and validation of risk prediction model for new-onset cardiovascular diseases among breast cancer patients: Based on regional medical data of Inner Mongolia / 北京大学学报(医学版)

OBJECTIVE@#To develop and validate a three-year risk prediction model for new-onset cardiovascular diseases (CVD) among female patients with breast cancer.@*METHODS@#Based on the data from Inner Mongolia Regional Healthcare Information Platform, female breast cancer patients over 18 years old who had received anti-tumor treatments were included. The candidate predictors were selected by Lasso regression after being included according to the results of the multivariate Fine & Gray model. Cox proportional hazard model, Logistic regression model, Fine & Gray model, random forest model, and XGBoost model were trained on the training set, and the model performance was evaluated on the testing set. The discrimination was evaluated by the area under the curve (AUC) of the receiver operator characteristic curve (ROC), and the calibration was evaluated by the calibration curve.@*RESULTS@#A total of 19 325 breast cancer patients were identified, with an average age of (52.76±10.44) years. The median follow-up was 1.18 [interquartile range (IQR): 2.71] years. In the study, 7 856 patients (40.65%) developed CVD within 3 years after the diagnosis of breast cancer. The final selected variables included age at diagnosis of breast cancer, gross domestic product (GDP) of residence, tumor stage, history of hypertension, ischemic heart disease, and cerebrovascular disease, type of surgery, type of chemotherapy and radiotherapy. In terms of model discrimination, when not considering survival time, the AUC of the XGBoost model was significantly higher than that of the random forest model [0.660 (95%CI: 0.644-0.675) vs. 0.608 (95%CI: 0.591-0.624), P < 0.001] and Logistic regression model [0.609 (95%CI: 0.593-0.625), P < 0.001]. The Logistic regression model and the XGBoost model showed better calibration. When considering survival time, Cox proportional hazard model and Fine & Gray model showed no significant difference for AUC [0.600 (95%CI: 0.584-0.616) vs. 0.615 (95%CI: 0.599-0.631), P=0.188], but Fine & Gray model showed better calibration.@*CONCLUSION@#It is feasible to develop a risk prediction model for new-onset CVD of breast cancer based on regional medical data in China. When not considering survival time, the XGBoost model and the Logistic regression model both showed better performance; Fine & Gray model showed better performance in consideration of survival time.

Clinicopathological characteristics and prognosis of patients with small bowel tumors: A single center analysis of 220 cases / 中华胃肠外科杂志

Objective: To analyze the clinicopathological characteristics and prognosis of patients with small bowel tumors. Methods: This was a retrospective, observational study. We collected clinicopathological data of patients with primary jejunal or ileal tumors who had undergone small bowel resection in the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University between January 2012 and September 2017. The inclusion criteria included: (1) older than 18 years; (2) had undergone small bowel resection; (3) primary location at jejunum or ileum; (4) postoperative pathological examination confirmed malignancy or malignant potential; and (5) complete clinicopathological and follow-up data. Patients with a history of previous or other concomitant malignancies and those who had undergone exploratory laparotomy with biopsy but no resection were excluded. The clinicopathological characteristics and prognoses of included patients were analyzed. Results: The study cohort comprised 220 patients with small bowel tumors, 136 of which were classified as gastrointestinal stromal tumors (GISTs), 47 as adenocarcinomas, and 35 as lymphomas. The median follow-up for all patient was 81.0 months (75.9-86.1). GISTs frequently manifested as gastrointestinal bleeding (61.0%, 83/136) and abdominal pain (38.2%, 52/136). In the patients with GISTs, the rates of lymph node and distant metastasis were 0.7% (1/136) and 11.8% (16/136), respectively. The median follow-up time was 81.0 (75.9-86.1) months. The 3-year overall survival (OS) rate was 96.3%. Multivariate Cox regression-analysis results showed that distant metastasis was the only factor associated with OS of patients with GISTs (HR=23.639, 95% CI: 4.564-122.430, P<0.001). The main clinical manifestations of small bowel adenocarcinoma were abdominal pain (85.1%, 40/47), constipation/diarrhea (61.7%, 29/47), and weight loss (61.7%, 29/47). Rates of lymph node and distant metastasis in patients with small bowel adenocarcinoma were 53.2% (25/47) and 23.4% (11/47), respectively. The 3-year OS rate of patients with small bowel adenocarcinoma was 44.7%. Multivariate Cox regression-analysis results showed that distant metastasis (HR=4.018, 95%CI: 2.108-10.331, P<0.001) and adjuvant chemotherapy (HR=0.291, 95% CI: 0.140-0.609, P=0.001) were independently associated with OS of patients with small bowel adenocarcinoma. Small bowel lymphoma frequently manifested as abdominal pain (68.6%, 24/35) and constipation/diarrhea (31.4%, 11/35); 77.1% (27/35) of small bowel lymphomas were of B-cell origin. The 3-year OS rate of patients with small bowel lymphomas was 60.0%. T/NK cell lymphomas (HR= 6.598, 95% CI: 2.172-20.041, P<0.001) and adjuvant chemotherapy (HR=0.119, 95% CI: 0.015-0.925, P=0.042) were independently associated with OS of patients with small bowel lymphoma. Small bowel GISTs have a better prognosis than small intestinal adenocarcinomas (P<0.001) or lymphomas (P<0.001), and small bowel lymphomas have a better prognosis than small bowel adenocarcinomas (P=0.035). Conclusions: The clinical manifestations of small intestinal tumor are non-specific. Small bowel GISTs are relatively indolent and have a good prognosis, whereas adenocarcinomas and lymphomas (especially T/NK-cell lymphomas) are highly malignant and have a poor prognosis. Adjuvant chemotherapy would likely improve the prognosis of patients with small bowel adenocarcinomas or lymphomas.

Prevention and treatment of lung cancer by regulating tumor-associated macrophages with traditional Chinese medicine / 中国中药杂志

Lung cancer is one of the common malignant tumors in the world, and its incidence and mortality is increasing year by year. Interactions between tumor cells and immune cells in the tumor microenvironment(TME) affect tumor proliferation, infiltration, and metastasis. Tumor-associated macrophages(TAMs) are prominent components of TME, and they have dual regulation effects on malignant progression of lung cancer. The number, activity, and function of M2 macrophages are related to the poor prognosis of lung cancer, and M2 macrophages participate in tumor angiogenesis and immune escape. It has been proved that traditional Chinese medicines(TCMs) and their active ingredients can enhance the antitumor effects, reduce the toxicity of chemotherapy and radiotherapy, and prolong the survival rates of patients with cancer. This paper summarized the role of TAMs in the lung cancer initiation and progression, explored the molecular mechanism of TCM in regulating the recruitment, polarization phenotype, activity, and expression of related factors and proteins of TAMs, and discussed related signal pathways in the prevention and treatment of lung cancer based on the TCM theory of "reinforcing healthy qi and eliminating pathogen". This paper is expected to provide new ideas for the immunotherapy of targeted TAMs.

Reinforced radiculoplasty for the treatment of symptomatic sacral Tarlov cysts: A clinical analysis of 71 cases / 北京大学学报(医学版)

OBJECTIVE@#To investigate the safety and efficacy of reinforced radiculoplasty in the treatment of symptomatic sacral Tarlov cysts (TCs).@*METHODS@#A retrospective analysis was performed on the clinical data and follow-up data of 71 patients with symptomatic sacral TCs who underwent reinforced radiculoplasty in the Neurosurgery Department of Peking University Third Hospital from June 2018 to March 2021. All the operations were performed under neuroelectrophysiological monitoring. Intraoperative cyst exploration, partial resection of the cyst wall, narrowing of the leak, nerve root sleeve radiculoplasty and artificial dural reinforcement were performed. The incidence of postoperative complications and new neurological dysfunction was analyzed. Visual analogue scale (VAS) was used to assess the changes of pain before and after surgery. The Japanese Orthopedics Association (JOA) low back pain score was used to evaluate the changes in nerve function before and after surgery.@*RESULTS@#In the study, 71 patients had 101 TCs, 19 (18.8%) TCs originated from the left S1 nerve, 26 (25.7%) originated from the left S2 nerve, 3 (3.0%) originated from the left S3 nerve, 14 (13.9%) originated from the right S1 nerve, 33 (32.7%) originated from the right S2 nerve, 6 (5.9%) originated from the right S3 nerve, all the TCs underwent reinforced radiculoplasty. Deep infection (1 case), subcutaneous effusion (1 case), fat li-quefaction (1 case) and urinary tract infection (4 cases) were recorded postoperatively. The patients were followed up for 12-43 months (median, 26 months). Two cases had new urinary retention after operation, and the catheter was removed at the end of the first and second months respectively. One case had new fecal weakness, which improved after 3 months. Compared with preoperation, VAS decreased significantly at the last follow-up [median, 6 (4-9) vs. 1 (0-5), Z=-7.272, P < 0.001], JOA score increased significantly [median, 20 (16-25) vs. 27 (18-29), Z=-7.265, P < 0.001]. There were 18 cured cases (25.4%), 41 excellent cases (57.7%), 8 effective cases (11.3%), and 4 invalid cases (5.6%). The total efficiency was 94.4% (67/71). Two (1.98%) cysts recurred.@*CONCLUSION@#For patients with symptomatic sacral TCs, reinforced radiculoplasty can significantly improve the pain and nerve function, which is safe and reliable.

Research progress in targeting autophagy of traditional Chinese medicine and natural compounds to regulate atherosclerosis / 中国中药杂志

Atherosclerosis(AS) is the common pathological basis of many ischemic cardiovascular diseases, and its formation process involves various aspects such as vascular endothelial injury and platelet activation. Vascular endothelial injury is the initiating factor of AS plaque. Monocytes are recruited to differentiate into macrophages at the damaged endothelial cells, which absorb oxidized low-density lipoprotein(ox-LDL) and slowly transform into foam cells. Smooth muscle cells(SMCs) proliferate and migrate continuously. As the only cell producing interstitial collagen fibers in the fibrous cap, SMCs largely determine whether the plaque ruptured or not. The amplifying inflammatory response during the formation of AS recruits platelets to adhere to the damaged area of vascular endothelium and stimulates excessive platelet aggregation. Autophagy activity is associated with vascular lesions and abnormal platelet activation, and excessive autophagy is considered to be a negative factor for plaque stability. Therefore, precise regulation of different types of vascular autophagy and platelet autophagy to treat AS may provide a new therapeutic perspective for the prevention and treatment of atherosclerotic ischemic cardiovascular disease. Currently, treatment strategies for AS still focus on lowering lipid levels with high-intensity statins, which often cause significant side effects. Therefore, the development of safer and more effective drugs and treatment modes is the focus of current research. Traditional Chinese medicine and natural compounds have the potential to treat AS by targeted autophagy, and have been playing an increasingly important role in the prevention and treatment of cardiovascular diseases in China. This paper summarizes the experimental studies on different vascular cell types and platelet autophagy in AS, and sums up the published research results on targeted autophagy of traditional Chinese medicine and natural plant compounds to regulate AS, providing new ideas for further research.

Searching for potential biomarkers reflecting early injury and progressive of podocytes in nephropathy based on cellular metabolomics combined with ROC analysis / 药学学报

The pathogenesis of the nephrotic syndrome is complex and the pathological types are diverse, so the minor symptoms in its early phases are difficult to detect. Renal biopsy is the gold indicator for the diagnosis of renal pathology and progression, but poor patient compliance shows, and the optimal treatment time is often delayed. Therefore, the discovery of biomarkers for early diagnosis and disease progression monitoring is of great clinical significance. In this study, doxorubicin-injured podocyte models were used to simulate human kidney disease at different stages of progression. LC-MS-based metabolomic technology combined with statistical methods was used to screen and identify the potential biomarkers associated with early injury or progression of podocytes. The results of cell viability, apoptosis tests and podocyte structural protein analysis showed that the model was successfully constructed, and the degree of podocyte injury was significantly different between the two modeling methods. According to VIP > 1 and P < 0.05 based on the orthogonal partial least squares discriminant analysis (OPLS-DA) model, nine differential metabolites reflecting early podocyte injury and twelve differential metabolites reflecting the injury progression were screened, respectively. ROC analysis was adopted to focus on the potential biomarkers that can reflecting the early podocyte injury including L-tryptophan, guanosine triphosphate (GTP), 5′-thymidylic acid (dTMP) and thymidine, and the biomarkers reflecting the injury progression of podocytes composed of L-phenylalanine, L-tyrosine acid, uridine 5′-diphosphate (UDP) and guanosine 5′-diphosphate (GDP) AUC > 0.85. It indicated that these eight metabolites may have high sensitivity and diagnostic ability. This study provides a reference for the research on biomarkers of progressive diseases.

Screening and identification of CD44v9 specific peptide ligand for gastric cancer detection / 西安交通大学学报(医学版)

【Objective】 To screen and verify a peptide ligand specific for CD44v9. 【Methods】 A 12-mer phage peptide library was screened on CD44v9 coated on solid phase. Candidate sequences emerged after sequencing. Candidate phages were selected using enzyme-linked immunosorbent assay. The best sequence was chosen for further study. Binding of C9-3 to CD44v overexpressed HEK-293 cells was determined using immunofluorescence. Binding affinity and specificity were verified on gastric cancer tissues with immunohistochemistry. 【Results】 Phages significantly were enriched during panning process. After sequencing, nine individual sequences occurred in 30 selected clones. Among the 9 candidate sequences, C9-3 exhibited the highest frequency. Results of ELISA showed that C9-3 had the highest OD value and selectivity. Thus, C9-3 was chosen for peptide probe synthesis. C9-3 probe stained CD44v overexpressed HEK-293 cells, but not empty vector transfected HEK-293 cells. Immunohistochemistry scores of C9-3 were significantly different between gastric cancer and paracancer tissues (t=3.953, P<0.01). A linear positive correlation was observed between C9-3 binding and CD44v9 expression (r=0.823, P<0.01). 【Conclusion】 In this study, peptide ligand of CD44v9 was successfully screened. The peptide can bind to cells and cancer tissues via CD44v9. It has potential for gastric targeting probes.

Long-term influence of donor graft thickness and size on corneal endothelial cell density of Descemet stripping automated endothelial keratoplasty / 中华实验眼科杂志

Objective:To explore the long-term influence of donor central graft thickness (CGT) and donor graft size on corneal endothelial cell density (ECD) after Descemet stripping automated endothelial keratoplasty (DSAEK).Methods:An observational case series study was conducted.One hundred and forty-four eyes of 134 patients who underwent DSAEK in Peking University Third Hospital from January 2013 to December 2017 with at least 24-month follow-up were enrolled.Preoperative donor ECD was evaluated by specular microscopy, and ECD was determined by in vivo confocal microscopy at 1, 3, 6, 12, and 24 months postoperatively.Donor CGT was measured by anterior segment optical coherence tomography.According to the 3-month postoperative donor CGT, the subjects were divided into thinner graft group (45 eyes with CGT<100 μm), medium-thick graft group (66 eyes with CGT≥100-<150 μm) and thicker graft group (33 eyes with CGT≥150 μm). According to the donor trephination size, the subjects were divided into smaller graft group (31 eyes with trephination size≥7-<8 mm) and larger graft group (113 eyes with trephination size≥8-<9 mm). The changes of the donor CGT and corneal endothelial cell loss rate were compared at different time points after surgery.The relationships between 24-month postoperative ECD and donor ECD, donor graft size and donor CGT were analyzed.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Peking University Third Hospital (No.IRB00006761-2008025). Written informed consent was obtained from each subject prior to any medical examination. Results:The donor CGT was 129.0 (90.8, 160.8), 115.5 (93.0, 146.0), 115.5 (89.0, 151.0), 112.5 (94.3, 146.8) and 114.0 (89.0, 144.5) μm at 1, 3, 6, 12 and 24 months after surgery, showing a statistically significant difference ( H=37.369, P<0.001). There was a statistically significant difference between 1-month and 3-month postoperative CGT ( P<0.001). There was no statistically significant difference in the endothelial cell loss rate among the three different donor CGT groups and between the two different donor graft size groups at any postoperative time points (all at P>0.05). Spearman correlation analysis showed that the 24-month postoperative ECD was strongly positively correlated with the preoperative donor ECD( rs=0.783, P<0.001), which was not associated with donor graft size and donor CGT ( rs=0.141, P=0.093; rs=-0.044, P=0.600). Conclusions:Larger postoperative ECD is correlated with larger preoperative ECD of donor graft.Lower long-term corneal endothelial cell loss rate after DSAEK is associated with thinner and larger diameter of donor graft.

Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids / 生理学报

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

Epidemiological characteristics of COVID-19 epidemic in Ejina banner, Inner Mongolia Autonomous Region, October 2021 / 中华流行病学杂志

Objective: To understand the epidemiological characteristics of COVID-19 epidemic in Ejina banner, Inner Mongolia, in October 2021 and provide evidence for the improvement of COVID-19 prevention and control. Methods: The information about the time, area and population distributions of COVID-19 cases in Ejina before November 13, 2021 and the gene sequencing result of the isolates were collected for a statistical descriptive analysis. Results: The first COVID-19 case in Ejina occurred on 7 October, 2021. A total of 164 COVID-19 cases were reported from October 19 to November 12. Most cases were distributed in 6 communities in Darahub (156 cases, 95.12%). The result of full gene sequencing of the isolates indicted that the pathogen was Delta variant (B.1.617.2). The male to female ratio of the cases was 1.3∶1. The age of cases ranged from 1 to 85 years, and the cases aged 20-59 years accounted for 78.66%. The main clinical symptoms were sore throat (91 cases, 91.92%), cough (49 cases, 49.49%) and fever (23 cases, 23.23%). Most cases were ordinary ones (81 cases, 49.39%) and mild ones (68 cases, 41.46%). The cases were mainly detected at the isolation points (84 cases, 51.22%) and through population based nucleic acid testing (62 cases, 37.80%). The basic reproduction number (R0) of COVID-19 was 5.3, the average incubation period was 3.9 days. The local government rapidly started Ⅳ level emergency response and conducted 10 rounds of nucleic acid tests. The transferring of travelers reduced the risk for the further spread of COVID-19 in Ejina. Conclusions: The epidemic of COVID-19 in Ejina characterized by strong transmission, short incubation period, herd susceptibility and case clustering. Delta variant (B.1.617.2) was the pathogen, which might be imported from Zeke port. Comprehensive prevention and control measures, such as closed-loop management and vaccination, should be continued. The successful transferring of the patients and travelers provided evidence for the effective and precise prevention and control of COVID-19 in a routine manner.

Inhibition of Escherichia coli nitroreductase by the constituents in Syzygium aromaticum / 中国天然药物

Gut bacterial nitroreductases play an important role in reduction of various nitroaromatic compounds to the corresponding N-nitroso compounds, hydroxylamines or aromatic amines, most of which are carcinogenic and mutagenic agents. Inhibition of gut nitroreductases has been recognized as an attractive approach for reducing mutagen metabolites in the colon, so as to prevent colon diseases. In this study, the inhibitory effects of 55 herbal medicines against Escherichia coli(E. coli) nitroreductase (EcNfsA) were examined. Compared with other herbal extracts, Syzygium aromaticum extract showed superior inhibitory potency toward EcNfsA mediated nitrofurazone reduction. Then, the inhibitory effects of 22 major constituents in Syzygium aromaticum against EcNfsA were evaluted. Compared with other tested natural compounds, ellagic acid, corilagin, betulinic acid, oleanic acid, ursolic acid, urolithin M5 and isorhamnetin were found with strong to moderate inhibitory effect against EcNfsA, with IC50 values ranging from 0.67 to 28.98 mol·L-1. Furthermore, the inhibition kinetic analysis and docking simulation demonstrated that ellagic acid and betulinic acid potently inhibited EcNfsA (Ki < 2 μmol·L -1) in a competitively inhibitory manner, which created strong interactions with the catalytic triad of EcNfsA. In summary, our findings provide new scientific basis for explaining the anti-mutagenic activity of Syzygium aromaticum, where some newly identified EcNfsA inhibitors can be used for developing novel agents to reduce the toxicity induced by bacterial nitroreductase.

Analysis on "the essence of tuina, arrival of qi ensuring curative effect" / 中国针灸

In reference with the systematic review of the thought of deqi (arrival of qi) put forward in Huangdi Neijing (Internal Classic of Yellow Emperor) and other classic books of traditional Chinese medicine, in view of detecting qi and identifying qi before treatment, as well as the prerequisites of deqi in tuina, meaning the accurate syndrome differentiation and manipulations, the importance of deqi in treatment with tuina is expounded. In association with clinical experience, the specific manifestations of deqi in patients during tuina are summarized, e.g. soreness, distention, pain, numbness, warm feeling and slight sweating, local changes in intestinal sound and skin color, as well as mind regulation. It is anticipated that deqi of tuina may be drawn the attention in clinical practice, and the relevant study be expanded.

Effect of Sodium Salicylate on Calcium Currents and Exocytosis in Cochlear Inner Hair Cells: Implications for Tinnitus Generation / 神经科学通报·英文版

Sodium salicylate is an anti-inflammatory medication with a side-effect of tinnitus. Here, we used mouse cochlear cultures to explore the effects of salicylate treatment on cochlear inner hair cells (IHCs). We found that IHCs showed significant damage after exposure to a high concentration of salicylate. Whole-cell patch clamp recordings showed that 1-5 mmol/L salicylate did not affect the exocytosis of IHCs, indicating that IHCs are not involved in tinnitus generation by enhancing their neuronal input. Instead, salicylate induced a larger peak amplitude, a more negative half-activation voltage, and a steeper slope factor of Ca2+ current. Using noise analysis of Ca2+ tail currents and qRT-PCR, we further found that salicylate increased the number of Ca2+ channels along with CaV1.3 expression. All these changes could act synergistically to enhance the Ca2+ influx into IHCs. Inhibition of intracellular Ca2+ overload significantly attenuated IHC death after 10 mmol/L salicylate treatment. These results implicate a cellular mechanism for tinnitus generation in the peripheral auditory system.

Multicenter real-world study on safety and efficacy of neoadjuvant therapy in combination with immunotherapy for colorectal cancer / 中华胃肠外科杂志

Objective: To provide reference and evidence for clinical application of neoadjuvant immunotherapy in patients with colorectal cancer through multicenter large-scale analysis based on real-world data in China. Methods: This was a retrospective multicenter case series study. From January 2017 to October 2021, data of 94 patients with colorectal cancer who received neoadjuvant immunotherapy in Peking University Cancer Hospital (55 cases), Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (19 cases), Sun Yat-sen University Cancer Center (13 cases) and Changhai Hospital of Navy Medical University (7 cases) were retrospectively collected, including 48 males and 46 females. The median age was 58 years. Eighty-one cases were rectal cancer and 13 cases were colon cancer (2 cases of double primary colon cancer). Twelve cases were TNM staging II and 82 cases were stage III. Forty-six cases were well differentiated, 37 cases were moderately differentiated and 11 cases were poorly differentiated. Twenty-six patients (27.7%) with mismatch repair defects (dMMR) and microsatellite instability (MSI-H) were treated with immunotherapy alone, mainly programmed cell death protein-1 (PD-1); sixty-eight cases (72.3%) with mismatch repair proficient (pMMR) and microsatellite stability (MSS) were treated with immune combined with neoadjuvant therapy, mainly CapeOx (capecitabine+oxaliplatin) combined with PD-1 antibody plus long- or short-course radiotherapy, or PD-1 antibody combined with cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody. Analysis and evaluation of adverse events during neoadjuvant immunotherapy were performed according to the National Cancer Institute Common Toxicity Standard version 3.0; the surgical complications were evaluated according to the Clavien-Dindo grading standard; the efficacy evaluation of neoadjuvant immunotherapy included the following indicators: major pathological remission (MPR) was defined as tumor regression induced by neoadjuvant therapy in pathology residual tumor ≤10%; pathological complete response (pCR) was defined as tumor regression induced by neoadjuvant therapy without residual tumor in pathology; the tumor response rate was disease control rate (DCR), namely the proportion of complete response (CR), partial response (PR) and stable disease (SD) in the whole group; the objective response rate (ORR) was CR+PR. Results: The median cycle of neoadjuvant immunotherapy was 4 (1-10) in whole group, and the incidence of immune-related adverse reactions was 37.2% (35/94), including 35 cases (37.2%) of skin-related adverse reactions, 21 cases (22.3%) of thyroid dysfunction and 8 cases (8.5%) of immune enteritis, of which grade III or above accounted for 1.1%. The median interval between completion of neoadjuvant therapy and surgery was 30 (21-55) days. There were 81 cases of radical resection of rectal cancer, 11 cases of radical resection of colon cancer, and 2 cases of colon cancer combined with other organ resection. The primary tumor resection of all the patients reached R0. The incidence of surgical-related complications was 22.3% (21/94), mainly anastomotic leakage (4 cases), pelvic infection (4 cases), abdominal effusion (3 cases), anastomotic stenosis (3 cases ) and abdominal and pelvic hemorrhage (2 cases). Grade I-II complications developed in 13 cases (13.8%), grade III and above complications developed in 8 cases (8.5%), no grade IV or above complications were found. During a median follow-up of 32 (1-46 ) months, DCR was 98.9% (93/94), ORR was 88.3 % (83/94), pCR was 41.5% (39/94), MPR was 60.6% (57/94). The pCR rate of 26 patients with dMMR and MSI-H undergoing simple immunotherapy was 57.7% (15/26), and MPR rate was 65.4% (17/26). The pCR rate of 68 pMMR and MSS patients undergoing combined immunotherapy was 35.3%(24/68), and MPR rate was 58.8% (40/68). Conclusions: Neoadjuvant immunotherapy has favorable tumor control rate and pathological remission rate for patients with initial resectable colorectal cancer. The incidences of perioperative adverse reactions and surgical complications are acceptable.

Escore de Risco Clínico Simples para Prever a Mortalidade Pós-Alta Hospitalar em Pacientes Chineses Hospitalizados por Insuficiência Cardíaca / A Simple Clinical Risk Score to Predict Post-Discharge Mortality in Chinese Patients Hospitalized with Heart Failure

Resumo Fundamento Doenças cardiovasculares são a principal causa de morte na China. Entretanto, os esforços atuais para se identificar os fatores de risco de morte em pacientes hospitalizados com insuficiência cardíaca (IC) estão direcionados principalmente para a mortalidade durante a internação e a mortalidade após 30 dias nos Estados Unidos. Dessa forma, é necessário um modelo semelhante ao modelo utilizado para prever o risco considerado para procedimentos cirúrgicos cardiovasculares em pacientes para avaliar o risco de pacientes internados com diagnóstico de IC. Objetivo Identificar variáveis que podem prever a mortalidade por IC um ano após a alta hospitalar, e desenvolver um escore de risco para avaliar o risco de morte no período de um ano. Métodos No presente estudo, 1.742 pacientes chineses com IC foram divididos aleatoriamente em dois grupos: um grupo de amostra de derivação e um grupo de amostra de teste. O método de simulação Monte Carlo via Cadeias de Markov foi usado para identificar variáveis que podem prever a mortalidade um ano após a alta hospitalar. Variáveis com uma frequência >1% na análise bivariada, e que foram consideradas clinicamente significativas, foram qualificadas para análises de modelagens posteriores. A probabilidade posterior de que uma variável estava estatística e significativamente associada ao resultado foi calculada como o número total de vezes em que o IC de 95% da variável não coincidiu com 1 (ou seja, o ponto de referência), dividido pelo número total de iterações. Uma variável com uma probabilidade de 0,9 ou mais alta foi considerado um fator de risco robusto para prever o resultado, e foi incluída na lista final de variáveis. O nível de significância estatística adotado foi 5%. Resultados Cinco variáveis que pudessem prever de maneira robusta a mortalidade um ano após a alta hospitalar foram identificadas: idade, sexo feminino, escore da New York Heart Association (Associação de Cardiologia de Nova Iorque) >3, diâmetro do átrio esquerdo, e índice de massa corporal. Os modelos de derivação e de teste tiveram uma área de curva característica de operação do receptor de 0,79. Essas variáveis selecionadas foram utilizadas para avaliar o escore de risco de mortalidade por IC após um ano, e este foi dividido em três grupos (baixo, moderado e alto). O grupo de alto risco corresponde a aproximadamente 86% das mortes, e o grupo de risco moderado corresponde a 12% das mortes. Conclusão Um escore de risco de 5 variáveis simples pode ser utilizado para avaliar a mortalidade um ano após a alta hospitalar de pacientes internados com IC.

Abstract Background Cardiovascular diseases are the leading causes of death in China. However, present efforts to identify the risk factors for death in patients hospitalized with heart failure (HF) are primarily focused on in-hospital mortality and 30-day mortality in the United States. Thus, a model similar to the model used for predicting the risk in patients considered for cardiovascular surgical procedures is needed to evaluate the risk of the patients admitted with a diagnosis of HF. Objective To identify variables that can predict post-discharge one-year HF mortality and develop a risk score to assess the risk of dying within one year. Methods In the present study, 1,742 Chinese patients with HF were randomly divided into two groups: a derivation sample group and a test sample group. A Markov Chain Monte Carlo simulation method was used to identify variables that can predict the one-year post-discharge mortality. Variables with a frequency of >1% in the bivariate analysis and that were considered clinically meaningful were eligible for further modeling analyses. The posterior probability that a variable was statistically and significantly associated with the outcome was calculated as the total number of times that the variable's 95% CI did not overlap with 1 (i.e., the reference point) divided by the total number of iterations. A variable with a probability of 0.9 or higher was considered a robust risk factor for predicting the outcome, and this was included in the final variable list. The level of statistical significance adopted was 5%. Results Five variables that could robustly predict the one-year post-discharge mortality were identified: age, female gender, New York Heart Association functional classification score >3, left atrial diameter, and body mass index. Both derivation and test models had a receiver operating curve area of 0.79. These selected variables were used to assess the one-year HF mortality risk score, and these were divided into three groups (low, moderate, and high). The high-risk group corresponds to nearly 86% of the deaths, while the moderate group corresponds to 12% of the deaths. Conclusion A simple 5-variable risk score can be used to assess the one-year post-discharge mortality of hospitalized Chinese patients with HF.

Collagen derived species-specific peptides for distinguishing donkey-hide gelatin (Asini Corii Colla) / 中草药·英文版

Objective: As an important food therapy product with traditional Chinese medicine (TCM) applications, donkey-hide gelatin (Asini Corii Colla, ACC) has been used for thousands of years. However, till now few effective strategy had been proposed to distinguish ACC from other animal hide gelatins, especially closely related horse- and mule-hide gelatins, which was an embarrassment of ACC quality control. Methods: Combined mass spectrometry and bioinformatic methods have been applied to identify and verify two ACC-specific peptides (Pep-1 and Pep-2) capable of distinguishing ACC from other closely related animal gelatins with high selectivity. Results: It confirmed that these two peptides could be not only used for distinguishing ACC from highly homologous horse-hide and mule-hide gelatins as well as other animal hide gelatins. Conclusion: The present study provides a simple method for species-specific peptides discovery, which can be used for assessing the quality of animal gelatin products, and ensure they are authenticable and traceable.

Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors / 中华胃肠外科杂志

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.

From rural practice to national strategy for colorectal cancer screening in China--Mr. Zheng Shu who is a pioneer and practitioner / 中华胃肠外科杂志

Haining City and Jiashan County in Zhejiang Province are the first areas to carry out colorectal cancer screening in China, which started in the early 1970s and has been going on for more than 40 years. Meanwhile, Haining and Jiashan have also become the first batch of National Demonstration Bases for Early Diagnosis and Treatment of Colorectal Cancer. In the past 40 years, owing to Professor Zheng Shu who is brave and innovative, with an indomitable spirit, as well as the unremitting efforts and active exploration of all the team members, colorectal cancer screening which was unknown by the public and implemented with difficulties, has gradually been widely accepted and benefited the population. Today, remarkable achievements have been fulfilled in the colorectal cancer screening of Haining and Jiashan which has become the pioneer power in promoting the progress of colorectal cancer prevention and control in China and has certain influence both on China and the world. Meanwhile, a set of colorectal cancer screening strategies suitable for China has been explored and further promoted to be used nationwide, which is of great significance to the prevention and control of colorectal cancer in China. Looking forward to the future, the prevention and control of colorectal cancer in China is still difficult. We will continue to give full play to our existing advantages, not forget our original intention, move forward, explore innovation, and create greater glories!