Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Analysis of the suspected cases of measles and rubella in Pudong New Area of Shanghai， 2013‒2022 / 上海预防医学

ObjectiveTo analyze the epidemic characteristics of measles and rubella in Pudong New Area of Shanghai from 2013 to 2022， and to provide data support for the elimination of measles and rubella. MethodsEnzyme linked immunosorbent assay was used to detect IgM antibodies in serum samples. The sequence of 630 nucleotides at the C-terminal of N gene of measles virus was amplified by reverse transcription-polymerase chain reaction and the phylogenic tree was constructed. ResultsA total of 1 529 suspected cases of measles were detected from 2013 to 2022， among which the positive rate of measles IgM antibody was 33.55% （513/1 529）. The highest positive rate （20.73%） was from March to May ， and the positive rate of rubella IgM antibody was 6.80% （104/1 529）. The positive rate of both IgM was higher in males than that in females （P<0.05）. The IgM against measles was mainly detected in 0‒ years old （63.16%， 96/152） and 20‒ years old （45.61%， 161/353）. The IgM against rubella was mainly detected in 10‒20 years old （27.27%， 18/66）. The IgM antibody could be detected more easily from 4 to 28 days after eruption， and the IgM antibody positive rate of measles/rubella from 2020 to 2022 was significantly lower than previous years （2013‒2019）. There were 2 D8 genotype strains， and the rest were H1a gene subtypes. ConclusionThe positive rate of IgM antibodies against measles/rubella in Pudong New Area of Shanghai decreased significantly. People aged 0‒ years and 20‒ years old are more susceptible to measles， and rubella is concentrated in 10‒ years old. It is necessary to strengthen the vaccination of school-age children， in order to achieve the goal of eliminating measles. The age group with high risk of exposure should be checked for vaccination status to ensure the enhanced immunization， and the surveillance of imported measles cases should be strengthened.

Analysis of detection of acute respiratory infection in children under 12 years old in Pudong New Area， Shanghai from 2019 to 2023 / 上海预防医学

ObjectiveTo investigate the impact of acute respiratory infections in children under 12 years old in Pudong New Area， Shanghai from 2019 to 2023. MethodsAcute respiratory infection samples of children under 12 years old from three sentinel hospitals in Pudong New Area， Shanghai from 2019 to 2023 were collected， and 42 respiratory infection pathogens， including influenza virus， adenovirus， parainfluenza virus， respiratory syncytial virus， human enterovirus/rhinovirus， human pulmonary virus， human bokavirus， coronavirus （229E， HKU1， NL63 and OC43）， and novel coronavirus， were detected with microfluidic chips. The situation of acute respiratory infections among outpatient and inpatient children in this area was analyzed for the before the implementation of non pharmacological intervention measures （2019.12‒2020.1）， during the period of non pharmacological intervention measures （2020.2‒2022.12）， and after non pharmacological intervention measures （2023.1‒2023.6）. ResultsFrom 2019 to 2023， a total of 1 770 samples were collected， and 445 pathogens were detected， with a detection rate of 25.14% （445/1 770）. The main pathogens detected during the study period were influenza virus： 8.70% （154/1 770）， respiratory syncytial virus： 4.41% （78/1 770）， human enterovirus/rhinovirus： 2.66% （47/1 770）， human adenovirus： 2.49% （44/1 770）， and parainfluenza virus： 2.20% （39/1 770）. Before the implementation of non pharmacological intervention measures， outpatients were primarily infected with influenza， parainfluenza virus， and respiratory syncytial virus， with detection rates of 8.09%， 4.49%， and 4.04%， respectively； inpatients were mainly infected with influenza， respiratory syncytial virus， and parainfluenza virus， with detection rates of 4.49%， 3.82%， and 3.15%， respectively. During the period of non pharmacological intervention measures， influenza， rhinovirus and respiratory syncytial virus were the main viruses detected in the samples of outpatient children， with detection rates of 4.04%， 3.60%， and 2.47%， respectively； inpatient samples mainly detected respiratory syncytial virus， rhinovirus， and influenza virus， with detection rates of 3.60%， 2.02%， and 1.80%， respectively. After non pharmacological intervention measures， influenza， rhinovirus and respiratory syncytial virus were the main pathogens detected in the outpatients， with detection rates of 9.89%， 2.92% and 2.02%， respectively； influenza， respiratory syncytial virus， and rhinovirus were the main pathogens detected in inpatient children， with detection rates of 6.29%， 1.57%， and 1.35%， respectively. ConclusionThe prevalence of pathogens related to acute respiratory infections in children is influenced by non pharmacological preventive measures.

Serotypes and drug resistance of salmonella in commercial food in Pudong New Area from 2020 to 2022 / 上海预防医学

ObjectiveTo understand the serotype distribution and drug resistance of salmonella contaminated in commercially available food. MethodsSalmonella detection， including the serotypes， was conducted in food products sold in Pudong New Area from 2020 to 2022. The antimicrobial susceptibility test of 15 antibiotics was conducted by the broth microassay. ResultsA total of 118 salmonella strains were detected in 2 497 pieces of food， with a total detection rate of 4.7%. The dominant detection categories were poultry meat， livestock meat and aquatic products. The 118 salmonella strains could be divided into 24 serotypes， Salmonella enteritidis （26.4%）， Salmonella Typhimurium （16.2%） and Salmonella delpy （14.4%） were the main dominant types. Salmonella had the highest resistance rate to ampicillin （63.6%）， followed by tetracycline， chloramphenicol， cotrimoxazole and nalidixic acid. Among the three dominant serotypes， the multidrug resistance rate of Salmonella typhimurium was the highest （89.5%）， followed by Salmonella delpy （70.6%） and Salmonella enteritidis （61.3%）. ConclusionLivestock， poultry meat， and aquatic products are seriously contaminated by salmonella with diverse serotypes. The livestock meat is mainly contaminated by Salmonella typhimurium and Salmonella delpy， and the poultry meat is mainly contaminated by Salmonella enteritidis. The drug resistance spectrum is wide and the multi-drug resistance rate is high. Different from the livestock and aquatic isolates， poultry meat-derived strains have high tolerance to ampicillin， nalidixic acid and polymyxin， and carry certain potential food safety risks.

Epidemiological analysis on the norovirus detection based on diarrhea syndromic surveillance in Pudong , Shanghai ,2012—2016 / 中华传染病杂志

Objective To understand the epidemiological characteristics of norovirus detection based on the diarrhea syndromic surveillance in Pudong ,Shanghai .Methods Diarrhea syndromic surveillance program was conducted in outpatient and emergency departments of 12 sentinel hospitals during 2012 -2016 .The clinical and epidemiological data of diarrheal patients were collected .The fecal specimens were also sampled . The detections for norovirus by polymerase chain reaction and gene sequencing were performed .Chi-square test or Fisher exact probability test was used to compare the detection rate .Binary logistic regression was used to explore the impact factors of norovirus infection among diarrheal patients . Results The detective rate of norovirus among diarrheal patients was 21 .59％ ,peaking from October to next March .Among all the age groups ,the detection rate was highest among patients with 25 - 64 years old .The patients with more severe diarrhea symptoms (> 5 times a day) were more likely to be infected with norovirus than those with diarrhea 3 - 5 times a day (χ2 = 21 .167 ,P< 0 .01) .Vomiting was also an indicator of norovirus infection .Patients presented with vomiting had a higher norovirus detection rate (χ2 = 198 .543 , P < 0 .01) . Norovirus G Ⅱ was the predominant genotype .Conclusions The recent epidemic of norovirus infection in diarrheal patients in Pudong new district has an apparent seasonality peaked from October to next March .Adult ,patients with vomiting and more severe diarrhea symptoms are at risk of norovirus infection .The long-term surveillance is critical for the norovirus infection control .

The analysis of influencing factors of emergency death in multiple trauma patients / 天津医药

Objective To analyze the related factors and the independent risk factors of death in patients with multiple injuries. Methods Data of 651 patients with multiple injuries treated in our hospital from June 2012 to June 2015 were retrospectively analyzed. According to the outcomes, patients were divided into effective group (n=608) and death group (n=43). Data of gender, age, cause of injury, the primary diseases related with the trauma, ISS score, number of trauma, time from injury to the treatment and the body parts of injury were compared between two groups. Logistic regression analysis was used to analyze the risk factors of death in multiple trauma patients. Results The proportion of patients≥60 years old, ISS score≥16 points, the number of trauma≥4, a major brain injury and time of trauma to the treatment ≥3 h were higher in death group than those of effective group (P<0.05). The independent risk factors for emergency death in multiple injuries included patients≥60 years old, major brain injury, ISS score ≥16 points and time of trauma to the treatment ≥ 3 h. The cause of death in patients with craniocerebral trauma (cerebral laceration) accounted for up to 27.91%(n=12), intracranial hematoma accounted for 20.93% (n=9), and traumatic hemothorax accounted for 11.63% (n=5). Conclusion The related factors and independent risk factors should be paid attention to doctors in emergency department, and the emergency plan should be made to reduce the death rate of emergency patients with multiple injuries.

A comparative study of laparoscopic neoplasty and open neoplasty on levels of procalcitonin and cell-mediated immunity in elderly patients with upper digestive tract ulcer perforation / 天津医药

Objective To study the effect of laparoscopic neoplasty and changes of procalcitonin (PCT) and cell-mediated immunity in elderly patients with duodenal ulcer perforation. Methods Forty-four elderly patients with duodenal ulcer perforation were divided into laparoscopic neoplasty group (n=20) and open neoplasty group (n=24).The level of PCT was assayed by colloid immunization. Blood levels of CD3+, CD4+, CD8+and natural killer (NK) cells were detected by flow cytometry before operation and at 0.5 h, 24 h, 48 h and the 7th day after operation.Surgical complications and postoperative hospital stay were observed in two groups. Results There was no significant difference in the activity of PCT before operation between two groups. There were no significant differences in CD3+, CD4+, CD8+ and NK cells 0.5 h before operation between two groups. The level of PCT was significantly lower at 24 h and 48 h after operation in laparoscopic group than that in open operation group (P<0.05). There were significant differences in the serum levels of CD3+, CD4+, CD8+and NK cells with time changes in two groups (P<0.05). There were significant decreases in CD3+, CD4+and CD8+at 24 h after operation than those before operation in two groups, which were significantly lower in open operation group than those of laparoscopic group except for CD8+. The levels of CD3+, CD4+and CD8+recovered to the levels before operation at 48 h after operation in laparoscopic group. In open operation group CD3+did not return to the level before operation at 7 d after operation. The levels of NK cells were decreased at 24 h after operation in two groups, but there was no significant difference in the level of NK cells between two groups. The level of NK cells returned to preoperative levels at 48 h after operation in laparoscopic group, while there was no significant difference in the level of NK cells before and after operation in open neoplasty group. Compared with the open neoplasty group, there were fewer complications and shorter hospital stay in laparoscopic group. Conclusion The laparoscopic repair operation for gastric and duodenal ulcer perforation has a fewer effects on the stress response and immune function in elderly patients, and has the advantages in the protection of immune function.

Clinical study of hyperbaric oxygen combining conventional therapy on traumatic brain injury with persistent vegetative state / 中国综合临床

Objective To investigate the efficacy and mechanism of hyperbaric oxygen combining conventional therapy on persistent vegetative state ( PVS).Methods Sixty-two cases of PVS patients were treated with hyperbaric oxygen ( HBO ) combinting with conventional therapy.( 1 ) Hyperbaric oxygen therapy:hyperbaric oxygen chamber was adopted and the air pressure was 0,18 -0.20 MPa.The patients breathed pure oxygen for 30 min,2 times per day with a 10 min interval,and continued for 10 days as a course with an average of 4 to 6 courses.(2)Conventional therapy:All patients received drug treatment in hyperbaric oxygen therapy at the same time,including hemostasis,dehydration,anti-infection,nerve cell nutrition agents,wake promoting agents and supportive therapy.All patients were divided to three groups according to the course of disease:26 - 59 days in A group,60-119 days in B group,120 -268 days in C group,and the relationship between disease course and HBO treatment efficacy was analyzed.Results Afer HBO combining conventional therapy,27 cases (43.5％) were recovered,18 cases(29.0％ ) had obvious effect,8 cases( 12.9％ ) had effect,9 cases( 14.5％ )were inefficacy.The efficiency related to the course of disease.The total efficiency rate was 85.5％.The efficacy of HBO treatment had significant difference in A,B and C group ( 96.2％,62.5％ and 41.7％ in A,B and C group respectively,x2 =24.83,P ＜ 0.01 ).The shorter course indicated the better efficacy.Conclusion Hyperbaric oxygen combining conven.

Extensions of PDZ domains as important structural and functional elements

'Divide and conquer' has been the guiding strategy for the study of protein structure and function. Proteins are divided into domains with each domain having a canonical structural definition depending on its type. In this review, we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function; we call these regions 'extensions'. We focus on the highly abundant PDZ (PSD-95, DLG1 and ZO-1) domain. Using bioinformatics, we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results ( http://bcz102.ust.hk/pdzex/ ). We propose, using well-studied PDZ domains as illustrative examples, that the roles of PDZ extensions can be classified into at least four categories: 1) protein dynamics-based modulation of target binding affinity, 2) provision of binding sites for macro-molecular assembly, 3) structural integration of multi-domain modules, and 4) expansion of the target ligand-binding pocket. Our review highlights the potential structural and functional importance of domain extensions, highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

Expression and significance of Ezrin and ICAM-1 in gastric carcinoma / 中国综合临床

Objective To investigate the expression and significance of Ezrin and ICAM-1 in gastric carci- noma.Methods The expression of Ezrin and ICAM-1 were examined by S-P immunohistochemistry assays in 78 ca- ses of gastric carcinoma.30 cases of nonmalignant tissue and 30 cases of normal stomach.The relationship between them and their pathological characteristics were analyzed.Results ①The expression rates of Ezrin and ICAM-1 were obviously higher in carcinoma group than that of nonmalignant group and normal group(P<0.01),in the lym- phatic metastasis group than that in non lymphatic metastasis group(P<0.05),and in T3.T4 group and than that in T1,T2 group(P<0.05).②The expression level of ICAM-1 was positively related with that of Ezrin(r=0.46. P=0.00).③The test of the expression of Ezrin and ICAM-1 simutaniously could obviously increase the sensitivity and specificy for detecting the metastasis of stomach malignant tumor(P<0.05).Condusion The over expression of Ezrin and ICAM-1 is related to the pathogenesis and invasion as well as metastasis of stomach carcinoma.The combined detection of two markers can obviously increase the sensitivity and specificy for predicting metastasis of stomach carcinoma.

Effects of different methods of anesthesia and analgesia on early postoperative cognitive dysfunction after non-cardiac surgery in the elderly / 北京大学学报(医学版)

Objective: To determine if different methods of anesthesia and analgesia will influence the incidence of early postoperative cognitive dysfunction (POCD) after non-cardiac surgery in the elderly. Methods: One hundred and three elderly patients undergoing elective abdominal surgery were randomly allocated to receive either general anesthesia followed with postoperative intravenous analgesia (general anesthesia group, 53 cases) or combined general-epidural anesthesia followed with postoperative epidural analgesia (combined general-epidural anesthesia group, 50 cases). Cognitive function was assessed preoperatively and 7 days postoperatively using a battery of nine neuropsychological tests. A postoperative deficit in any test was defined when decline by more than or equal to 20% of the preoperative value of that test occurred. Any patient showing deficit in 2 or more tests was defined as having postoperative cognitive dysfunction. Results: Ninety-two patients completed both preoperative and postoperative neuropsychological tests. On day 7, POCD occurred in 20/45 patients (44.4%) in the general anesthesia group and in 23/47 patients (48.9%) in the combined general-epidural anesthesia group. No significant difference was found between the two groups. Logistic regression analysis showed that short duration of education and operation of general surgery were independent risk factors of the occurrence of early POCD. Conclusion: Early POCD occurred in 46.7% of the elderly patients undergoing abdominal surgery. However, there was no significant difference between the effects of two different methods of anesthesia and postoperative analgesia on the incidence of POCD. Short duration of education and operation of general surgery were risk factors of early POCD.

The expression of cyclin G in gastric carcinoma and its significance / 中国普通外科杂志

Objective To investigate the expression of cyclin G1、cyclin G2 in gastric carcinoma and its significance. Methods The mRNA expression of cyclin G1、cyclin G2 in 55 cases of gastric carcinoma was measured with RT-PCR. The protein expression of cyclin G1 and cell cycle were detected by flow cytometry.Results Expression rate of cyclin G1 in gastric carcinoma was 58%,which was higher than that in normal tissue(P

The Inhibitory Effect of VEGF Antisense RNA on the Growth of Esophageal Cancer Cells in vitro / 中国肿瘤生物治疗杂志

Objective: To investigate the inhibitory effect of VEGF antisense RNA on the growth of human esophageal cancer cells in vitro, in order to further investigate the feasibility of VEGF antisense RNA gene therapy of esophageal cancer. Methods: The plasmid carrying with VEGF antisense cDNA was transfected into esophageal cancer cells, and confirmed its expression by RT-PCR. The expression level of VEGFmRNA and VEGF protein was examined in antisense group by insitu hybridization and immunohistochemistry staining. The cell growth rate was detected by MTT assay. Apoptotic rate in transfected cells was detected by FCM assay. Results: The expression of exogenous antisense VEGFmRNA was confirmed in transfected cells, and the VEGF protein and endogenous VEGFmRNA were dramatically decreased. The growth rate of transfected cells was not inhibited. Apoptotic cells were not found in transfected cells. Latent period of the tumor formation of the antisense group was lengthened, while body weight, volume of tumors was significantly smaller than that of empty vector group and control group. Conclusions: VEGF antisense RNA could decrease the expression of VEGF of e-sophageal cancer and cell proliferation in vivo, which may apply a useful theory basis for gene therapy of esophageal canc-er.