The dichotomous role of immunoproteasome in cancer: Friend or foe?

Immunoproteasome is a variant of proteasome with structural differences in 20S subunits optimizing them for the production of antigenic peptides with higher binding affinity to major histocompatibility complex (MHC)-I molecules. Apart from this primary function in antigen presentation, immunoproteasome is also responsible for the degradation of proteins, both unfolded proteins for the maintenance of protein homeostasis and tumor suppressor proteins contributing to tumor progression. The altered expression of immunoproteasome is frequently observed in cancers; however, its expression levels and effects vary among different cancer types exhibiting antagonistic roles in tumor development. This review focuses on the dichotomous role of immunoproteasome in different cancer types, as well as summarizes the current progression in immunoproteasome activators and inhibitors. Specifically targeting immunoproteasome may be a beneficial therapeutic intervention in cancer treatment and understanding the role of immunoproteasome in cancers will provide a significant therapeutic insight for the prevention and treatment of cancers.

Rapid and Accurate Identification of SARS-CoV-2 Omicron Variants Using Droplet Digital PCR (RT-ddPCR)

BackgroundMutations in the receptor binding domain of the SARS-CoV-2 Spike protein are associated with increased transmission or substantial reductions in vaccine efficacy, including in the recently described Omicron variant. The changing frequencies of these mutations combined with their differing susceptibility to available therapies have posed significant problems for clinicians and public health professionals. ObjectiveTo develop an assay capable of rapidly and accurately identifying variants including Omicron in clinical specimens to enable case tracking and/or selection of appropriate clinical treatment. Study DesignUsing three duplex RT-ddPCR reactions targeting four amino acids, we tested 419 positive clinical specimens from February to December 2021 during a period of rapidly shifting variant prevalences and compared genotyping results to genome sequences for each sample, determining the sensitivity and specificity of the assay for each variant. ResultsMutation determinations for 99.7% of detected samples agree with NGS data for those samples, and are accurate despite wide variation in RNA concentration and potential confounding factors like transport medium, presence of additional respiratory viruses, and additional mutations in primer and probe sequences. The assay accurately identified the first 15 Omicron variants in our laboratory including the first Omicron in Washington State and discriminated against an S-gene dropout Delta specimen. ConclusionWe describe an accurate, precise, and specific RT-ddPCR assay for variant detection that remains robust despite being designed prior to the emergence of Delta and Omicron variants. The assay can quickly identify mutations in current and past SARS-CoV-2 variants, and can be adapted to future mutations.

WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

Development and validation of caregivers′knowledge-attitude-practice scale on safety precautions of children′s falling from bed in hospital / 中国实用护理杂志

Objective:To develop a scale of caregivers′ knowledge, attitude and practice (KAP) on safety precautions of children′s falling from bed in hospital, and test its reliability and validity.Methods:Based on the theory of KAP, the item pool was constructed by literature review and expert consultation. A convenient sampling method was used to investigate 380 caregivers of children admitted to Shanghai Children′s Medical Center, School of Medicine, Shanghai Jiao Tong University in May 2021. The reliability and validity of the scale was tested. Critical ratio method and correlation analysis method were used for item analysis of the scale. Validity analysis was conducted by detecting content validity and construct validity; reliability analysis was conducted by detecting internal consistency reliability and split-half reliability.Results:The formal scale finally developed comprised 17 items in 3 dimensions on knowledge, attitude and practice. The Cronbach′s α coefficient and split-half reliability of the overall scale were 0.739 and 0.841. The content validity of the scale was 0.991, and the content validity of each item was 0.890-1.000. Exploratory factor analysis has extracted 3 common factors, and the cumulative variance contribution rate was 60.57%.Conclusion:The scale of caregivers′ KAP on safety precautions of children′s falling from bed in hospital has good reliability and validity, and can be used as a tool to evaluate the knowledge, willingness or behavior of caregivers' participation in preventing falls.

Anti-SARS-CoV-2 antibody levels are concordant across multiple platforms but are not fully predictive of sterilizing immunity

With the availability of widespread SARS-CoV-2 vaccination, high-throughput quantitative anti-spike serological testing will likely become increasingly important. Here, we investigated the performance characteristics of the recently FDA authorized semi-quantitative anti-spike AdviseDx SARS-CoV-2 IgG II assay compared to the FDA authorized anti-nucleocapsid Abbott Architect SARS-CoV-2 IgG, Roche elecsys Anti-SARS-CoV-2-S, EuroImmun Anti-SARS-CoV-2 ELISA, and GenScript surrogate virus neutralization assays and examined the humoral response associated with vaccination, natural protection, and breakthrough infection. The AdviseDx assay had a clinical sensitivity at 14 days post-symptom onset or 10 days post PCR detection of 95.6% (65/68, 95% CI: 87.8-98.8%) with two discrepant individuals seroconverting shortly thereafter. The AdviseDx assay demonstrated 100% positive percent agreement with the four other assays examined using the same symptom onset or PCR detection cutoffs. Using a recently available WHO International Standard for anti-SARS-CoV-2 antibody, we provide assay unit conversion factors to international units for each of the assays examined. We performed a longitudinal survey of healthy vaccinated individuals, finding median AdviseDx immunoglobulin levels peaked seven weeks post-first vaccine dose at approximately 4,000 IU/mL. Intriguingly, among the five assays examined, there was no significant difference in antigen binding level or neutralizing activity between two seropositive patients protected against SARS-CoV-2 infection in a previously described fishing vessel outbreak and five healthcare workers who experienced vaccine breakthrough of SARS-CoV-2 infection - all with variants of concern. These findings suggest that protection against SARS-CoV-2 infection cannot currently be predicted exclusively using in vitro antibody assays against wildtype SARS-CoV-2 spike. Further work is required to establish protective correlates of protection for SARS-CoV-2 infection.

Specific allelic discrimination of N501Y and other SARS-CoV-2 mutations by ddPCR detects B.1.1.7 lineage in Washington State

Real-time epidemiological tracking of variants of interest can help limit the spread of more contagious forms of SARS-CoV-2, such as those containing the N501Y mutation. Typically, genetic sequencing is required to be able to track variants of interest in real-time. However, sequencing can take time and may not be accessible in all laboratories. Genotyping by RT-ddPCR offers an alternative to sequencing to rapidly detect variants of concern through discrimination of specific mutations such as N501Y that is associated with increased transmissibility. Here we describe the first cases of the B.1.1.7 lineage of SARS-CoV-2 detected in Washington State by using a combination of RT-PCR, RT-ddPCR, and next-generation sequencing. We screened 1,035 samples positive for SARS-CoV-2 by our CDC-based laboratory developed assay using ThermoFishers multiplex RT-PCR COVID-19 assay over four weeks from late December 2020 to early January 2021. S gene dropout candidates were subsequently assayed by RT-ddPCR to confirm four mutations within the S gene associated with the B.1.1.7 lineage: a deletion at amino acid (AA) 69-70 (ACATGT), deletion at AA 145, (TTA), N501Y mutation (TAT), and S982A mutation (GCA). All four targets were detected in two specimens, and follow-up sequencing revealed a total of 10 mutations in the S gene and phylogenetic clustering within the B.1.1.7 lineage. As variants of concern become increasingly prevalent, molecular diagnostic tools like RT-ddPCR can be utilized to quickly, accurately, and sensitively distinguish more contagious lineages of SARS-CoV-2.

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

The development of vaccines against SARS-CoV-2 would be greatly facilitated by the identification of immunological correlates of protection in humans. However, to date, studies on protective immunity have only been performed in animal models and correlates of protection have not been established in humans. Here, we describe an outbreak of SARS-CoV-2 on a fishing vessel associated with a high attack rate. Predeparture serological and viral RT-PCR testing along with repeat testing after return to shore was available for 120 of the 122 persons on board over a median follow-up of 32.5 days (range 18.8 to 50.5 days). A total of 104 individuals had an RT-PCR positive viral test with Ct <35 or seroconverted during the follow-up period, yielding an attack rate on board of 85.2% (104/122 individuals). Metagenomic sequencing of 39 viral genomes suggested the outbreak originated largely from a single viral clade. Only three crewmembers tested seropositive prior to the boats departure in initial serological screening and also had neutralizing and spike-reactive antibodies in follow-up assays. None of these crewmembers with neutralizing antibody titers showed evidence of bona fide viral infection or experienced any symptoms during the viral outbreak. Therefore, the presence of neutralizing antibodies from prior infection was significantly associated with protection against re-infection (Fishers exact test, p=0.002).

Comparative Performance of SARS-CoV-2 Detection Assays using Seven Different Primer/Probe Sets and One Assay Kit

More than 100,000 people worldwide are known to have been infected with SARS-CoV-2 beginning in December 2019. The virus has now spread to over 93 countries including the United States, with the largest cluster of US cases to date in the Seattle metropolitan area in Washington. Given the rapid increase in the number of local cases, the availability of accurate, high-throughput SARS-CoV-2 testing is vital to efforts to manage the current public health crisis. In the course of optimizing SARS-CoV-2 testing performed by the University of Washington Clinical Virology Lab (UW Virology Lab), we tested assays using seven different primer/probe sets and one assay kit. We found that the most sensitive assays were those the used the E-gene primer/probe set described by Corman et al. (Eurosurveillance 25(3), 2020, https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000045) and the N2 set described by the CDC (Division of Viral Diseases, Centers for Disease Control and Prevention, 2020, https://www.cdc.gov/coronavirus/2019-ncov/downloads/rt-pcr-panel-primer-probes.pdf). All assays tested were found to be highly specific for SARS-CoV-2, with no cross-reactivity with other respiratory viruses observed in our analyses regardless of the primer/probe set or kit used. These results will provide invaluable information to other clinical laboratories who are actively developing SARS-CoV-2 testing protocols at a time when increased testing capacity is urgently needed worldwide.

The analysis of sensitivity and specificity of Humpty Dumpty pediatric fall assessment tool for hospitalized children / 中国实用护理杂志

Objective@#To determine the sensitivity and specificity of the Humpty Dumpty Fall Scale (HDFS) in predicting the falls in hospitalized children.@*Methods@#A retrospective matched case-control study was conducted. A chart review of 52 pediatric cases who fell and 52 controls who did not fall, were pair-matched by age, gender and diagnosis and matching ratio of 1∶1. The HDFS was used to evaluate the risk factors.@*Results@#The area of the ROC curve was 0.610. When the cutoff point of HDFS was 16, the sensitivity of it was 0.558, and the specificity was 0.635. There was a significant difference in two groups when the cutoff point was 13 (P<0.05), the score in fall case and non-fall case was (15.77 ± 1.46), (15.22 ± 1.21) points.@*Conclusions@#The HDFS can identify high risk of falls in hospitalized children in some degree. The optimal operating point is 13. The theoretical diagnostic value of the scale is at a low level. Further research is needed to verify or to improve the assessment tool that contribute to fall reduction.

The analysis of sensitivity and specificity of Humpty Dumpty pediatric fall assessment tool for hospitalized children / 中国实用护理杂志

Objective To determine the sensitivity and specificity of the Humpty Dumpty Fall Scale (HDFS) in predicting the falls in hospitalized children. Methods A retrospective matched case-control study was conducted. A chart review of 52 pediatric cases who fell and 52 controls who did not fall, were pair-matched by age, gender and diagnosis and matching ratio of 1∶1. The HDFS was used to evaluate the risk factors. Results The area of the ROC curve was 0.610. When the cutoff point of HDFS was 16, the sensitivity of it was 0.558, and the specificity was 0.635. There was a significant difference in two groups when the cutoff point was 13 (P<0.05), the score in fall case and non-fall case was (15.77 ± 1.46), (15.22 ± 1.21) points. Conclusions The HDFS can identify high risk of falls in hospitalized children in some degree. The optimal operating point is 13. The theoretical diagnostic value of the scale is at a low level. Further research is needed to verify or to improve the assessment tool that contribute to fall reduction.

The diagnosis value and prognosis analysis of systematic ultrasound examination in fetal lung disease / 中国医师杂志

Objective To explore the clinical significance and diagnosis value of ultrasonography for fetal lung disease.Methods A total of 61 cases of fetal lung disease was diagnosed and the data were retrospectively analyzed.Results In the 61 fetus of lung disease,(1) there were 31 fetuses with congenital cystic adenomatoid adenomatoid malforamation (CCAM),the ultrasound found that there were mass in fetus lung,they were mixed echo or large cyst or more little cyst or a hyperechoic in the mass.Among them,there were 2 cases of type Ⅰ,16 cases of type Ⅱ,and 13 cases of type Ⅲ;21 cases were labored,who were CCAM-confirmed by pathology,3 fetus masses were disappeared,7 cases were CCAM-confirmed with magnetic resonance (MR) after birth.(2) There were 19 fetuses with pulmonary sequestration (PS),the sonography was slightly hyperechoic mass in the lung,including 7 cases of induced labor and confirmed by pathology as PS,and 4 cases of mass disappeared,8 cases confirmed by MR or computed tomography (CT) after birth.(3) There were 6 cases of congenital diaphragmatic hernia,the abdomnial viscera was seen in the chest,5 cases were induced labor,and 1 survived after operation.(4) There were 5 cases of pleural effusion (PE),4 cases were induced labor and 1 case of PE disappeared.Conclusions Systemic prenatal ultrasonographic examination is an reliable method which can be short-term follow-up to observe the progress and the outcome,and to provide valuable information for clinical prognosis.

Accelerating the professional clinical research team building in the process of transforming towards research-oriented hospitals / 上海交通大学学报（医学版）

Building a professional clinical research team inside hospitals is in favor improving their research abilities,accelerating the clinical discipline construction,improving their comprehensive influence.Also it fits the objective of general hospital development under gate-keeping system.Now in domestic,the percentage of professional research staff in large hospitals accounts was much less than the international level.The main reasons included the misunderstanding of constructing the research-oriented hospitals,insufficient human resources enrollment,less attractive environment to the highlevel researchers and the absence of relevant degree training programs.To enhance the construction of research-oriented hospitals,it's of key importance to build the professional research team in hospitals.Besides,the hospital has to update management conception,broaden the channels of talent cultivation,grasp the development of the subject accurately and interact with the basic medicine and public health subject,increase the financial investment and perfect the relevant management regulations.

Effect of fluvastatin on the expressions of caspase-12, CHOP and JNK in ischemia-reperfusion brain injury in rats / 中国医师杂志

Objective To investigate the effect of fluvastatin on the expressions of caspase-12,CCAAT/enhancer-binding protein homologous protein(CHOP), and c-Jun N-terminal kinases (JNK) in ischemia-reperfusion brain injury in rats.Methods Forty two rats were randomly divided into sham operation group (6 rats), ischemia-reperfusion (I/R) group (18 rats), and fluvastatin (Flu) group (18 rats).The rats of I/R and Flu groups were molded by modified Longa intraluminal thread, then put to death at 2 h occlusion and 24 h reperfusion point.Expressions of caspase-12, CHOP, and JNK were detected with immunohistochemistry and Western blot.Results Immunohistochemistry and Western blot showed that the expressions of caspase-12, CHOP, and JNK were increased at 24 h reperfusion.Compared to I/R group, the expressions of caspase-12 and CHOP in Flu group were decreased significantly (all P ＜0.01);and the expression of JNK had no difference between I/R and Flu groups(P ＞ 0.05).Conclusions The increased expression of caspase-12, CHOP, and JNK showed that endoplasmic reticulum stress was involved in the pathological process of ischemia-reperfusion brain injury.Fluvastatin could inhibit the expression of caspase12 and CHOP, and could delete endoplasmic reticulum stress (ERS) in ischemia-reperfusion brain injury.

Study of cerebrovascular reserve capacity in obstructive sleep apnea-hypopnea syndrome / 中国综合临床

Objective To assess cerebrovascular reserve capacity in patients with obstructive sleep apnea-hypopnea syndrome(OSAHS).Methods One hundred and fourteen patients with OSAHS and 43 normal persons were enrolled in this study.The patients were divided into mild,moderate,severe according to apnea hypopnea index (AHI) and LSaO2 (lowest arterial oxygen saturation).All the patients and normal persons were routinely examined using transcranial Doppler (TCD) and end-tidal carbon dioxide partial pressure(ETCO2) to evaluate cerebrovascular reserve.Hypercapnia was induced by inhaling the CO2 which produced by the patients themselves,and hypocapnia was elicited by voluntary hyperventilation.Results CVR in the severe and moderate OSAHS were significantly lower than that in the control group [ (1.80 ± 1.34) ％/mm Hg and (1.43 ±1.05)％/mm Hg vs (2.93 ±0.93)％/mm Hg,P ＜0.05] when patients in the condition of hypocapnia.And there was no significant difference on CRV between the mild OSAHS group and control group [ (2.53 ±1.83 ) ％/mm Hg vs ( 2.93 ± 0.93 ) ％/mm Hg,P ＞ 0.05 ].When patients in the condition of Hypercapnia,CRV in the severe and moderate OSAHS were also significantly lower than that in the control group [ ( 1.83 ±1.32) ％/mm Hg and (1.08 ± 1.00)％/mm Hg vs (3.32 ± 1.53)％/mm Hg,P ＜ 0.05),AHI was negatively correlated with the cerebrovascular reserve at the condition of hypercapnia and hypocapnia (r=-0.665,-0.721; P ＜ 0.05 ).Conclusion Inhaling CO2 is a effective method for assessing CVR.Cerebrovascular reserve capacity is associated with AHI.Reduced CVR causes hemodynamics change being severe hypoxia in the moderate and severe OSAHS.

The clinical feature and gene mutation of three pedigrees with spinocerebellar ataxia MA / 中国医师杂志

Objective To investigate the clinical features and the gene mutation of patients with spinocerebellar ataxia type3 and type7.Methods The trinucleotide repeat mutations were detected by polymerase chain reaction (PCR),agarose gel electrophoresis method,and DNA sequencing in 13 patients,4 related members and 4 common members from 3 spinocerebellar ataxia families.Results Among the 13 patients,four patients had SCA3/MJD(CAG) n expansion mutation(n = 65 ～ 74),nine patients had SCA7 allele expansion for 40 ～ 52 times.Patients with type 3 or 7 showed significant difference in nervous system injury.Conclusion The difference of clinical feature might be used in diagnosis of SCA3/MJD and SCA7,but genotype determination would be the only method of definite diagnosis.

Ethical dilemma and coping strategies of nurses involving in caring dying patients / 中华护理杂志

Objective To explore nurses' experiences of ethics dilemma and coping strategies involed in caring dying patients. Methods Interviews were conducted with 25 nurses from four different levels of hospitals in Shanghai. Results The ethical dilemmas that participants encountered with were derived from different standpoint and ethics decision-making between "relieve pain" and "extend life span","life value" and "insufficient medical resources","agent execution for patients' rights of being informed consent" and"medical intervention rights". Nurses' coping strategies included patiently communicating with family members to achieve agreement,failing to change family's decision then passively accepting it by self-adjustment,and following hospital rules and regulation or relying on team decision-making. Conclusion The study analyzed and discussed the reasons behind ethical dilemmas,as well as providing some suggestions on how to improve the coping abilities for nurse staffs. It can provide reference and basis for ethical decision-making.

Effect of different anesthesia methods on hemodynamics in gynecological laparoscopic operation / 中国基层医药

Objective To observe the effects of peridural and general anesthesia on haemodynamics in gynecological laparoscopic operation.Methods 106 patients with gynecological laparoscopic operation were randomly divided into epidural anesthesia group(n=53)and general anesthesia group(n=53)respectively.The changes of heart rate(HR),systolic blood pressure(SBP),diastolic blood pressure(DBP),SPO_2 were monitored before anesthesia,at 20min after pneumoperitoneum(pp),end of operation.Results The sober time in epidural anesthrsia geoup(7.1 ±2.5)min was significantly faster than that in general anesthesia group(20.8 ± 6.3)min(t=2.068,P＜0.05).At 20min after pp,HR in general anesthesia group(91 ±17)was significantly faster than that in ppidural anesthesia group before anesthesia(t=2.593,P＜0.05),and it was significantly higher than epidural anesthesia group(t=3.417,P＜0.05).SBP in epidural anesthesia group was singnificantly lower than before anesthesia(t=2.806,P＜0.05),and it was significantly lower than general anesthesia group(t=3.917,P＜0.05).Conclusion General anesthesia does not significantly better than epidural anesthesia in gynecological laparoscopic operation,but they should enhance the clinical monitoring of hemodynamics.

The changes of PECAM-1,Bcl-2 and Bax after focal cerebral ischemia in rats / 中国医师杂志

Objective To observe the changes of PECAM-1,Bcl-2 and Bax expressed by ischemic cerebrum of adult rats after focal cerebral ischemia. Methods Middle cerebral artery occlusion (MCAO) models were made by operation with Longa suture method in Wistar rats. The expression levels of PECAM-1,Bcl-2 and Bax at the 6th,12th,18th,24th,48th,72nd hour after MCAO were detected by immunohistochemistry staining. Results The expression levels of PECAM-1,Bcl-2 and Bax in cerebrum were significantly increased after MCAO. The expression levels of Bcl-2 we、re up to the peak at the 12th hour after MCAO, while the levels of Bax and PECAM-1 were up to the peak at the 24th and 48th hour after MCAO. At the 72nd hour after MCAO, the expression levels of PECAM.1.Bcl-2 and Bax were still higher than that in the control group(all P＜0.001).Conclusions PECAM-1,Bcl-2 and Bax participate in the different pathological stages of focal cerebral ischemia.

Study on risk factors of plasma hyperosmolality in severe stroke / 中华神经科杂志

100 g/d), hypernatremia and hyperglycemia were the three main risk factors resulting in plasma hyperosmolality. The 4-week survival rate of hyperosmolality group(47.1%) was significantly lower than that of non-hyperosmolality group(78.3%, P

Changes of expression of PECAM-1,P-selectin in activated platelet in patients with acute cerebral infarction / 中华神经科杂志

Objective To explore the changes of expression of platelet PECAM-1,P-selectin in patients with acute cerebral infarction.Methods The platelet expression levels of PECAM-1,P-selectin in 35 patients with acute cerebral infarction were serially measured with whole blood flow cytometry 24,48 hours and 5,7,14 days after the onset,and were compared with those of 30 normal controls.Results The platelet expression levels of PECAM-1 and P-selectin in patients with cerebral infarction 24 hours after the onset(78.35?10.48,7.75?3.04 respectively)were higher than those of controls(48.89?10.84,2.18?0.83 respectively,all P