Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment:A phase 2 clinical trial

BACKGROUND Progressive pancreaticβcell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus(T2DM).Recently,mesenchymal stem cell(MSC)transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreaticβcells.However,current studies have focused on its efficacy,and there are few clinical studies on its safety.AIM To evaluate the safety of human umbilical cord(hUC)-MSC infusion in T2DM treatment.METHODS An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital.Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk.Twenty-four patients in the hUC-MSC group received hUC-MSCs(1×106 cells/kg)intravenously once per week for 3 wk.Diabetic clinical symptoms and signs,laboratory findings,and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment.RESULTS No serious adverse events were observed during the 24-wk follow-up.Four patients(16.7%)in the hUC-MSC group experienced transient fever,which occurred within 24 h after the second or third infusion;this did not occur in any patients in the placebo group.One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation.Significantly lower lymphocyte levels(weeks 2 and 3)and thrombin coagulation time(week 2)were observed in the hUC-MSC group compared to those in the placebo group(all P<0.05).Significantly higher platelet levels(week 3),immunoglobulin levels(weeks 1,2,3,and 4),fibrinogen levels(weeks 2 and 3),D-dimer levels(weeks 1,2,3,4,12,and 24),and neutrophil-to-lymphocyte ratios(weeks 2 and 3)were observed in the hUC-MSC group compared to those in the placebo group(all P<0.05).There were no significant differences between the two groups for tumor markers(alpha-fetoprotein,carcinoembryonic antigen,and carbohydrate antigen 199)or blood fat.No liver damage or other side effects were observed on chest X-ray.CONCLUSION Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM.It can improve human immunity and inhibit lymphocytes.Coagulation function should be monitored vigilantly for abnormalities.

Validation of the chinese version of the EORTC QLQ-CR29 in patients with colorectal cancer

AIM To assess the validity and reliability of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29) in Chinese patients with colorectal cancer (CRC). METHODS From March 2014 to January 2015, 356 patients with CRC from four different hospitals in China were enrolled in the study, and all patients self-administered the EORTC QLQ-CR29 and the quality of life core questionnaire (EORTC QLQ-C30). Evaluation of the scores was based on the Karnofsky Performance Scale (KPS). The reliability and validity of the questionnaires were assessed by Cronbach's proportional to coefficient, the Spearman correlation test and Wilcoxon rank sum test. RESULTS The EORTC QLQ-CR29 showed satisfactory reliability (proportional to > 0.7), although the urinary frequency and blood and mucus in stool dimensions had only moderate reliability (proportional to = 0.608). The multitrait scaling analyses showed good convergent (r > 0.4) and discriminant validity. Significant differences were obtained for each item in the different KPS subgroups (KPS <= 80; KPS > 80). Body image and most single- item dimensions showed statistically significant differences in patients with a stoma compared with the rest of the patients. CONCLUSION The EORTC QLQ-CR29 exhibits high validity and reliability in Chinese patients with CRC, and can therefore be recommended as a valuable tool for the assessment of quality of life in these patients.

Correspondence of CT perfusion imaging to pathological manifestations in rabbit models of hyperacute cerebral infarction

BACKGROUND： Could the infarction be diagnosed quickly and accurately at the acute stage by CT perfusion imaging （CTPI） technology？ Whether the images of CTPI will correspond with the pathological changes or not？ All the questions need to be solved by experimental and clinical studies. OBJECTIVE： To reveal the rules of perfusion map changes and guide the early diagnosis of hyperacute cerebral infarction by analyzing the correlation of CTPI with pathological manifestations for hyperacute cerebral infarction. DESIGN： A randomized controlled animal experiment. SETTING： Experimental Center of Medical Radiology, Longgang Central Hospital of Shenzhen City. MATERIALS： Forty-two adult New Zealand rabbits of （2.6±0.5） kg, either male or female, were randomly divided into experimental group （n =36） and control group （n =6）. Six rabbits in the experimental group were observed after ischemia for 0.5, 1, 2, 3, 4 and 6 hours respectively, and 1 rabbit in the control group was observed at each corresponding time point. METHODS： The experiments were carried out in the Experimental Center of Medical Radiology, Longgang Central Hospital of Shenzhen City from March 2003 to July 2004. Rabbit models of cerebral infarction were established by modified O＇Brein method. （1） The rabbits in the experimental group were scanned at 0.5, 1, 2, 3, 4 and 6 hours after ischemia respectively. The dynamic CT scan slice was 13 mm from the anterior edge of the frontal cortex, and six fake color functional images were obtained, including cerebral blood flow map （CBF map）, cerebral blood volume map （CBV map）, peak to enhancement map （PE map）, flow without vessels map, time to peak map （TP map）, time to start map （TS map）. The manifestations and changes of the functional maps in different interval were observed. （2） Bilateral symmetric ranges of interest （ROI） were drawn separately on the CBF map, CBV map, TP map and TS map. The blood flow parameters of focal and contralateral cerebral tissues could be obtained to calculate relative cerebral blood flow （rCBF, rCBF=focal CBF/contralateral CBF）, relative cerebral blood volume （rCBV, rCBV= focal CBV/contralateral CBV）, a relative time to peak （rTP, rTP= focal TP - contralateral TP）, a relative time to start （rTS, rTS= focal TP - contralateral TP）. （3） The perfusion maps were input into AutoCAD software. The percents of ischemic cores and peri-ischemic areas accounting for contralateral cerebral hemisphere were calculated. （4） The animals were anesthetized and killed, then the cerebellum and low brain stem were taken out. The brain tissues were cut on coronal plane at 14 mm from the anterior edge of the frontal cortex, a 2-mm piece anterior to the incision, and a 3-mm piece posterior to the incision. The anterior piece was fixed, stained and observed. A 1-mm slice was cut from the front of the posterior piece tissues as electron microscope sample, the remnant was fixed and then taken out, and the location and size of stained ＂white＂ areas were observed as the reference for electron microscope sample. （5） The correlation between CTPI and pathological manifestations was observed. MAIN OUTCOME MEASURES： （1） Laws of time and spatial changes of ischemic areas; （2） Pathological changes of the ischemic tissues; （3） Correspondency between CTPI and pathological manifestations. RESULTS： （1） Laws of time and spatial changes of ischemic areas： Relative ischemic-core areas were consistent in each perfusion map, increased incessantly along with the ischemic times. Relative peri-ischemic areas were inconsistent in each perfusion map, on CBF map from 1 to 6 hours after ischemia, the area of ischemic core increased from （1.503±0.523）% to （7.125± 1.054）%, the ascending trend occurred. But the peri-ischemic areas showed a descending trend on CBF map, the areas decreased from （8.960±0.719）% to （5.445 ± 0.884）% from 0.5 to 6 hours; The relative areas were the largest one on TP maps, the average value was （32.796±3.029）% at 0.5 hour after ischemia happening （60.540±1.683）% at 6 hours. The trend of ischemic areas was increased. No obvious change was observed on TS maps. （2） Pathological changes of the ischemic tissues： Under light microscope, there was no obvious change at 0.5- 2 hours after ischemia, edema at 3 hours, karyopycnosis at 4 hours and eosinophilous changes at 6 hours; Under electron microscope, there was edema in ischemic cores within 4 hours after ischemia, whereas karyopycnosis or structure vanished after 4 hours; Edema was observed in peri-ischemic areas. （3） Correlation between CTPI and pathological manifestations： On CTPI maps, the ischemic core was blue on CBF and CBV maps, black on TP and TS maps. Along with the ischemic times, the rCBF and rCBV decreased, whereas the rTP and rTS prolonged. Hemodynamic parameters were not significantly different within 2 hours of ischemia and 2 hours after ischemia. The rTP and rTS became 0 after 1 and 2 hours respectively. On CTPI maps the peri-ischemic area was red on CBF and CBV maps, red and yellow on TS maps, red on TP maps. Along with the ischemic times, the rCBF decreased, and the lowest level was always at about 20%, whereas the rTP and rTS prolonged. CONCLUSION： （1） CTPI manifestations corresponded well with pathological findings, and it is a sensitive, stable and reliable technique to diagnose hyperacute cerebral infarction. （2） TP map was more sensitive than CBF map and TS map in exhibiting the peri-ischemic areas, thus TP maps could be a good choice for observing peri-ischemic areas.

Treatment of primary hepatic carcinoma by transcatheter arterial perfusion of batroxobin combined with TACE:a preliminary clinical study

Objective:The aim of the study was to explore the therapeutic efficacy and safety of batroxobin in patients with primary hepatic carcinoma(PHC) and the advantages of transcatheter arterial perfusion of batroxobin combined with transcatheter arterial chemoembolization(TACE).Methods:Forty patients with PHC were randomized into experimental group(transcatheter arterial perfusion of batroxobin combined with TACE treatment,20 patients) and control group(TACE alone group,20 patients).The patients were followed up and the data were recorded,compared and analyzed.Results:(1) Compared with the control group,the FIB level in the experimental group was significantly decreased at the first month after treatment(P < 0.05).(2) The baseline of the tumor was shortened in both groups after the treatment.There was a significant difference between the two groups at different time intervals(P < 0.05).(3) After the treatment,there was a significant difference of progression-free survival(PFS) levels between the two groups(t =2.877,P < 0.05).(4) The incidence of metastasis were 5.0%(1/20) in both groups at 6 months after treatment,and that after one year was 10.0%(2/20) in the experimental group and 25.0%(5/20) in the control group.However,the difference was not significant(χ2 = 0.693,P > 0.05).Conclusion:Batroxobin can rapidly and effectively decrease the FIB level of the PHC cases.Therefore it may be used as an effective and safe adjuvant drug for the treatment of primary hepatic carcinomas.Transcatheter arterial perfusion of batroxobin combined with TACE therapy has advantages in comparison with TACE alone therapy.It could be taken as a new therapeutic regimen in the PHC treatment.

Effectiveness and safety of human umbilical cord-mesenchymal stem cells for treating type 2 diabetes mellitus

BACKGROUND Progressive pancreaticβ-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus(T2DM).Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of isletβ-cells.AIM To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell(hUC-MSC)infusion in T2DM treatment.METHODS Sixteen patients were enrolled and received 1×10^(6) cells/kg per week for 3 wk as intravenous hUC-MSC infusion.The effectiveness was evaluated by assessing fasting blood glucose,C-peptide,normal glycosylated hemoglobin A1c(HbA1c),insulin resistance index(homeostatic model assessment for insulin resistance),and isletβ-cell function(homeostasis model assessment ofβ-cell function).The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events(AEs).RESULTS During the entire intervention period,the fasting plasma glucose level was significantly reduced[baseline:9.3400(8.3575,11.7725),day 14±3:6.5200(5.2200,8.6900);P<0.01].The HbA1c level was significantly reduced on day 84±3[baseline:7.8000(7.5250,8.6750),day 84±3:7.150(6.600,7.925);P<0.01].The patients’isletβ-cell function was significantly improved on day 28±3 of intervention[baseline:29.90(16.43,37.40),day 28±3:40.97(19.27,56.36);P<0.01].The dosage of hypoglycemic agents was reduced in all patients,of whom 6(50%)had a decrement of more than 50%and 1(6.25%)discontinued the hypoglycemic agents.Four patients had transient fever,which occurred within 24 h after the second or third infusion.One patient(2.08%)had asymptomatic nocturnal hypoglycemia after infusion on day 28±3.No liver damage or other side effects were reported.CONCLUSION The results of this study suggest that hUC-MSC infusion can improve glycemia,restore isletβ-cell function,and reduce the dosage of hypoglycemic agents without serious AEs.Thus,hUC-MSC infusion may be a novel option for the treatment of T2DM.

Nurses’ knowledge, perceptions, and behaviors regarding antineoplastic drugs:the mediating role of protective knowledge

Objective:To explore the relationships between Chinese nurses’knowledge,perceptions,and attitudes and their behavior and actual implementation of safety measures when handling antineoplastic drugs(ADs)in their daily work.Methods:This was a multisite study conducted in 8 public hospitals in China.A self-administered questionnaire was sent to par ticipants querying the degree of contact with ADs.The hypothesized relations were explored using structural equation modelling via the bootstrap method.Mediation analysis was applied to explore the mediating role of protective knowledge regarding AD exposure on the associations among protective training,using warning labels,and using protective masks.Results:A total of 305 nurses were enrolled.The average age of all par ticipants was 30.2(standard deviation[SD]:6.2)years.Nurses who had received protective training for AD exposure were more likely to use labels for ADs after age,body mass index(BMI),length of service,marital status,education,and department were controlled as covariates.The bias-corrected bootstrap of 95%confidence interval(CI)indicated that protective knowledge significantly mediated(23.4%)the association between protective training and using labels(indirect effect=0.202,95%CI:0.009,0.495);the proportion of mediation was 23.4%.Protective knowledge significantly mediated the association between protective training and using protective masks(indirect effect=0.157,95%CI:0.048,0.325);the propor tion of mediation was 27.2%.Conclusions:The findings of this study have provided baseline information on the current state of Chinese nurses’perceptions,knowledge,and preventive behaviors toward ADs as the crisis is happening.Training is also recommended to improve nurses’perceptions of the risks associated with ADs.

Printed Biosensors for the Detection of Alzheimer’s Disease Based on Blood Biomarkers

Alzheimer’s disease(AD)is a chronic neurodegenerative disorder,and early diagnosis plays a crucial role in its prevention and treatment.In recent years,blood-based biomarkers for early AD diagnosis have gained attention due to their non-invasiveness and minimal adverse reactions,which make them an attractive approach.Since the onset of the COVID-19 pandemic,visiting large medical examination centers for blood tests has become increasingly challenging.The trend is shifting towards community or home-based sampling,which relies on the development and application of portable,miniaturized,and highly sensitive sensors.Among the various sensors used for detecting blood biomarkers in AD,printed sensors demonstrate great potential in AD blood biomarker detection due to their ease of miniaturization,scalability for mass production,and compatibility with various detection methods.In this review,we focus on discussing the application of printed sensors in the analysis of blood biomarkers for AD.We also explore the challenges faced by printed sensors in early diagnosis based on AD blood biomarkers and propose potential solutions to address these challenges.

Self-assembly multifunctional DNA tetrahedron for efficient elimination of antibiotic-resistant bacteria

Antibiotic resistance is a major challenge in the clinical treatment of bacterial infectious diseases.Herein,we constructed a multifunctional DNA nanoplatform as a versatile carrier for bacteria-specific delivery of clinical antibiotic ciprofloxacin(CIP)and classic nanoantibiotic silver nanoparticles(AgNP).In our rational design,CIP was efficiently loaded in the self-assembly double-bundle DNA tetrahedron through intercalation with DNA duplex,and single-strand DNA-modified AgNP was embedded in the cavity of the DNA tetrahedron through hybridization.With the site-specific assembly of targeting aptamer in the well-defined DNA tetrahedron,the bacteria-specific dual-antibiotic delivery system exhibited excellent combined bactericidal properties.With enhanced antibiotic accumulation through breaking the out membrane of bacteria,the antibiotic delivery system effectively inhibited biofilm formation and promoted the healing of infected wounds in vivo.This DNAbased antibiotic delivery system provides a promising strategy for the treatment of antibiotic-resistant infections.

FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma

Objective:FGFR is considered an important driver gene of lung squamous cell carcinoma(LSCC).Thus,identification of the biological events downstream of FGFR is important for the treatment of this malignancy.Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells.However,the biological functions of the FGFR/RACK1 complex remain poorly understood.Methods:Anchorage-independent assays and in vivo tumorigenesis assays were performed to evaluate cancer cell malignancy.Distant seeding assays were performed to evaluate cancer cell metastasis.β-gal staining was used to examine cell senescence,and immunoprecipitation assays were performed to examine the interactions among FGFR,RACK1,and MDM2.Results:FGFR/RACK1 was found to regulate the senescence of LSCC cells.Treatment with PD166866,an inhibitor of FGFR,or knockdown of RACK1 induced senescence in LSCC cells(P<0.01).A molecular mechanistic study showed that FGFR/RACK1/MDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence.PD166866 and RG7112,an MDM2/p53 inhibitor,cooperatively inhibited the colony formation and distal seeding of LSCC cells(P<0.01),and upregulated the expression of p53 and p21.Conclusions:Together,our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence.This understanding should be important in the treatment of LSCC.

Consistency between magnetic resonance diffusion-weighted images and pathological findings in a hyperacute cerebral infarction rabbit model

BACKGROUND： Because magnetic resonance diffusion-weighted imaging is sensitive to water molecule movement, it has particular advantages for early diagnosis of cerebral infarction. However, the relationship between apparent diffusion coefficient changes with ischemia time, particularly relative apparent diffusion coefficient and tissue pathological changes remains controversial. OBJECTIVE： To explore the correlation between apparent diffusion coefficient changes and pathologic changes in hyperacute cerebral infarction. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment of neuroimaging. The study was performed at the Laboratory of Radiology Department, Longgang Central Hospital of Shenzhen from October 2007 to October 2008. MATERIALS： Magnetic resonance scanner was purchased from Philips Medical Systems, Best, the Netherlands. METHODS： A total of 42 healthy, adult, New Zealand rabbits were randomly assigned into sham-operation, ischemia 0.5-, 1-, 2-, 3-, 4-, and 6-hour groups, with six animals in each group. Local cerebral ischemia model was established by right middle cerebral artery occlusion, and cranial MRI scanning and pathologic observation were performed, respectively, at 0.5, 1,2, 3, 4, and 6 hours following ischemia. The middle cerebral artery of sham-operation group was only exposed, but not occluded. Images at the above-mentioned time points were also collected. MAIN OUTCOME MEASURES： Apparent diffusion coefficient and relative apparent diffusion coefficient values of abnormal signal on diffusion-weighted imaging were calculated and compared with pathological changes in the ischemic region. RESULTS： No abnormal diffusion-weighted imaging signals or pathological changes were observed in the sham-operation group. Abnormal signal intensity on diffusion-weighted imaging was first observed in the 0.5-hour group. Apparent diffusion coefficient and relative apparent diffusion coefficient values decreased in all middle cerebral artery occlusion rabbits and reached lowest levels at 3 hours, followed by a gradual increase. The right ischemic basal ganglia region with high signal intensity on diffusion-weighted imaging extended with increasing time of occlusion, and the pathologic outcome corresponded with MRI changes. CONCLUSION： Relative apparent diffusion coefficient values changed regularly with ischemia time and displayed good correspondence to pathological manifestations.

The analysis of injured and poisoned patients during the construction of urbanization and industrialization from 1998 to 2002

Objective: To analyze the causes of injury and poisoning during construction of urbanization and industrialization and to explore proper measures. Methods: The data of the patients with injury and poisoning during construction of urbanization and industrialization treated in out hospital from 1998 to 2002 were retrospectively analyzed. Results: The number of discharged patients of injury and poisoning accounted for (29.2)% of the total number ((49 800)) of discharged patients in the corresponding period in our hospital, which was greater than that of other city and county hospitals, and accounted for (94.3)% of the total number ((15 411)) of discharged patients of the Surgery Department in the corresponding period in our hospital. Injuries caused by motor vehicle traffic accidents, cutting and piercing instruments or objects, homicide and injury purposely inflicted by other persons and accidental falls held (78.9)%. The number of the inpatients in 2002 increased by (83.3)% compared with that of 1998, the number of injured and poisoned inpatients increased by (76.1)% and these patients aged mainly at age of 15-39 years, holding (80.1)%. In a year, the peak period of trauma patients was in summer because of hot weather; the fewest in February for the floating people went home for Spring Festival holidays. Conclusions: During construction of rural urbanization and industrialization, injuries and poisoning increase evidently and are the main tasks of surgical management. So to raise its treatment level and therapeutic effect is a key point.

Analysis of closed abdominal injury in pregnant women

Objective: To explore the characteristics of closed abdominal injury in pregnancy women and its treatment.Methods: The clinical data of 37 pregnancy patients with closed abdominal injury treated in our hospital from June 1993 to June 2003 were collected and analyzed.Results: All the 37 patients were treated with operation. Among them 2 early pregnancy patients with intestinal rupture and 1 patient with retroperitoneal hematoma were treated under laparoscope; in other 34 pregnancy patients laparotomy was performed. Of the 34 patients 8 used cesarean section because premature separation of placenta and enlarged womb interrupted the management of intra-abdominal organ injury. In the 37 patients 33 ( 89.1%) were cured, 4 ( 10.8%) die, postoperative complication rate was 16.2% (6/37). Two patients ( 5.4%) suffered from abdominal cavity infection, 3 ( 8.1%) from pulmonary infection, and 1 ( 2.7%) had multi-organ failure.Conclusions: For pregnancy patients with closed abdominal injury, besides obsteric diseases intra-abdominal injury should be given much attention. Accurate diagnosis and timely treatment can gain the time to save the life of both mother and fetus.

Direct interaction between CD155 and CD96 promotes immunosuppression in lung adenocarcinoma

Despite the advance in targeted therapy,lung adenocarcinoma(LUAD)remains one of the leading causes of death in patients with cancer.CD155,a member of poliovirus receptor–related(PRR)family,has been identified as the ligand of the Ig-like receptors tactile(CD96)and DNAM-1(CD226)on T cells.The interaction of CD155 with CD96 transmits an inhibitory signal and suppresses immune response.The interaction of CD155 with CD226 enhances the immune response.1,2,3 CD155 expression has been shown to be elevated in many types of cancers4,5 and is involved with immune suppression in melanoma.6 However,how CD155/CD96 is involved in immune response in the tumor microenvironment of LUAD remains unknown.