Chemoimmunotherapy has attracted much attention as an emerging therapy pattern for the treatment of cancers. Exploring effective drug combination schemes and reasonable delivery methods remained the key issue in current research. Herein, we designed sorafenib (SF) and anti-Tim-3 monoclonal antibody (Tim-3 mAb) co-loaded MMP2-responsive mesoporous silica nanoparticles (ST-MSNs) for combined chemoimmunotherapy of hepatocellular carcinoma (HCC). The shell of ST-MSNs was fabricated by Tim-3 mAb through matrix metalloproteinase 2 (MMP2) sensitive peptides as "gatekeepers" to prevent drug release during the blood circulation. In tumor microenvironment, the high levels of MMP2 caused the responsive shedding of Tim-3 mAb, leading to the triggerred release of SF and Tim-3 mAb. Then, SF could be delivered to tumor cells and Tim-3 mAb could be delivered to T cells, respectively. In vivo tumor inhibition study results demonstrated that ST-MSNs can significantly enhance synergistic antitumor activity compared with sequential administration of free SF solution and Tim-3 mAb solution. Meanwhile, the expression of antitumor cytokines IFN-γ, IL-12 and the percentage of CD3⁺CD4⁺ cells, CD3⁺CD8⁺ cells in tumors were upregulated after the administration of ST-MSNs, demonstrating good immunomodulatory ability. In addition, within the dosage range, the ST-MSNs had low cytotoxicity and hemolysis, and no obvious tissue toxicity was observed. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of Shandong University. In conclusion, this study provided a promising drug combination of chemoimmunotherapy with good application prospects for clinical HCC treatment, and exhibited a potential drug carrier for clinical chemoimmunotherapy.

OBJECTIVETo investigate the relationship between thrombolysis in myocardial infarction (TIMI) risk score and efficacy of different treatment strategies in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).

METHODSFrom Oct. 2001 to Oct. 2003, 545 consecutive patients with NSTE-ACS were randomly assigned to early conservative strategy (n = 284) or early invasive strategy group (n = 261). The combined cardiovascular events (a combination of cardiac death, nonfatal myocardial infarction, nonfatal heart failure and re-hospital admission due to recurrent ischemia angina) within 30 days and 6 months were analyzed and related to the TIMI risk score at admission.

RESULTSRehospitalization due to recurrent ischemia angina of 30 days and the combined cardiovascular events of 30 days and 6 months were significantly lower in early invasive strategy group (3.5%, 10.0%, 21.1%) compared with early conservative strategy group (8.1%, 16.9%, 28.2%, all P < 0.05). Subgroup analysis indicated early invasive strategy could significantly decrease the 30 d incidence of the combined end point events in patients with high TIMI risk score and the 6 months incidence of the combined end point events in patients with moderate and high TIMI risk score (all P < 0.01), but the incidence was similar between the two different strategies in patients with low TIMI risk score.

CONCLUSIONSEarly invasive strategy may significantly reduce combined cardiovascular events in NSTE-ACS patients with moderate and high TIMI risk score compared with early conservative strategy.

Aged ; Angina, Unstable ; drug therapy ; physiopathology ; Coronary Disease ; drug therapy ; physiopathology ; Electrocardiography ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; drug therapy ; Risk Assessment ; Thrombolytic Therapy

In order to investigate the transmission risk of H5N1 avian influenza viruses (AIV) from sewage in Changsha poultry markets, the evolution relationship and molecular characteristics of non-structural (NS) genes of H5N1 AIV from sewage were analyzed. Nine H5N1 AIV environmental sewage specimens were collected from Changsha poultry markets. The NS genes were amplifyed by PCR and then sequenced with TA cloning. Amino acid(aa) sequence alignment and phylogenetic tree analysis were conducted by Lasergene and Mega5 software. Eight NS genes TA cloning were constructed successfully. Phylogenetic tree indicated that they were belonged to the allele A subgroup. Aa homology analysis showed 90.1% 92.5% identity in NS1 proteins and 91.0% - 92.6% identity in NS2 proteins compared with reference viruses of the allele A (A/chicken/ Hubei/ w h/ 1999). The homologies of the amino sequences of NS1 and NS2 in this study were 93.8%-100.0% and 98.4%-100.0%, respectively. The C terminal of all eight H5N1 NS1 proteins from sewage in poultry markets carried a ESEV of PL motif and the 92 amino acids were E, furthermore, the 80 to 84aa were missed which were the characteristics of highly pathogenic AIV. The NS genes of H5N1 AIV from sewage in poultry markets have molecular characteristics of highly pathogenic and have the potential risk of H5N1 virus spreading.
Amino Acid Sequence ; Animals ; Influenza A Virus, H5N1 Subtype ; chemistry ; classification ; genetics ; isolation & purification ; Influenza in Birds ; transmission ; virology ; Molecular Sequence Data ; Phylogeny ; Poultry ; Sequence Homology, Amino Acid ; Sewage ; virology ; Viral Nonstructural Proteins ; chemistry ; genetics

Objective To explore the effect of gene mutations of arsenic transport proteins-muhidrug resistance-associated proteins(MRP1 and MRP2)on phenotype of endemic arsenic poisoning.Methods Two hundreds and thirty-nine rural residents in 3 villages of Shuocheng Region,Shanxi Province were interviewed and examined by simple random sampling who had been lived there for 20 yearn at least.All the objects were divided into two groups on the basis of clinical examination with"The Standard Diagnosis of Endemic Arsenic Poisoning" (WT/S 211-2001):subjectives with skin lesion as a arsenic poisoning group and without skin lesion as a control group. One hundred and ninety-three blood samples were collected from each participanL Seventy-five arsenic poisoning cases and 118 controls were detected the gene mutations in the 2,17,23 exons of M RPI and the 10,18,31 exons of MRP2 by PCR-single strand conformation polymorphism (PCR-SSCP) and compared by multivariate Logistic regression model. Results Seventy-five cases and 164 controls underwent questionnaires. Age[ (58.85±11.26) vs (45.73±11.92),OR = 3.378,P ＜ 0.05],gender[male,57.3%(43/75)vs 27.4%(45/164),OR = 3.553,P＜ 0.01 ],smoking[46.7%(35/75) vs 21.3%(35/164),OR = 3.225,P ＜ 0.01 ],drinking[ 17.3%(13/75) vs 8.5% (14/164),OR = 1.836,P ＞ 0.05],vegetable and fruit intake[5.3%(4/75) vs 9.1%(15/164),OR = 0.560,P ＞ 0.05],egg and meat intake[34.7%(26/75) vs 30.5%(50/164),OR = 1.210,P ＞ 0.05],exposure of pesticide [41.3%(31/75) vs 29.3%(48/164),OR = 1.864,P ＜ 0.05] were tested by Logistic regression model. There was no gene mutation detected in the 23 exon of MRP1 and the 18 exon of MRP2. The gene mutations frequencies of the 2 exons of MRP1 in arsenic poisoning and control groups were 8.00% (6/75) and 5.93% (7/118),respectively;they were 13.33%(10/75) and 8.47%(10/118) of the 17 exons of MRP1,respectively;they were 22.67%(17/75) and 18.64%(22/118) of the 10 exons of MRP2,respectively;they were 5.33%(4/75) and 2.54%(3/118) of the 31 exons of MRP2,respectively. There was no significant difference between two groups(x2 = 0.312,1.165,0.460, 2.794,respectively,all P ＞ 0.05). After age,gender,smoking,drinking,nutritional level and exposure of pesticide being adjusted by multivariate Logistic regression model,there was no significant difference between two groups (OR = 0.803,1.892,2.388,1.098,respectively,all P ＞ 0.05). Conclusions The gene mutations of 2,17,23 exons of MRPI and the 10,18,31 exons of MRP2 may have no effect on the phenotype of endemic arsenic poisoning.

A group of 25 rabies viruses (RABVs),recovered from 24 dogs and one human case,were collected from various areas in China between 2004 and 2006.Genetic and phylogenetic analyses of the G-L intergenic region were carried out in 25 street RABV isolates and CTN vaccine strains of 7 generations.The study was based on the comparison of a 519 bp nucleotide sequence,encompassing the G-L intergenic region.The nucleotide sequence homologies of Chinese street strains were from 95.5% to 100%.The phylogenetic analysis showed that all Chinese isolates clearly supported the placement of all Chinese viruses in Lyssavirus genotype 1 and they were distributed according to their geographical origins.All of the Chinese strains were closely related but they could still be divided into two groups:group of street strains and group of CTN strains.This study presents details about the molecular epidemiology of rabies viruses based on the sequences of the G-L Intergenic region.

Objective To investigate the risk of H5Nl subtype avian influenza virus (AIV)transmission in the poultry market environment in Changsha city.H5N1 antibody levels among the groups related occupational exposure and AIV nucleic acid in the environment of poultry markets were detected.The characteristics of hamagglutinin (HA) genes of H5N1 AIV in the environment were analyzed.Methods One district and one county from Changsha city were selected randomly and two poultry markets at inner city or township levels were selected in the same district or county respectively.H5N1 antibody of the occupational exposure groups in the poultry market was tested and AIV nucleic acid in the poultry market environnent monitored.One hundred and two blood samples of the occupational exposure groups were tested for H5N1 antibody with single radioimmunoassay diffusion hemolysis (SRH) while 160 environment samples(from sewage,birds stools,feathers and smearing samples of poultry cages) in the poultry market were also detected for AIV nucleic acid with real-time PCR method.Four sewage samples of H5N1 subtype AIV were collected from poultry markets in Changsha,and the HA genes of H5N1 subtype AIV amplified by RT-PCR and then sequenced with TA cloning.Amino acid sequence alignment and phylogenetic tree analysis were conducted by Lasergene and Mega 5.0 software.Results The results through H5N1 antibody monitoring program showed that H5N1 antibody positive rates from workers were 25.5％ (26/102),50.0％ (9/18) and 25.4％ (17/67) respectively in the poultry markets of township and inner cities.H5N1 antibody positive rate in the township poultry markets was higher than in the inner cities poultry markets.Results from the surveillance on AIV nucleic acid showed that the overall H5 subtype positive rate in Changsha poultry markets was 31.3％ (50/160),and the positive rate of townships poultry markets was 37.3％ (31/83 ),which were both higher than those from the inner cities poultry markets (24.7％,19/77).H5 subtype AIV positive rate was different in the tested specimens,with ranking of positive rates were sewage (50.0％,24/48),feathers (44.5％,4/9 ),birds stools ( 29.8％,14/47) and smearing samples of poultry cages (14.3％,8/56),with statistically significant differences (P＜0.01).Four H5N1 HA genes TA cloning were successfully constructed and identified as Eurasian branch,similar to viruses isolated in mainland China and Hong Kong in the same group,according to genetic analysis.Sequence data of the four HA genes showed the same feature of high pathogenicity,compared to the H5N 1 AIV from mainland China of human origin.The receptor specificities were still with avian influenza origin (QSG)and the connecting peptide between HA1 and HA2 possessing the polybasic motif (RERRRKK or RERRGKK).Conclusion One of the reasons for H5N1 antibody positive rate of 25.5％ among poultry markets workers was that there were large numbers of H5N 1 subtype AIV detected in the environment of poultry markets and HA genes of H5N 1 subtype AIV in the poultry markets environment carried molecular characteristics of highly pathogenic which could increase the risk for H5N1 subtype AIV transmission in the environment of poultry markets.

OBJECTIVETo explore the way of promoting the efficacy of surgical treatment for ventricular septal rupture (VSR) after acute myocardium infarction in terms of perioperative and long term survival.

METHODSThe clinic data of 37 VSR cases underwent surgical treatment from October 1994 to October 2007 were analyzed retrospectively. There were 24 male and 13 female, and the age was (63.4 +/- 7.6) years old. The whole group was divided into the VSR repair plus revascularization group (group A, 26 cases) and simple VSR repair group (group B, 11 cases).

RESULTSThere were 4 operative deaths in group A (15.4%), 7 deaths in group B (63.6%), P = 0.006. With the follow-up of (34.0 +/- 29.8) months ranged from 2 to 103 months of the 26 operational survivors, there were 5 late deaths, of which 2 deaths in group A and 3 deaths in group B. According to the Kaplan-Meier survival curve, the actuarial survival rate at 6 to 8 year was (64.3 +/- 21.0)% for group A and the actuarial survival rate at 4 year was (25.0 +/- 21.7)% for group B, P = 0.011. Of the 21 mid-long term survivors, 17 cases were in NYHA class I to II and 4 cases in NYHA class III to IV. There were 4 cases suffered from VSR recurrence. According to Logistic regression, the risk factors for the early death were not adoptive of revascularization, cardiogenic shock and emergency surgical procedure, while the risk factors for late death were not adoptive of revascularization and low cardiac output after the procedures.

CONCLUSIONSVSR repair plus revascularization could improve the perioperative and mid-long term survival for the surgical treatment of VSR. The appropriate timing and procedures of the surgical operation are very important to promote perioperative survival and to prevent VSR recurrence.

Aged ; Female ; Follow-Up Studies ; Heart Rupture, Post-Infarction ; surgery ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; complications ; Retrospective Studies ; Treatment Outcome ; Ventricular Septal Rupture ; etiology ; surgery

OBJECTIVETo explore the relationship between the overexpression of PKA RIalpha mRNA and cliniopathological parameters in lung cancer.

METHODSRT-PCR was used to detect the expression of PKA RIalpha mRNA in 54 cases with human lung cancer and matched normal tissues.

RESULTS(1) The expression of PKA RIalpha mRNA was significantly higher in cancer tissue (66.7%) than in normal tissues (20.4%) (P < 0.01). (2) The expression was significantly correlated with TNM stage (P < 0.01), being increased with TNM stage. (3) The expression was significantly higher in patients with positive lymph nodes than in those with negative lymph nodes (P < 0.01). (4) There were no significant associations of PKA RIalpha mRNA expression with histological type, differentiation grade or size of the tumor.

CONCLUSIONThis study indicates that the overexpression of PKA RIalpha mRNA may play an important role in the progression, metastasis and prognosis of lung cancer.

Adenocarcinoma ; metabolism ; secondary ; Adult ; Aged ; Carcinoma, Squamous Cell ; metabolism ; secondary ; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit ; Cyclic AMP-Dependent Protein Kinases ; biosynthesis ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; RNA, Messenger ; biosynthesis ; genetics

OBJECTIVETo compare the quality of life in patients with prevertebral or retrosternal reconstruction after cervical tubular gastroesophagostomy.

METHODSA total of 167 patients enrolled in this prospective study from July 2008 to June 2012 in Shantou Central Hospital, and divided into prevertebral route group(85 cases) and retrosternal route group(82 cases) according to the random number table method. Quality of life questionnaire was investigated 1, 3, 6, 9, and 12 months after operation respectively.

RESULTSThe incidence of anastomotic stenosis was lower in the prevertebral route group (P<0.05). However, the differences in perioperative general conditions between the two groups were not statistically significant(all P>0.05). One hundred and forty-nine patients completed the postoperative quality of life questionnaire. Dysphagia and swallowing retching symptom were better, while acid reflux and heartburn symptom were more serious in prevertebral route group as compared to retrosternal route group(all P<0.05). Overall quality of life score difference between the two groups was not statistically significant(P>0.05).

CONCLUSIONSFor digestive tract reconstruction after resection of esophageal cancer, tubular gastroesophagostomy by prevertebral or retrosternal route both can obtain better quality of life after surgery. Swallowing function after surgery of the former is superior to the latter, but the reflux symptoms is more serious. Therefore the two mehods have their own advantages and disadvantages, and the choice of route should be depended on clinical experience and patient condition.

Deglutition Disorders ; Digestive System Surgical Procedures ; Esophageal Neoplasms ; Esophagectomy ; Gastrectomy ; Humans ; Postoperative Period ; Prospective Studies ; Quality of Life ; Reconstructive Surgical Procedures

This study evaluated the scientific nature and effectiveness of iterative optimization of prevention and control measures for local outbreaks caused by the BA.2 and BA.5.2 COVID-19 strains in Fujian Province in 2022,to provide a scientif-ic basis for responding to future new or recurrent respiratory infectious diseases.According to the theory of infectious disease dynamics,relevant information regarding the local epidemic situation caused by the BA.2 sub-type Omicron virus strain in March 2022 and BA.5.2 sub-type Omicron virus strain in October 2022 in Fujian Province was collected.The susceptible exposed infectious removed(SEIAR)model of COVID-19 infection with a latent period and asymptomatic infected persons was used to analyze the transmission dynam-ics of two local epidemic situations,and evaluate the preven-tion and control effects.The incubation period of the BA.2 epidemic was 3 days(1～9 days),the intergenerational inter-val was 3 days(1～5 days),and the initial Rt was 3.0(95％CI:2.7～3.3).The incubation period of the BA.5.2 epidemic was 2 days(1～6 days),the intergenerational interval was 1 day(0～2 days),and the initial R,was 1.9(95％CI:1.7～2.1).The fittingresults for the BA.2 and BA.5.2 epidemics were good,and no statistical difference was observed between the predic-ted and actual numbers of cases(x2BA.2=31.53,x2BA.5.2=27.88,P＞0.05).If an emergency response had not been initiated,the BA.2 epidemic would have continued to spread andpeak on April 7th,with an estimated 638 035 cases.The BA.5.2 epidemic would have rapidly spread,reaching a peak on November 14th,with an estimated 685 940 cases.If one incubation period were detected early,the scale of the BA.2 epidemic would have decreased by 25.73％;if two incubation periods were detected early,the scale would have decreased by 79.56％,and if one incubation period had been delayed,the scale would have expanded by 13.72％.If one incubation period had been detected early in the BA.5.2 epidemic,the scale would have decreased by 35.04％;if two incubation periods had been detected early,the scale would have decreased by 92.47％;and if one incubation period had been delayed,the scale would have increased by 19.75％.The guiding ideology,and the prevention and control measures for handling two local epidemics were optimized and iterated.Our study indicated that implementing the"four early"measures ef-fectively decreased the scale of the epidemic,and earlier detection was associated with more significant control effects.This study provides valuable information for the prevention and control of new or recurrent respiratory infectious diseases.