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Objective To investigate the potential significance of FOXP3 expression in BRCA1/2-mutant breast cancer. Methods A total of 48 BRCA mutation carriers (16 with BRCA1 and 32 with BRCA2) and 78 age-matched non-carriers were included in this study. Immunohistochemistry was used to detect the expression of FOXP3 in breast cancer tissues. The FOXP3 RNA expression in 39 BRCA1, 36 BRCA2, and 948 non-carrier breast cancer patients from TCGA-BRCA and the correlation with homologous recombination deficiency scores were evaluated to validate the immunohistochemistry results. Results The FOXP3 positive rate was 43.8% (7/16) in BRCA1 mutation carriers, 59.4% (19/32) in BRCA2 mutation carriers, and 9.0% (7/78) in non-carriers. The FOXP3 positive rates in patients with BRCA1/2 mutant breast cancer were significantly higher than those in non-carriers (P=0.002; P<0.001). TCGA-BRCA results showed that the FOXP3 RNA level in BRCA1/2 mutant breast cancer was significantly higher than that in non-carriers (P=0.02, P=0.004). The FOXP3 RNA level was positively correlated with the homologous recombination deficiency score (Spearman R=0.30, P<2.2e-16). Conclusion Patients with BRCA1/2 mutant breast cancers have higher FOXP3 expression than non-carriers, and may be more sensitive to immunotherapy.
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Colorectal cancer (CRC) is one of the most common malignant tumors recorded worldwide. This condition has high morbidity and mortality and seriously endangers people's health. Traditional diagnostic models fail to meet people's current needs for real-time monitoring of tumors. Compared with traditional detection methods, ctDNA detection is not only noninvasive but can also attain real-time detection of comprehensive genomic information of tumors. The advancement of detection technology has gradually highlighted the potential of ctDNA detection in the clinical treatment of CRC. This article reviews the advancements on the clinical application of ctDNA in early screening, minimal residual disease detection, and guidance on individualized treatment of CRC patients.
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Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.
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Objective To investigate the characteristics of adverse drug reactions(ADRs)induced by tislelizumab and to provide reference for clinic drug safety.Methods The ADR of tislelizumab in Beijing Friendship Hospital Affiliated to Capital Medical Univeristy from July 2021 to December 2022 were retrospectively analyzed.The case reports of ADR induced by tislelizumab from January 2019 to December 2022 in PubMed,ScienceDirect,Embase,Wanfang,VIP databases were searched.Age,sex,original diseases,adverse reaction time,clinical manifestation,treatment measures and clinical outcome were analyzed.Results A total of 30 patients including 8 cases in hospital and 22 cases in literature were collected.Among these patients,male accounted for 83.33%(25/30),and the highest proportion was from patients over 60 years old(21 patients,70.00%).Most ADRs occurred in 1-2 dose cycles of medication,mainly including skin toxicity in 8 patients,digestive disease in 6 patients and kidney injury in 4 patients.After the symptomatic treatment,29 patients improved and 1 patient died.Conclusion During the medication with tislelizumab,ADRs of skin,gastrointestinal tract and renal should be vigilant,and the changes of relevant indicators should be closely monitored.
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Objective: To investigate the correlation between the prenatal exposure of per-/polyfluoroalkyl substances (PFASs) and the neonatal outcome. Methods: A total of 506 maternal infant cohort samples were collected in Hangzhou, Zhejiang province from 2020 to 2021. The exposure levels of seven PFASs in maternal serum before delivery were detected by solid-phase extraction-ultra performance liquid chromatography tandem mass spectrometry. Multivariable linear regression model was used to analyze the influence of prenatal exposure of PFASs on birth weight, birth length and Apgar score. Results: The maternal age, prenatal body mass index and gestation age were (31.3±4.3) years old, (26.7±3.2) kg/m2 and (265.0±28.3) days, respectively. The birth weight, birth length and scores of Apgar-1 and Apgar-5 were (3.1±0.8) kg, (49.3±2.9) cm, (9.88±0.47) points and (9.99±0.13) points, respectively. PFASs were widely distributed in maternal serum, with the highest concentration of (18.453±19.557) ng/ml, (6.756±9.379) ng/ml and (5.057±8.555) ng/ml for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and 6∶2 chlorinated polyfluorinated ether sulfonate (Cl-PFESA), respectively. Maternal age, parity and delivery mode were associated with the exposure level of PFASs (P<0.05). Subgroup analysis showed that PFOS had negative effects on birth weight (β=-0.958), birth length (β=-0.073) and Apgar-5 score (β=-0.288) for neonates in the low birth weight (LBW) group. 6∶2 Cl-PFESA and 8∶2 Cl-PFESA inhibited the birth weight (β=-0.926; β=-0.552) and length (β=-0.074; β=-0.045) of newborn in the LBW group. In addition, 4∶2 fluorotelomer sulfonate (FTS) was associated with increased birth weight (β=0.111) and decreased Apgar-5 score (β=-0.030) in the normal weight group. Conclusion: Prenatal exposure to PFASs is associated with birth weight, birth length and Apgar-5 score. It is necessary to continue to pay attention to the impact of PFASs on fetal growth and development through maternal-fetal transmission.
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Pregnancy , Infant, Newborn , Female , Humans , Adult , Birth Weight , Prenatal Exposure Delayed Effects , Alkanesulfonic Acids/analysis , Alkanesulfonates/analysis , Fluorocarbons/analysis , Ethers/analysis , Ethyl Ethers/analysis , Environmental Pollutants/analysis , Maternal Exposureالملخص
[Objective]To investigate the mechanism of Compound Fuling Granule(CFG)in inhibiting the glucose metabolism and metastasis of ovarian cancer cells.[Methods]Ovarian cancer cell HEY-T30 were cultured in vitro and incubated with different concentration(0.25,0.5,1,1.5,2 mg·mL-1)of CFG for 24 h.Cell counting kit-8(CCK-8)assay was performed to detect the effect of CFG on the cell proliferation,Transwell assay was used to investigate cell migration ability,lactic acid detection kit and glucose detection kit were used to detect lactic acid production and glucose consumption,the expressions of dynamin-related protein 1(DRP1),some key glycolysis-related proteins and metastasis-related proteins were detected by Western blot,Mito-Tracker Red was used to label mitochondria to observe mitochondria morphology.Lentivirus transfection technique was used to achieve the stable DRP1 knockdown HEY-T30 cells.Real-time quantitative polymerase chain reaction(Real-time qPCR)was used to detect the expression of DRP1 mRNA,the effect of CFG on lactic acid production and glucose consumption of HEY-T30 after DRP1 knockdown was detected by lactic acid detection kit and glucose detection kit,Transwell assay was used to investigate the migration ability of HEY-T30 with DRP1 knockdown after treated with CFG,the effect of CFG on the expression of glycolysis-related proteins and metastasis-related proteins in HEY-T30 with DRP1 knockdown was detected by Western blot.[Results]Compared with control group,the cell survival rate in 0.5,1,1.5,2 mg·mL-1 CFG groups reduced significantly(P<0.01).The average length of mitochondria in 0.5,1 mg·mL-1 group was markedly increased(P<0.01),the protein expression of DRP1 was significantly reduced(P<0.05,P<0.01),and the lactate production and glucose consumption in 0.5 and 1 mg·mL-1 groups were significantly decrease(P<0.01).The number of migration cell was significantly reduced in 0.25,0.5 and 1 mg·mL-1 concentration groups(P<0.05,P<0.01).After knockdown of DRP1,the glycolysis level and migration of HEY-T30 were decreased(P<0.05,P<0.01),and the expressions of glycolysis-related proteins and metastasis-related proteins were decreased(P<0.05,P<0.01).The inhibitory effect of CFG on glycolysis and metastasis of ovarian cancer cells was also weakened.[Conclusion]By targeting DRP1 to regulate glucose metabolism reprogramming,CFG could inhibit the metastasis of ovarian cancer.
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Due to the limitations professional status and training channels, the training of pediatric imaging talents in China is seriously insufficient. Pediatric imaging doctors are concentrated in children's hospitals. Pediatric imaging knowledge and talents in primary medical institutions are scarce, which is not conducive to the construction of hierarchical diagnosis and treatment system. Large-scale telemedicine and online medical treatment based on mobile Internet have become the mainstream platforms for medical consultation and teaching, providing a good opportunity for remote teaching of pediatric imaging, and are expected to become a powerful tool for training pediatric imaging talents. The analysis of literature, mobile phone application market software and cost-effectiveness shows that the current large-scale telemedicine construction cycle is long, the construction and maintenance costs are high, and it is vulnerable to geographical and environmental constraints. It is still a long way to go for remote teaching in hospitals below the county level. The use of mobile terminals and mobile Internet is very convenient. It is an excellent choice to realize the remote teaching of pediatric imaging. It is expected to solve the problem of pediatric imaging talent training and skill dissemination.
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Objective:To explore health utility value, evaluate health-related quality-of-life(QOL)of pediatric liver transplantation(LT)recipients and examine its influencing factors to provide rationales for related health economic evaluations.Methods:This cross-sectional QOL was conducted through a questionnaire in pediatric LT recipients aged 5-17 years.The interviewees undergoing initial LT from June 2013 to September 2021 were reviewed regularly.Those children and their parents unwilling to participate or failing to understand the contents of questionnaire were excluded.The questionnaire was designed on the basis of Child Health Utility 9D Instrument(CHU9D)and answered online by one of primary caregiver.Chinese score system of CHU9D was employed for converting the responses into health utility values and the influencing factors were analyzed.Univariate analysis was performed by nonparametric tests and multivariate analysis by multiple linear regression model. P<0.05 was deemed as statistically significant. Results:A total of 140 valid questionnaires were obtained.Mean age of pediatric LT recipients was(7.95±2.74)years and mean postoperative time(4.90±2.17)years.Among them, 19 cases had experienced acute rejection and 101(72.1%)cases were living-related LT recipients.CHU9D scale indicated that average health utility value was(0.85±0.14)points.Univariate analysis revealed that age( P=0.008), education level( P<0.001)and primary disease( P=0.010)influenced the postoperative level of QOL.Multivariate analysis indicated that QOL was correlated with education level(behind schedule: 95% CI: -0.146, -0.034, P=0.002; leave of absence: 95% CI: -0.251, -0.068, P=0.001). Conclusions:Health utility of pediatric LT recipients is high with an excellent QOL.Poor QOL is associated with absence from school or dropping out of school.
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Objective:To investigate the association between plasma uric acid and hypertension and the gender difference in community-dwelling middle-aged and elderly population.Methods:A community-based cross-sectional study was conducted in Beijing Tongzhou Yongshun Community Health Service Center from June to December 2021, among residents aged 45 years or older selected by cluster sampling method. According to plasma uric acid (UA) level in quartiles, the subjects were divided into 4 groups; and stratified by gender, the subjects were further divided into subgroups. Multivariate logistic regression model was used to analyze the related factors of hypertension, and restricted cubic spline fitting logistic regression model was used to analyze the nonlinear association between uric acid and hypertension and the cut-off values of uric acid.Results:A total of 6 229 residents with the age of (63.2±7.3) years were enrolled in the study. In 1 874 male participants (30.1%), 946 participants (50.5%) had hypertension, and the uric acid level was 359 (309, 418)μmol/L; in 4 355 female participants (69.9%), 2 003 participants (46.0%) had hypertension, and the uric acid level was 306 (261, 359)μmol/L. Multivariate logistic regression analysis showed that after adjusting for factors that were statistically significant in univariate analyses or potentially clinically relevant (including age, body mass index, diabetes mellitus, coronary heart disease, cerebrovascular disease, albumin, estimated glomerular filtration rate, and cholesterol), uric acid was independently associated with hypertension ( P<0.001), for total participants the risk of hypertension in Q4 group was 1.33 times of that in Q1 group ( OR=1.33,95% CI 1.13-1.56, P=0.001); while for females the risk of hypertension in Q4 group was 1.38 times of that in Q1 group ( OR=1.38,95% CI 1.13-1.68, P=0.002), but no significant association was observed for males ( P>0.05). The results of restricted cubic spline fitting logistic regression analysis showed that there was a linear association between uric acid level and hypertension in the total population and males, and the risk of hypertension increased with uric acid level ( P<0.001 for the total population, P=0.016 for male). However, there was a non-linear association in females. When uric acid>307 μmol/L in females, the risk of hypertension increased significantly as the level of uric acid increased ( P<0.001). Conclusions:Uric acid level was independently associated with hypertension in the community-dwelling middle-aged and elderly population, and there was a gender difference in the correlation. The association was nonlinear in females and the cut-off value of uric acid in females was 307 μmol/L.
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Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
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Humans , Middle Aged , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Immune Checkpoint Inhibitors/therapeutic use , Neoadjuvant Therapy , Prospective Studies , Rectal Neoplasms/pathology , Thrombocytopenia/drug therapy , Treatment Outcomeالملخص
Hepatocellular carcinoma (HCC), which makes up the majority of liver cancer, is induced by the infection of hepatitis B/C virus. Biomarkers are needed to facilitate the early detection of HCC, which is often diagnosed too late for effective therapy. The tRNA-derived small RNAs (tsRNAs) play vital roles in tumorigenesis and are stable in circulation. However, the diagnostic values and biological functions of circulating tsRNAs, especially for HCC, are still unknown. In this study, we first utilized RNA sequencing followed by quantitative reverse-transcription PCR to analyze tsRNA signatures in HCC serum. We identified tRF-Gln-TTG-006, which was remarkably upregulated in HCC serum (training cohort: 24 HCC patients vs. 24 healthy controls). In the validation stage, we found that tRF-Gln-TTG-006 signature could distinguish HCC cases from healthy subjects with high sensitivity (80.4%) and specificity (79.4%) even in the early stage (Stage I: sensitivity, 79.0%; specificity, 74.8%; 155 healthy controls vs. 153 HCC patients from two cohorts). Moreover, in vitro studies indicated that circulating tRF-Gln-TTG-006 was released from tumor cells, and its biological function was predicted by bioinformatics assay and validated by colony formation and apoptosis assays. In summary, our study demonstrated that serum tsRNA signature may serve as a novel biomarker of HCC.
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Humans , Biomarkers , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/diagnosis , Hepatitis B virus , Liver Neoplasms/diagnosis , RNA, Transfer/geneticsالملخص
Microribonucleic acid (miRNAs) is a widely existing endogenous single-stranded non-coding small RNA, which is stably expressed in tissues and body fluids. By complementing messenger RNA(mRNA) sequences, miRNAs degrade target mRNA and block the expression of protein-coding genes, playing a key role in post-transcriptional regulation and different biological processes. In recent years, more and more studies have shown that miRNAs are closely related to the occurrence and development of tumors. Among them, as a member of the miRNAs family, microribonucleic acid-196 (miR-196) is abnormally expressed in the serum, tissues and cells of patients with non-small cell lung cancer, participating in the occurrence and development of non-small cell lung cancer and playing an important regulatory role in various biological processes such as proliferation, invasion and metastasis, providing diagnostic evidence for early screening of non-small cell lung cancer.This paper reviews the progress of miR-196 in the development and diagnosis of non-small cell lung cancer.
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Objective:To analyze the influence of clinicopathological features on the prognosis of anorectal malignant melanoma (AMM), and to establish a more accurate prognosis prediction model.Methods:From January 1, 2006 to December 31, 2018, at Fudan University Shanghai Cancer Center, the data of 89 patients diagnosed with AMM and underwent operation were retrospectively analyzed. The Cox proportional hazard regression model was used to analyze factors affecting the prognosis. Backward elimination was used to select variables, Nomogram prognosis prediction model was established and verified internally, and the consistency index was calculated.Results:Among 89 AMM patients, 65 (73.0%) were female, 78(87.6%) were <70 years old, and the most common tumor location was the rectum (48.3%, n=43), followed by the anal canal (31.5%, n=28) and the anorectal canal (20.2%, n=18). Thirty-eight (42.7%) patients directly received abdominal-perineal resection (APR), 37 patients (41.6%) received interferon-based immunotherapy, and 11 patients (12.4%) received both systemic chemotherapy and immunotherapy. The 3-year disease-specific survival (DSS) rate was 41.6%(37/89), and the 5-year DSS rate was 31.5%(28/89). The results of multivariate Cox analysis showed that age ≥70 years old and T2 stage were risk factors of the prognosis of AMM patients (hazard ratio ( HR)=11.29, 4.83; 95% confidence interval ( CI) 2.89 to 44.13, 1.66 to 14.11; both P<0.01), while neurovascular invasion, immunotherapy treatment, systemic chemotherapy combined with immunotherapy, APR after extensive local resection, directly APR and APR combined with inguinal lymphadenectomy were protective factors of the prognosis ( HR=0.09, 0.23, 0.10, 0.13, 0.26, 0.02; 95% CI 0.02 to 0.34, 0.10 to 0.57, 0.02 to 0.49, 0.03 to 0.52, 0.08 to 0.90, 0.00 to 0.27; all P<0.05). The Nomogram model was further established with age, gender, tumor location, T stage, distant metastasis, medication chemotherapy and surgical treatment. The results of the Nomogram model internal verification indicated that the accuracy of the model in predicting 1-year, 3-year and 5-year DSS was good, and the consistency index was 0.749, which was significantly higher than the consistency index of traditional TNM stage (0.607). Conclusions:Most AMM patients are <70 years old, and the majority of them are female. The common location of AMM is rectum, and many patients receive immunotherapy. Age ≥70 years old and T2 stage are risk factors affecting the prognosis of AMM patients. Neurovascalar invasion, immunotherapy based comprehensive treatment, APR after extensive local resection, directly APR and APR combined with inguinal lymphadenectomy are protective factors of the prognosis. Nomogram prognosis prediction model established based on the clinicopathological features and treatment of AMM patients has higher accuracy and clinical reference value than the traditional TNM stage system.
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Objective@#To investigate thyroid hormone concentration and associated factors among pubertal girls in Minhang District of Shanghai.@*Methods@#From January to March 2019, a stratified sampling method was used to select junior high schools from the east, south, north, and middle areas in Minhang district. A total of 386 girls of grade 6 in selected schools were included in the study. Physical examination was conducted, and their urine and blood samples were collected to determine urinary iodine concentration (UIC) and thyroid function. Puberty Development Self-rating Scale (PDS) was used to define the pubertal stage. Logistic regression models were conducted to analyze the associations between pubertal stage and thyroid function.@*Results@#The median urinary iodine concentration was 163.57(106.57, 232.96) μg/L. The geometric mean values of TSH, TT3, FT3 and FT4 were 0.29 mU/L, 0.26 nmol/L, 0.68 pmol/L and 1.18 pmol/L.The mean value of TT4 was 91.64 nmol / L. The abnormal rates of TGAb and TPOAb were 6.22% and 4.15%. The rate of abnormal TGAb combined with abnormal TPOAb was 3.68%. Girls in puberty and post-puberty had the lower level of TT4 (OR=0.47,0.43) as compared with girls in pre-puberty stage. Obese girls had higher level of TT3(OR=9.08, 95%CI=1.52-54.07). With the increase of exercise time(0.5-1, >1 h/d), FT4 level was increased (OR=2.45, 2.19). TSH levels were significantly higher in girls with higher TGAb and TPOAb. Girls had higher TT4 or FT4 levels if their TGAb levels were higher and TPOAb levels were normal.@*Conclusion@#There is an association between pubertal stage, obesity, exercise and thyroid function in school-aged girls during puberty in iodine sufficient areas. TSH, FT4 and TT4 levels are correlated with TGAb and TPOAb levels.
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ZSP1601, a novel pan-phosphodiesterase inhibitor is in development for the treatment of nonalcoholic steatohepatitis. A physiologically-based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of ZSP1601 in human. The PBPK model following intravenous and oral dose of ZSP1601 in rats and dogs was firstly built using preclinical in vitro and in vivo data. The PBPK model in human was then built based on models in animal. The in vitro-in vivo extrapolation (IVIVE) method and some allometric scaling methods were used to predict the clearance in human, respectively. The PBPK models using IVIVE and allometry of unbound CL plus the rule of exponents methods predicted the pharmacokinetics of ZSP1601 in healthy Chinese subjects successfully. The predicted parameters Cmax and AUC following single oral dose administration were within 0.5-2 folds of the observed data. The model was optimized and the final model was used to predict the pharmacokinetics of ZSP1601 in North European Caucasian, Geriatrics, Obese and Morbidly Obese, respectively. Animal studies were approved by the Animal Management and Use Committee of Suzhou AppTec Inc., and the approved No. is SZ20140916.
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OBJECTIVE:To study the improvement effects of Sijunzi decoction on skeletal muscle atrophy in chronic kidney disease-protein energy wasting (CKD-PEW)model mice ,and to explore its potential mechanism . METHODS :A total of 80 mice were randomly divided into sham operation group (n=10)and modeling group (n=70). CKD-PEW model was established by removing 5/6 kidneys and giving a low-protein diet (4% casein)for mice in modeling group. Totally 50 modeled mice were randomly divided into model group ,Sijunzi decoction low-dose ,medium-dose and high-dose groups [ 2.34,4.68,9.36 g/(kg·d), by crude drug] ,Compound α-ketoacid tablets group [positive control ,1 g/(kg·d)],with 10 mice in each group. Administration groups were given relevant medicine intragastrically ;sham operation group and model group were given constant volume of normal saline intragastrically ,once a day ,for consecutive 14 d. After last medication ,body weight of mice and wet mass of left tibialis anterior muscle (TA)were weighed ;TA cross-sectional area was determined ;protein synthesis and decomposition metabolism ability of TA were detected ;mRNA expressions of Bcl-2,Bax and Caspase-3 in TA were detected by Real-time PCR ;protein expressions of muscular dystrophin Fbox- 1 (Atrogin-1),myofloin-1 (MuRF-1),Rho-related protein kinase 1 (ROCK1), phosphorylated PTEN (p-PTEN),phosphatidylinositol-3-kinase(PI3K)and phosphorylated Akt (p-Akt)in TA were detected by Western blotting. RESULTS :Compared with the sham operation group ,the body weight ,TA wet weight ,protein synthesis metabolism ability of TA as well as protein expressions of PI 3K and p-Akt were decreased significantly in model group (P<0.05); the cross-sectional area of TA decreased significantly (P<0.05);protein decomposition metabolism ability of TA ,Bax/Bcl-2 ratio, Caspase-3 mRNA expression ,protein expressions of Atrogin- 1,MuRF-1,ROCK1 and p-PTEN were increased significantly (P< 0.05). Compared with model group ,above indexes of mice were all improved significantly in Sijunzi decoction medium-dose , high-dose groups and Compound α-ketoacid tablets group (P<0.05). CONCLUSIONS :Sijunzi decoction can increase the body weight of CKD-PEW model mice and alleviate the skeletal atrophy ;the mechanism may be related to regulating ROCK 1/PTEN/Akt signaling pathway activity ,inhibiting the expression of Atrogin- 1 and MuRF- 1.
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Objective To determine the epidemic characteristics of cholera in Chongming Island from 1962 to 2018 and provide evidence for administrative intervention. Methods Data of cholera reports were collected in Chongming Island from 1962 to 2018 and epidemiological characteristics were described. Results From 1962 to 2018, cholera cases were reported in 35 years in Chongming Island.A total of 1 812 cases of cholera were documented with average annual incidence being 5.12/100 000.In addition, there were 545 carriers identified with average annual proportion being 1.54/100 000.The dominant strain was Ogawa 1b in 1962-1978, 1984-1987 and 1994-1999, Inaba 1d in 1979-1983 and 1988-1993, and O139 in 2000-2018.The majority of the cases were young adults and occurred from May to October. Conclusion It would facilitate the prevention and control of cholera to improve cross-regional and cross-departmental cooperation, supervise foreign aquatic products, regulate catering services in rural areas, strengthen the monitoring of diarrheal diseases, and implement early detection of imported cases and tracking of carriers.
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Objective:To analyze the clinical value of different doses of recombinant human brain natriuretic peptide (rhBNP) in the treatment of acute decompensated heart failure (ADHF) combined with renal insufficiency.Methods:Eighty patients with ADHF combined with renal insufficiency admitted to Jiaxing Second Hospital from December 2018 to January 2020 were selected. According to the random number table method, they were divided into A, B group, with 40 cases in each group. Two groups were treated with the conventional anti heart failure combined with rhBNP. The rhBNP loading doses of A and B group were 0.1 μg/kg. Group A was continually given rhBNP 0.01 μg/(kg·min) for 24 h after the loading dose, while group B was continually given 0.015 μg/(kg·min) rhBNP for 24 h. The efficacy of the two groups was compared, changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory frequency (RR), heart rate (HR) and the degree of dyspnea of patients before and after the medication were monitored, and changes of serum creatinine (Scr), Cystatin C (Cys-C), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), N-terminal pro B-type natriuretic peptide (NT-proBNP) and other cardiorenal function indexes of patients were determined. The changes of 24 h urine output were calculated, estimated glomerular filtration rate (eGFR) was counted, and the occurrence of adverse reactions and the incidence of major cardiovascular adverse events in the last 4 weeks in the two groups were observed.Results:There was no significant difference in the efficacy classification between group A and group B ( P > 0.05). After 24 h of administration, the scores of HR and dyspnea in group B were lower than those in group A [(83.86 ± 4.75) times/min vs. (86.52 ± 5.77) times/min, (1.52 ± 0.43) points vs. (1.89 ± 0.34) points] ( P<0.05). At the end of the treatment, the level of LVEF in group B was higher than that in group A [(47.52 ± 5.41)% vs. (43.75 ± 4.53)%], and the level of NT-proBNP was lower than that in group A [(3 652.41 ± 462.56) ng/L vs. (3 986.57 ± 314.21) ng/L] ( P<0.05). At the end of the treatment, the level of Scr of the two groups decreased and 24 h urine output increased, but there was no statistically significant difference between the two groups ( P>0.05). There was no statistically significant difference in the incidence of adverse reactions and adverse cardiovascular events between groups A and B ( P>0.05). Conclusions:0.015 μg/(kg·min) rhBNP maintenance therapy is more effective in improving cardiac function compared with that of 0.01 μg/(kg·min) maintenance doses in the treatment of ADHF combined with renal insufficiency, and it is safe and feasible without aggravating renal impairment of patients.
الملخص
Objective:To investigate the value of total laparoscopic simultaneous resection for left-sided colorectal cancer (CRC) and synchronous liver metastases (SLM).Methods:A retrospective analysis of the clinical data of patients with left-sided CRC and SLM who underwent simultaneous resection in the Shanghai Cancer Center, Fudan University from March 2014 to December 2017. The patients were divided into laparoscopy group, open surgery group and hybrid surgery group. The intraoperative information, postoperative short-term outcome and long-term survival were analyzed among the three groups.Results:A total of 96 patients were enrolled. The total laparoscopic group enrolled 29 patients, including 21 males and 8 females, aged (57.8±1.6) years old; the open surgery group enrolled 28 patients, including 18 males and 10 females, aged (57.3±2.0) years old; 39 cases were included in the hybrid surgery group, including 27 males and 12 females, aged (55.3±1.8) years old. The distribution ratio of the two lobes of liver metastases in the open surgery group was higher than that in the total laparoscopic group and hybrid surgery group (all P<0.05), and there was no significant difference in the other clinical baseline characteristics between the three groups (all P>0.05). In laparoscopy group, open surgery group and hybrid surgery group, the mean operative time was (241.5±12.9) min, (209.3±10.7) min and (234.9±12.4) min, respectively. The median intraoperative blood loss was 200.0 ml, 300.0 ml and 200.0 ml, respectively. The median postoperative hospital stay was 8.0 days, 9.0 days and 9.0 days, respectively. There were no statistical differences in these indicators (all P>0.05). The patients in the open surgery group had a longer initial defecation time than those in the other two groups ( P<0.05). The incidence of postoperative complications was 31.0% (9/29), 39.3% (11/28) and 35.9% (14/39), respectively, with no difference among the three groups ( P>0.05). In laparoscopy group, open surgery group and hybrid surgery group, 1-year overall survival were 93.0%, 85.0% and 94.0%; 3-year overall survival were 72.0%, 81.0% and 74.0%, respectively ( P>0.05). One-year disease free survival were 70.0%, 52.0% and 55.0%; 3-year disease free survival were 36.0%, 30.0% and 39.0%, respectively ( P>0.05). Conclusion:Laparoscopic simultaneous resection for left-sided CRC and SLM shows slight advantages in the safety and short-term outcome, and does not affect the long-term survival.
الملخص
The study aimed to investigate the effect and mechanism of aspirin combined with vinorelbine on the proliferation and apoptosis of non-small cell lung cancer cells. 3-(4-dimethylthiazolyl-2)-2-diphenyltetrazolium bromide(MTT) was used to detect the cytotoxic effect of aspirin and vinorelbine on H460 and A549 cells, and half of inhibitory concentration(IC_(50)) value of drugs as well as synergistic effect were calculated. The results showed that both aspirin and vinorelbine inhibited the cancer cells proliferation by a concentration-dependent manner with IC_(50 )values of 1.553 mmol·L~(-1) and 0.033 μmol·L~(-1) in H460 cells, respectively. The IC_(50 )values of aspirin and vinorelbine were 1.70 mmol·L~(-1)and more than 20 μmol·L~(-1) in A549 cells. The combination index(CI) value was used to evaluate the combined effect of two drugs. Aspirin combined with vinorelbine had synergistic effects at the ratio of 100∶1 on H460 cells and 1∶10 on A549 cells(CI<1). Clone formation and 4',6-diamidino-2-phenylindole(DAPI)/propidium iodide(PI) staining assays were used to verify the effect of the combination of two drugs on proliferation of H460 cells. Compared with the aspirin single group, the combination group had stronger inhibitory effect on the proliferation of H460 cells and the clone formation rate was 49.5%(P<0.05). Furthermore, apoptosis, mitochondrial membrane potential, reactive oxygen species and Western blot experiments were used to explore the synergistic mechanism of aspirin combined with vinorelbine in inhibiting cell proliferation. The results showed that the cancer cell apoptosis rate was 52.8%, the mitochondrial membrane potential was decreased to 33.1%, and the levels of reactive oxygen species was increased to 73.3% in combination group, which were significantly different from those of the single drug treatment groups(P<0.05). Western blot showed that combination group significantly up-regulated the expressions of Bax, p53, cleaved caspase-3 and cytochrome C, while down-regulated the expression of anti-apoptosis proteins such as Bcl-xL and Bcl-2 when compared with single groups. Our results suggested that aspirin combined with vinorelbine could synergistically inhibit the proliferation of H460 cells by inducing the cell apoptosis through the mitochondrial pathway.