Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

Child ; Humans ; Factor VII Deficiency

Objective: To analyze the incidence and related factors of drug resistance in HIV-infected pregnant and postpartum women in some areas of three western provinces of China from 2017 to 2019. Methods: From April 2017 to April 2019, face-to-face questionnaires and blood sample testing were conducted in all health care institutions providing maternal and perinatal care and midwifery-assisted services in 7 prevention of mother-to-child transmissi project areas in Xinjiang, Yunnan and Guangxi provinces/autonomous regions. Information was collected during the perinatal period and viral load, CD4⁺T lymphocytes and drug resistance genes were detected at the same time. The multivariate logistic regression model was used to analyze the relationship between different factors and drug resistance in HIV-infected pregnant and postpartum women. Results: A total of 655 HIV-infected pregnant and postpartum women were included in this study. The incidence of drug resistance was 3.4% (22/655), all of whom were cross-drug resistant. The rate of low, moderate and high drug resistance was 2.1% (14/655), 1.2% (8/655) and 0.8% (5/655), respectively. The drug resistance rate in the people who had previously used antiviral drugs was 1.9% (8/418), and the drug resistance rate in the people who had not used drugs was 5.9% (14/237). The NNRTI drug resistance accounted for 2.8% (18/655) and the NRTI drug resistance rate was 2.5% (16/655). The multivariate logistic regression model showed that the risk of HIV resistance was lower in pregnant women who had previously used antiviral drugs (OR=0.32, 95%CI: 0.11-0.76). Conclusion: Strengthening the management of antiviral drug use and focusing on pregnant and postpartum women who have not previously used antiviral drugs can help reduce the occurrence of drug-resistant mutations. Personalized antiviral therapy should be considered to achieve viral inhibition effects in clinical practice.
Female ; Humans ; Pregnancy ; HIV Infections/drug therapy* ; Incidence ; China/epidemiology* ; Infectious Disease Transmission, Vertical/prevention & control* ; Postpartum Period ; Drug Resistance, Viral/genetics* ; Antiviral Agents/therapeutic use*

Objective: To analyze the incidence and related factors of drug resistance in HIV-infected pregnant and postpartum women in some areas of three western provinces of China from 2017 to 2019. Methods: From April 2017 to April 2019, face-to-face questionnaires and blood sample testing were conducted in all health care institutions providing maternal and perinatal care and midwifery-assisted services in 7 prevention of mother-to-child transmissi project areas in Xinjiang, Yunnan and Guangxi provinces/autonomous regions. Information was collected during the perinatal period and viral load, CD4⁺T lymphocytes and drug resistance genes were detected at the same time. The multivariate logistic regression model was used to analyze the relationship between different factors and drug resistance in HIV-infected pregnant and postpartum women. Results: A total of 655 HIV-infected pregnant and postpartum women were included in this study. The incidence of drug resistance was 3.4% (22/655), all of whom were cross-drug resistant. The rate of low, moderate and high drug resistance was 2.1% (14/655), 1.2% (8/655) and 0.8% (5/655), respectively. The drug resistance rate in the people who had previously used antiviral drugs was 1.9% (8/418), and the drug resistance rate in the people who had not used drugs was 5.9% (14/237). The NNRTI drug resistance accounted for 2.8% (18/655) and the NRTI drug resistance rate was 2.5% (16/655). The multivariate logistic regression model showed that the risk of HIV resistance was lower in pregnant women who had previously used antiviral drugs (OR=0.32, 95%CI: 0.11-0.76). Conclusion: Strengthening the management of antiviral drug use and focusing on pregnant and postpartum women who have not previously used antiviral drugs can help reduce the occurrence of drug-resistant mutations. Personalized antiviral therapy should be considered to achieve viral inhibition effects in clinical practice.
Female ; Humans ; Pregnancy ; HIV Infections/drug therapy* ; Incidence ; China/epidemiology* ; Infectious Disease Transmission, Vertical/prevention & control* ; Postpartum Period ; Drug Resistance, Viral/genetics* ; Antiviral Agents/therapeutic use*

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.
Animals ; Bile ; Bile Acids and Salts ; Endothelial Cells/metabolism* ; Hepatic Veno-Occlusive Disease/pathology* ; Inflammation/pathology* ; Liver Cirrhosis/drug therapy* ; Mice ; Powders ; Pyrrolizidine Alkaloids/adverse effects* ; Ursidae

Numerous in vitro studies have shown that most pyrrolizidine alkaloids (PAs) are hepatotoxic after being metabolically activated by cytochrome P450 (CYP) 3A4. However, the key role of CYP3A4 has not been confirmed in vivo. Therefore, the CYP3A4 chemical inhibitor ritonavir was employed in this work and the effect of ritonavir on Gynura japonica-induced liver injury in rats was investigated. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. Acute liver injury was induced by a single gavage of Gynura japonica extracts (GJE, 8 g·kg^-1); rats in the protection group were gavaged with ritonavir (RIT, 30 mg·kg^-1) 1 h before GJE treatment. The results show that RIT could significantly attenuate GJE-induced liver injury in rats. Rats in the protection group showed decreased serum activities for alanine aminotransferase and aspartate aminotransferase, as well as lower total bile acids. In addition, the infiltration of inflammatory cells, sinusoidal hemorrhage, and hepatic necrosis in GJE-treated rats were markedly attenuated in the protection group. The content of pyrrole-protein adducts (PPAs), a recommended biomarker for PA-induced hepatotoxicity in clinics, was determined at 10 min to 24 h after GJE treatment. The content of 13 bile acids was also quantified. RIT treatment reduced the content of PPAs in serum dramatically and restored the impaired bile acid homeostasis caused by GJE. These studies indicate that RIT attenuated Gynura japonica-induced liver injury in rats, which was closely related to the inhibition of the metabolic activation of PAs and the regulation of bile acid metabolism. These results provide a better understanding of the relationship between CYP3A4 and PA-induced toxicity. This work will also be helpful in developing effective treatments for PA-induced liver injury and making a reasonable evaluation of the safety of drugs containing PAs in clinic.

Neoadjuvant chemotherapy (NAC) has shown promising results in patients with locally advanced penile cancer. However, no consensus exists on its applications for locally advanced penile cancer. Thus, it is unclear which kind of chemotherapy regimen is the best choice. Consequently, a systematic search of PubMed, Web of Science, and EMBASE was performed in March 2021 to assess the efficacy and safety of NAC for the treatment of patients with locally advanced penile cancer. The Newcastle-Ottawa Scale was used to assess the risk of bias in each study. This study synthesized 14 published studies. The study revealed that patients who achieved an objective response to NAC obtained a better survival outcome compared with those who did not achieve an objective response. In addition, the objective response rates (ORRs) and pathological complete response (pCR) rates were 0.57 and 0.11, respectively. The incidence of grade ≥3 toxicity was 0.36. Subgroup analysis found that the ORR and pCR of the taxane-platinum (TP) regimen group performed better than those of the nontaxane-platinum (NTP) regimen group (0.57 vs 0.54 and 0.14 vs 0.07, respectively). Moreover, the TP regimen group had more frequent toxicity than the NTP regimen group (0.41 vs 0.26). However, further studies were warranted to confirm the findings.
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Humans ; Male ; Neoadjuvant Therapy/methods* ; Penile Neoplasms/drug therapy* ; Platinum ; Treatment Outcome

Objective: To analyze the clinical epidemiological characteristics including composition of pathogens , clinical characteristics, and disease prognosis acute bacterial meningitis (ABM) in Chinese children. Methods: A retrospective analysis was performed on the clinical and laboratory data of 1 610 children <15 years of age with ABM in 33 tertiary hospitals in China from January 2019 to December 2020. Patients were divided into different groups according to age,<28 days group, 28 days to <3 months group, 3 months to <1 year group, 1-<5 years of age group, 5-<15 years of age group; etiology confirmed group and clinically diagnosed group according to etiology diagnosis. Non-numeric variables were analyzed with the Chi-square test or Fisher's exact test, while non-normal distrituction numeric variables were compared with nonparametric test. Results: Among 1 610 children with ABM, 955 were male and 650 were female (5 cases were not provided with gender information), and the age of onset was 1.5 (0.5, 5.5) months. There were 588 cases age from <28 days, 462 cases age from 28 days to <3 months, 302 cases age from 3 months to <1 year of age group, 156 cases in the 1-<5 years of age and 101 cases in the 5-<15 years of age. The detection rates were 38.8% (95/245) and 31.5% (70/222) of Escherichia coli and 27.8% (68/245) and 35.1% (78/222) of Streptococcus agalactiae in infants younger than 28 days of age and 28 days to 3 months of age; the detection rates of Streptococcus pneumonia, Escherichia coli, and Streptococcus agalactiae were 34.3% (61/178), 14.0% (25/178) and 13.5% (24/178) in the 3 months of age to <1 year of age group; the dominant pathogens were Streptococcus pneumoniae and the detection rate were 67.9% (74/109) and 44.4% (16/36) in the 1-<5 years of age and 5-<15 years of age . There were 9.7% (19/195) strains of Escherichia coli producing ultra-broad-spectrum β-lactamases. The positive rates of cerebrospinal fluid (CSF) culture and blood culture were 32.2% (515/1 598) and 25.0% (400/1 598), while 38.2% (126/330)and 25.3% (21/83) in CSF metagenomics next generation sequencing and Streptococcus pneumoniae antigen detection. There were 4.3% (32/790) cases of which CSF white blood cell counts were normal in etiology confirmed group. Among 1 610 children with ABM, main intracranial imaging complications were subdural effusion and (or) empyema in 349 cases (21.7%), hydrocephalus in 233 cases (14.5%), brain abscess in 178 cases (11.1%), and other cerebrovascular diseases, including encephalomalacia, cerebral infarction, and encephalatrophy, in 174 cases (10.8%). Among the 166 cases (10.3%) with unfavorable outcome, 32 cases (2.0%) died among whom 24 cases died before 1 year of age, and 37 cases (2.3%) had recurrence among whom 25 cases had recurrence within 3 weeks. The incidences of subdural effusion and (or) empyema, brain abscess and ependymitis in the etiology confirmed group were significantly higher than those in the clinically diagnosed group (26.2% (207/790) vs. 17.3% (142/820), 13.0% (103/790) vs. 9.1% (75/820), 4.6% (36/790) vs. 2.7% (22/820), χ²=18.71, 6.20, 4.07, all P<0.05), but there was no significant difference in the unfavorable outcomes, mortility, and recurrence between these 2 groups (all P>0.05). Conclusions: The onset age of ABM in children is usually within 1 year of age, especially <3 months. The common pathogens in infants <3 months of age are Escherichia coli and Streptococcus agalactiae, and the dominant pathogen in infant ≥3 months is Streptococcus pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. ABM should not be excluded even if CSF white blood cell counts is within normal range. Standardized bacteriological examination should be paid more attention to increase the pathogenic detection rate. Non-culture CSF detection methods may facilitate the pathogenic diagnosis.
Adolescent ; Brain Abscess ; Child ; Child, Preschool ; Escherichia coli ; Female ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Male ; Meningitis, Bacterial/epidemiology* ; Retrospective Studies ; Streptococcus agalactiae ; Streptococcus pneumoniae ; Subdural Effusion ; beta-Lactamases

OBJECTIVE: To observe the tubulointerstitial damage (TID) in lupus nephritis (LN) and investigate the relationship between autoantibodies and TID in lupus nephritis. METHODS: This cross-sectional study was conducted in a comprehensive tertiary hospital in Peking University Shenzhen Hospital. From March 2012 to July 2021, LN patients who performed renal biopsy were enrolled in the study. Clinical, laboratory and pathology data were collected. We classified the patients into none-or-mild group and moderate-to-severe groups according to the severity of interstitial fibrosis (IF) /tubular atrophy (TA) or tubulointerstitial inflammation (TII). The t test, U test and Chi-square test were used for statistical analysis as appropriate. RESULTS: A total of 226 patients were included, of who 190 (84%) were female with a median age of 32 (26, 39) years. 89% (201/226) of the patients who pathologically proved to be proliferative LN by renal biopsy. The frequency of moderate-to-severe TII and moderate-to-severe IF/TA was 30% (67/226) and 34% (76/226) respectively. For autoantibodies, the patients with moderate-to-severe TII had a lower rate of positive serum anti-ribonucleoprotein (anti-RNP) antibodies than the patients with none-or-mild TII (34% vs. 51%), and moderate-to-severe IF/TA had a lower rate of positive anti-ribosomal P protein (anti-P) antibodies than patients with none-or-mild IF/TA (19% vs. 33%). For other clinical indicators, the patients with moderate-to-severe TII and moderate-to-severe IF/TA were more often combined with proliferative LN, hypertension and anemia than the patients with none-or-mild TII and none-or-mild IF/TA, respectively. The patients with moderate-to-severe TII had higher serum creatinine values and lower glomerular filtration rates than the patients with none-or-mild TII. The patients with moderate-to-severe IF/TA had higher serum creatinine values, and lower glomerular filtration rates than the patients with none-or-mild IF/TA. CONCLUSION In patients with LN in Southern China, anti-RNP antibodies and anti-P antibodies may be potential protective factors for TII and IF/TA, respectively. More studies are needed to identify the risk factors of lupus patients with TID and investigate the correlation between autoantibodies and TID, which are critical for developing better preventive and therapeutic strategies to improve the survival rate of LN.
Humans ; Female ; Male ; Lupus Nephritis ; Kidney/pathology* ; Creatinine ; Cross-Sectional Studies ; Inflammation ; Antibodies, Antinuclear ; Autoantibodies