Objective:To study the change of plasma calcitonin gene-related peptide(CGRP) and endothelin(ET) concentrations and relationship with incidence of preeclampsia in plateau region.Methods:31 patients with severe preeclampsia were compared with 30 normal late pregnant women in plateau region,the plasma CGRP and ET levels were determined before and one week after delivery by radioimmunoassay.Results:The plasma CGRP level(71.71±3.75 ng/L) was significantly lower in patients with severe preeclampsia than that(110.51±7.55 ng/L) of control group(P0.01);but ET level(68.96±11.27 ng/L) was significantly higher than that(44.70±4.46 ng/L) of control group(P0.01).The patients' conditions with preeclampsia were significantly relieved within one week after delivery.Compared to the control group,their parameters changed remarkably,plasma CGRP level increased(101.21±7.46 ng/L)(P0.01) and ET level decreased to normality(51.89±7.87 ng/L)(P0.05).Conclusions:Levels of plasma CGRP and ET are important to reflect onset of patients with severe preeclampsia and to evaluate patients' condition in plateau region.
Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.
Chronic low-grade inflammation and oxidative stress play important roles in the development of obesity-induced cardiac hypertrophy. Here, we investigated the role of Fibronectin type III domain containing 5 (FNDC5) in cardiac inflammation and oxidative stress in obesity-induced cardiac hypertrophy. Male wild-type and FNDC5−/− mice were fed normal chow or high fat diet (HFD) for 20 weeks to induce obesity, and primary cardiomyocytes and H9c2 cells treated with palmitate (PA) were used as in vitro model. The therapeutic effects of lentiviral vector-mediated FNDC5 overexpression were also examined in HFD-induced cardiac hypertrophy. High fat diet manifested significant increases in body weight and cardiac hypertrophy marker genes expression, while FNDC5 deficiency aggravated cardiac hypertrophy evidenced by increased Nppa, Nppb and Myh7 mRNA level and cardiomyocytes area, in association with enhanced cardiac inflammatory cytokines expression, oxidative stress level and JAK2/STAT3 activation in HFD-fed mice. FNDC5 deficiency in primary cardiomyocytes or FNDC5 knockdown in H9c2 cells enhanced PA-induced inflammatory responses and NOX4 expression. Exogenous FNDC5 pretreatment attenuated PA-induced cardiomyocytes hypertrophy, inflammatory cytokines up-regulation and oxidative stress in primary cardiomyocytes and H9c2 cells. FNDC5 overexpression attenuated cardiac hypertrophy as well as cardiac inflammation and oxidative stress in HFD-fed mice. FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-cardiac inflammation and oxidative stress. The cardio-protective role of FNDC5 shed light on future therapeutic interventions in obesity and related cardiovascular complications.
Human cord blood CD34~(+) cells could be enriched to the purity of 80%-87%. Some cytokines had obvious synergistic effect. The effects of combined cytokines on the expansion of CD34~(+) cells were higher than that of single cytokine. IL-3 was the critical cytokine promoting the expansion of total nucleated cell and CFC in the presence of SCF+FL. Cytokines SCF+FL+IL-3 and SCF+FL+IL-3+IL-6 were identified as the most potent combinations for the expansion of total nucleated cells and CFC, and increased CFC 38.3±4.4 fold and 29.6±2.7 fold at 14-day incubation, respectively.
Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension.Primary VSMCs from the aorta of NLRP3 knockout (NLRP3-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3-/- mice.NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3-/- mice.NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.
Mesenchymal stem cell (MSC) membrane‐coated metal–organic frameworks (MOFs) represent an innovative approach to enhance the uptake and therapeutic efficacy of copper‐based MOFs (Cu‐MOFs) in tumor cells. By leveraging the natural homing abilities and biocompatibility of MSC membranes, Cu‐MOFs can be effectively targeted to tumor sites, promoting increased cellular uptake. This coating not only facilitates superior internalization by cancer cells but also augments the therapeutic outcomes due to the enhanced delivery of copper ions. In vitro studies demonstrate that MSC membrane‐coated Cu‐MOFs (MSC‐Cu‐MOFs) significantly improve the cytotoxic effects on tumor cells compared to uncoated Cu‐MOFs. This novel strategy presents a promising avenue for advancing the precision and effectiveness of cancer treatment modalities, showcasing potential for clinical applications in oncology.
ABSTRACT Well-use histories were obtained and dermatological examinations were conducted for 3,179 of the 3,228 (98.5%) residents of 3 villages in Inner Mongolia with well water arsenic levels as high as 2,000 ppb (ug/L). Eight persons were found to have skin cancer, 172 had hyperkeratoses, 121 had dyspigmentation, 94 had both hyperkeratoses and dyspigmentation, and, strikingly, none had Blackfoot disease. All 8 subjects with skin cancer also had both hyperkeratoses and dyspigmentation. Arsenic levels were measured for 184 wells and individual well-use histories were obtained. Arsenic exposure histories were summarized as both highest arsenic concentration (highest exposure level for at least 1-year duration) and cumulative arsenic exposure (ppb-years). Sixty-nine percent of the participants had highest arsenic concentrations below 100 ppb; 71% had cumulative arsenic exposures below 2,000 ppb-years. Exposure-response analyses included frequency-weighted, simple linear regression, and most-likely estimate (hockey-stick) models. Skin cancer cases were only found for those with a highest arsenic concentration greater than 150 ppb, and those with exposure less than 150 ppb had a statistically significant deficit. A frequency-weighted model showed a threshold at 150 ppb, and a hockey-stick model showed a threshold at 122 ppb. Considerations of duration, age, latency, and misclassification did not appear to markedly affect the analysis. The non-malignant skin findings showed thresholds of 40–50 ppb in the hockey-stick models. Application of these analytic models to the data from other epidemiological studies of arsenic ingestion and malignant and non-malignant skin disorders can be used to examine patterns of arsenic carcinogenicity. Key Words: arsenic-related skin effectsskin cancer riskInner Mongoliathreshold (hockey-stick) modelView correction statement:Erratum ACKNOWLEDGMENTS This analysis was funded in part by a grant [# H75/ATH682885] to the University of Texas—Houston Medical School (Department of Dermatology) from the Agency for Toxic Substances and Disease Registry [ATSDR]. We thank the colleagues of the Huhhot Center for Disease Control and Prevention, Inner Mongolia, China [formerly, the Huhhot Sanitation and Anti-Epidemic Station] for their diligence and maintenance of the study and their follow-through on the care of the patients. We thank the residents of the three villages for providing the information upon which this study is based and the acceptance of the investigators. We thank Katharine Shelley for assistance in development of this article. This article was presented in part at the American Association for Cancer Research meeting (2006) section on chemical carcinogenesis. We wish particularly to thank Sharon S. Campolucci, project director of the ASTDR grant, whose personal encouragement, interest, and support has been greatly appreciated. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Agency for Toxic Substances and Disease Registry. Notes *Well-use data missing for 45 and dermatological findings missing for 4 participants. *Age missing on four participants (three from Hei He and one from Tie Men Geng). *A-mean = arithmetic mean; A-std = arithmetic standard deviation; Min = minimum; P25 = 25th percentile value; Med = Median; P75 = 75th percentile value; Max = maximum. *A-mean = arithmetic mean; A-std = arithmetic standard deviation; G-mean = geometric mean; G-std = geometric standard deviation; Min = minimum; P25 = 25th percentile value; Med = Median; P75 = 75th percentile value; Max = maximum. *Percent of total population, i.e., those examined and with well-use history. **Skin cancer cases as a percent of subjects with listed skin disorder. +Unit risk per ppb. * p < 0.05. *Threshold significantly different from zero at p < 0.05. *Significantly different from zero at p < 0.05 (two-tail). +Significantly different from zero at p < 0.05 (one-tail). *Time interval in years from beginning of highest exposure until examination date (1992). *Double numbers indicate that two threshold points satisfactorily fit the model.
Background T cell receptor (TCR)-T cell therapy is an innovative form of cancer immunotherapy that genetically modifies patients’ T cells to target and destroy cancer cells. However, the current status of clinical trials of TCR-T cell therapy for the treatment of cancer remains unclear. This study aimed to comprehensively analyze the registration trials related to TCR-T cell therapy for the treatment of cancer. Methods A comprehensive search was conducted in the Trialtrove database for all clinical trials related to TCR-T cell therapy registered by August 1, 2024. Inclusion criteria focused on trials targeting TCR-T cell therapy for oncology, and excluded observational studies and incomplete data. Statistical analysis was performed on key trial characteristics, with between-group comparisons utilizing chi-square or Fisher’s exact tests. Results Analysis of 174 eligible clinical trials revealed that TCR-T cell therapy exhibits significant efficacy across various tumor types, particularly in refractory hematologic malignancies and certain solid tumors. Additionally, combining TCR-T cell therapy with other immunotherapies enhanced these anti-tumor effects. Conclusion TCR-T cell therapy holds substantial promise for cancer treatment. Future research should focus on optimizing treatment protocols, enhancing efficacy, and minimizing prices to fully realize the potential of this therapy.
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