Asia Pacific Academy of Science Pte. Ltd.
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Analysis of the Failure to Reach the Standard of Vancomycin Blood Trough Concentration in Critically Ill Patients and Its Influencing Factors
No full textObjective: This study analyzes the failure of vancomycin blood trough concentration in critically ill patients and the influencing factors to provide a theoretical basis for its rational application. Methods: The data of 45 critically ill patients with infections induced by vancomycin treatment were retrospectively collected. Patients with a vancomycin blood trough concentration of <10 mg/L were assigned into the substandard group (n = 18), and those with a vancomycin blood trough concentration of ≥10 mg/L were assigned into the standard group (n = 27). Data such as age, gender, underlying diseases, treatment methods, albumin, creatinine, and glomerular filtration rate were analyzed, then multivariate analysis was performed using binary logistic regression. Results: The age, drug blood trough concentration, peak concentration, and blood creatinine concentration were significantly lower in the substandard group than in the standard group (p < 0.05), and the epidermal growth factor receptor (eGFR) level was significantly higher than in the standard group (p < 0.001). The rate of renal replacement therapy (RRT) was higher in the standard group than in the substandard group (p = 0.031). The factors with statistical differences between the two groups (age, blood drug peak concentration, eGFR, treatment methods, and continuous RRT) were used as the independent variables (X). Whether the blood concentration of vancomycin reached the standard was used as the dependent variable (Y). Binary multivariate logistic regression analysis was conducted. The results show that serum creatinine (p = 0.037, OR (odds ratio) = 1.248) and eGFR (p = 0.026, OR = 0.913) were independent influencing factors of vancomycin. Conclusions: The failure rate of vancomycin trough concentration in critically ill patients is higher. Serum creatinine and eGFR are independent associated factors for the substandard rate of vancomycin trough concentration
Celecoxib Attenuates Brain Hippocampal Damage in PTZ-Induced Epilepsy Rats by Inhibiting NF-κB
No full textBackground: Epileptic seizures negatively impact cognitive function and increase the levels of prostaglandins and nuclear transcription factor-κB (NF-κB) in the brain, leading to neuroinflammation. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to inhibit inflammatory mediators. This study aims to determine whether celecoxib reduces the production of inflammatory mediators in status epilepticus (SE) by regulating the NF-κB pathway and has a protective effect on neurons. Methods: Male Wistar rats received 35 mg/kg/day of pentylenetetrazole (PTZ) intraperitoneally (i.p.) for 28 days. The effects of pre-treatment with celecoxib (10 mg/kg) and celecoxib plus NF-κB/p65 (p65) inhibitor, caffeic acid phenethyl ester (CAPE;15 mg/kg), against PTZ-kindled seizures were investigated. After treatment with celecoxib or celecoxib plus CAPE for 5, 10, 15 and 21 days, PTZ was injected and the seizure scores were analyzed. The hippocampus histopathology examination was completed after hematoxylin-eosin staining (H&E) staining and Nissl staining. The mRNA expression levels of PGE2 (Prostaglandin E2), PGI2 (Prostaglandin-I-2), and p65 were examined by real time quantitative PCR (RT-qPCR). The production of PGE2 and PGI2 were analyzed by enzyme linked immunosorbent assay (ELISA). The protein expression levels of nuclear p65, total p65, and total phosphorylated p65 were determined by western blot and immunofluorescence. Results: Celecoxib treatment or celecoxib plus CAPE co-treatment after SE seizure significantly reduced the seizure scores and protected hippocampal neurons from SE damage. Celecoxib also down-regulated the mRNA expression levels of PGE2, PGI2, and p65, as well as the reduction of PGE2 and PFI2 production. In addition, celecoxib significantly suppressed the protein expression levels of nuclear p65 and total phosphorylated p65. The therapeutic effects of celecoxib were more significant after CAPE down-regulated the NF-κB pathway. Conclusions: Celecoxib may inhibit the expression of PGE2 and PGI2 by regulating the NF-κB pathway and has a protective effect on neurons, which may appear as a promising antiepileptic drug
Identification of Key Genes and Pathways Associated with Adriamycin Resistance in Breast Cancer
No full textObjective: Drug resistance to the chemotherapeutic drug Adriamycin (ADR) is a key clinical impediment to successful breast cancer treatment (BrCa). However, the molecular mechanism and targets that mediate ADR resistance remain unclear. Therefore, the identification of ADR response biomarkers to improve the treatment of patients with BrCa is an urgent issue. Methods: The GSE24460 dataset on Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) was employed in this investigation, which covers gene expression profiles of parental and ADR-resistant cell lines of MCF-7 (cell lines in the human breast cancer). Differentially expressed genes (DEGs) in parental and ADR-resistant cells, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway studies, and the interactions of protein-protein were used to identify the overall biological alterations (PPIs). The most prevalent DEGs in the PPI, GO, and KEGG pathways were discovered and using GSE34138 dataset from the GEO database were validated, and their ability to forecast overall survival (OS) and relapse-free survival (RFS) was clinically validated. The link between the DEGs and OS/RFS was studied after further verification of the most common DEGs in those pathways. The most significant crucial gene, collagen type-IV alpha 1 (COL4A1), was discovered in the MCF-7 and MCF-7/ADR cells using the quantitative real-time reverse transcription PCR, Western blot, and Cell Counting Kit-8 assays to further highlight the distinctions. Results: 207 DEGs in total were discovered, with 111 upregulated and 96 downregulated. After mapping the GOs, pathways, and PPI networks, six genes—cyclin-dependent kinase inhibitor 2A (CDKN2A), retinoblastoma 1 (RB1), C-X-C motif ligand 12 (CXCL12), COL4A1, intercellular cell molecule-1 of adhesion (ICAM1), and cadherin 1 (CDH1)—were found to be frequently enriched. COL4A1 was found to be favorably associated with ADR resistance and poor OS, as well as strongly associated with RFS. The correlation between CDH1 and ADR resistance was negative, which was substantial in terms of poor RFS. In MCF-7/ADR cells, COL4A1 also expression was noted to have increased, and COL4A1 knockdown significantly reduced the inhibitory concentration 50% value of ADR in those cells. Conclusions: Our data identified the significant pathways and genes for predicting the emergence of ADR resistance and revealed that COL4A1 regulated the proliferation of MCF-7/ADR and played a crucial role in ADR resistance. Therefore, COL4A1 shows that it can be novel target for improving patients prognosis with ADR-resistant BrCa
Downhill Running Increases Bone Mass Accumulation and Bone Tissues Morphology through the TGF-β/Smad Pathway in the Bone of Growing Mice
No full textBackground: Substantial evidence has demonstrated that impact exercise can help adolescents to accumulate more bone mass. However, the effect of OB (osteoblast) on promoting bone formation during impact exercise remains to be explored. This study aimed to examine the mechanism for downhill running promoting bone formation ability and bone mineralization ability by activating the TGF-β (transforming growth factor-β)/Smad (drosophila mothers against decapentaplegic protein) pathway in growing mice. Methods: Four-week-old C57BL/6 female mice (n = 28) were randomly divided into exercise and control groups. Mice in the exercise group received a forty-minute downhill training on a descending treadmill (descent 9°) every day for eight weeks. After eight weeks, BMSCs (bone marrow mesenchymal stem cells) were collected and cultured for assessment of osteoblastic differentiation and the capacity of osteoblastic mineralization. We determined the protein and mRNA expression of TGF-β, Smad2/3/4, and Runx2 (runt-related transcription factor 2) in bone tissues. The BMD (bone mineral density) and histomorphological changes were also examined. Results: The study showed that the eight-week downhill training significantly increased BMD and ALP (alkaline phosphatase-positive) activity in the tibial epiphysis. Also, downhill running promoted BV/TV (bone volume fraction), Tb.N (trabecular number), and Tb.Th (trabecular thickness), while it decreased Tb.Sp (trabecular separation). Additionally, the numbers of ALP+CFU-f (colony forming units-fibroblastic) cells and the area of mineralized nodule formation were significantly higher in the exercise group compared with that of the control group. Lastly, the mRNA expression of TGF-β, Smad2/3/4, and Runx2 was significantly elevated in the exercise group, and the protein expression of p-Smad2/3/4, and Runx2 was also increased. Conclusions: The findings indicated that downhill running enhanced bone mass accumulation and bone tissue morphology in growing mice by activating the TGF-β/Smad pathway
Associations of Body Mass Index with Outcomes of Sepsis: A Meta-Analysis
No full textBackground: Sepsis is an atypical systemic reaction to infection with high morbidity and mortality. Recently, an association between improved prognosis and obesity in sepsis has been reported;However, the results remain controversial. The objective of the present study was to investigate the association between body mass index (BMI) and sepsis mortality by performing a meta-analysis. Methods: Considering pre-established inclusion and exclusion criteria, eligible studies were retrieved from PubMed, Embase, and Web of Science. Cochran’s Q test and I2 test were used to evaluate the heterogeneity among studies for each outcome. Statistical analysis was conducted using Stata12.0 software (version 12 SE;Stata Corporation, College Station, TX, USA). Odds ratios (OR) and 95% confidence intervals (CI) were used as effect sizes to evaluate differences in hospital, intensive care unit (ICU), 30-day, 90-day, and 1-year mortality in underweight, overweight, and obese patients with sepsis when compared with those with normal-weight. Results: In patients with sepsis, underweight was associated with increased in-hospital, ICU, and 1-year mortality (all odds ratio [OR] >1, p < 0.05), whereas no significant association was detected with 30- and 90-day mortality (all OR >1, p > 0.05). The association between underweight and in-hospital mortality disappeared in the non-Asian (OR [95% CI] = 1.13 [0.90, 1.41], p = 0.310) and non-adjusted subgroups (OR [95% CI] = 1.19 [0.92, 1.53], p = 0.186). Overweight was associated with decreased ICU mortality, 30-day mortality, 90-day mortality, and 1-year mortality in patients with sepsis (all OR <1, p < 0.05), exhibiting no significant association with in-hospital mortality (OR [95% CI] = 0.89 [0.78, 1.01], p = 0.074). Obesity was associated with decreased in-hospital, ICU, 30-day, 90-day, and 1-year mortality in patients with sepsis (all OR <1, p < 0.05). Conclusions: The results of the present meta-analysis supported the view of the “obesity paradox”. An underweight BMI was associated with increased sepsis mortality, whereas overweight and obesity were associated with low mortality in sepsis. These findings suggest that the clinical management of sepsis should follow the principle of a personalized approach, and the impact of obesity on the pattern of infection, fluids, and antibiotic administration should be carefully considered
Exploring the Impact of Sirt1 on Oxidative Stress and Inflammation in Alzheimers Disease Cell Models Through p53 Regulation: A Preliminary Study
No full textObjective: Sirtuin (Sirt), an NAD+-dependent deacetylase, is known for its regulatory role in cellular metabolism, aging, and disease. Evidence suggests that Sirt1 is linked to the pathogenesis of Alzheimers disease (AD). This study aims to elucidate how Sirt1 regulates p53, focusing on the AD cell models inflammatory response and oxidative stress. Methods: Cell experiments were divided into three groups: the Control group, the Model group, and the Resveratrol group. The Control group underwent regular media changes, while the Model group was exposed to a mixture of Amyloid-beta (Aβ) oligomers (0.55 μM) and IBO (0.6 μM) for 48 hours to create an AD model. The Resveratrol group was treated similarly to the Model group but was exposed to 10 μM resveratrol for 24 hours before assessment. Through immunoprecipitation, proteomic analysis, and Venn analysis, Sirt1s acetylation substrate was identified as p53. An AD cell model was established using BV2 microglial cells, and the effects of Sirt1 on oxidative stress and inflammation, mediated by p53 regulation, were determined using immunofluorescence, Enzyme-linked immunosorbent assay (ELISA), Western Blot (WB), and qPCR technologies. Results: This study identifies p53 as a substrate for Sirt1 acetylation, corroborated through immunoprecipitation experiments and proteomic analysis. In microglial cells, the activation level in the Model group was significantly higher than in the Control and Resveratrol groups (p < 0.01). ELISA results revealed a significant increase in the expression levels of various substances in the AD Model group compared to the Control group, with a notable decrease in superoxide dismutase (SOD) expression (p < 0.01). However, these were improved in the Resveratrol group. The analysis of WB and qPCR indicated that Sirt1 decreased significantly in the Model group, while E74-like factor 1 (Elf-1), Nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3), Acetylated p53 (acetyl-p53) and other indicators increased significantly (p < 0.01). Compared with the Model group, Sirt1 in the Resveratrol group increased significantly (p < 0.01), and the indicators such as Elf-1, NLRP3 decreased. There was no significant difference in the mRNA transcription level of p53 among the Control group, Model group and Resveratrol group (p > 0.05). Conclusions: The results of this study suggest that Sirt1 may affect the inflammatory response and oxidative stress in AD cell models by regulating p53
The Role of Carbonic Anhydrases in Glucose-Stimulated Insulin Secretion from Insulinoma MIN6 Cells
No full textBackground: Carbonic anhydrase (CA) catalyzes the formation of bicarbonate ions and protons from carbon dioxide and water, and also the reverse reaction, thus regulating acid-base balance and processes requiring HCO3- in the cell. Previous data from us and others have suggested that CAs participate in the regulation of insulin secretion. The aim of this study was to examine sublines of insulin-secreting MIN6 cells in terms of CA isoform transcript levels, and to analyze their roles in insulin secretion. Methods: Differential expression of CA isoforms in MIN6 cells differing in glucose responsiveness were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Next, we established stable cell lines with a doxycycline-inducible system overexpressing several of the CA isoforms. We also generated MIN6 sublines with shRNA-mediated suppression and studied glucose-stimulated insulin secretion, as well as glucose metabolism, using radiolabeled glucose in these cells. Results: We confirmed expression of a mitochondrial CA isoform, CA VB, and a cytosolic isoform, CA XIII, was significantly greater (4.18-fold, p < 0.01 for CA VB; 48.3-fold, p < 0.01 for CA XIII), while expression of CA XI, a cytosolic isoform that lacks catalytic activity, was lower (0.50-fold, p < 0.01), in highly glucose-responsive sublines. CA VB overexpression increased (1.32-fold, p < 0.05), while its knockdown suppressed (0.77-fold, p < 0.05), glucose-stimulated insulin secretion. In contrast, CA XIII overexpression and CA XIII knockdown failed to modulate insulin secretion evoked by glucose. CA XI overexpression produced no changes in insulin secretion. Changes in insulin secretion due to CA VB overexpression or knockdown were not accompanied by changes in [5-3H]glucose and [U-14C]glucose metabolism. Conclusions: CA VB serves as a positive regulator of glucose-stimulated insulin secretion in MIN6 cells
Assessment of the Immunogenicity of COVID-19 Heterogeneous Booster Vaccination Following the Full Immunization of Inactivated Vaccines
No full textObjective: To study the immunogenicity of COVID-19 (Corona Virus Disease 2019) booster vaccines, produced via different technical routes, following the first two doses of inactivated COVID-19 vaccine. Methods: A total of 320 healthy subjects, aged 18 to 59 years old, who had already received the first two shots of the inactivated COVID-19 vaccine were recruited. They were randomly divided into four groups (A, B, C, and D), with 80 subjects in each group. These subjects then received a booster dose of the same inactivated COVID-19 vaccine as in the first two shots, or a booster dose of a different inactivated COVID-19 vaccine, adenoviral vector vaccine, and recombinant protein vaccine (CHO cells). Blood samples were collected before the booster immunization and on days 14 and 28 after booster immunization, to determine the level of neutralizing antibodies. Results: There was no statistically significant difference between the four groups in age or gender between all four study groups (p > 0.05). All four groups showed a significant increase in COVID neutralizing antibody level on day 14 and day 28 (p < 0.05). Group C and group D showed a significant increase compared with group A or group B (p < 0.05). And, the highest GMT (geometric mean titer) level was observed in group C on day 14 among all four groups and all three time points. The antibody positive conversion rate was 100% on day 28. Conclusions: A booster dose of heterologous COVID-19 vaccine six months after the first two shots led to significantly higher immunogenicity than when the same type of vaccine used for basic immunization was used for the booster. Heterologous booster immunization is of high importance for raising the immunization efficiency
A Ten-Gene Prognostic Signature Associated with Cold-Hot Tumor Typing in Clear Cell Renal Carcinoma
No full textBackground: Understanding the molecular differences between cold and hot tumors and selecting biomarkers associated with clear-cell renal carcinoma (ccRCC) may provide a reference for evaluating the efficiency of immunotherapy and the prognosis of ccRCC patients. The purpose of this study was to analyze cold-hot tumor typing in ccRCC. Methods: The Cancer Genome Atlas (TCGA) and European Bioinformatics Institute (EBI) ArrayExpress databases were used to download the mRNA expression data of ccRCC, and the cell infiltration proportion and tumor subtypes were evaluated using single sample Gene Set Enrichment Analysis (ssGSEA) and ConsensusClusterPlus, respectively. Subsequently, the immune scores classified all the ccRCC samples into “cold tumors” and “hot tumors”. Then, differentially expressed genes (DEGs) and checkpoint genes were analyzed in cold and hot tumor samples. Finally, a prognosis model was built using the optimized genes, and gene expression levels were validated using the E-MTAB-3267 dataset. Result: Patients with cold tumors have a better clinical prognosis than those with hot tumors. After comparison, 707 DEGs were identified between cold and hot tumor samples, and 10 immune checkpoint genes in hot tumors were found to be upregulated. Additionally, 10 optimized genes, PPARGC1A, SLC22A8, and IL20RB, were screened to build a risk score (RS) prognostic prediction model, and the expression tendencies of the 10 genes (except for DLX4) in TCGA were consistent with those in the E-MTAB-3267 dataset. Conclusions: The 10 important genes may be used as biomarkers for cold and hot tumors in ccRCC, and their related RS model could be used for risk assessment and prognosis prediction of ccRCC
The Application of the Transcervical Approach in the Surgical Management of Thyroid Tumor
No full textBackground: Clinical evidence suggests that most thyroid diseases require surgical intervention for effective treatment. However, traditional open thyroid surgery often leads to conspicuous trauma, which can result in unacceptable aesthetic concerns for patients. As an alternative to traditional surgical methods, the transcervical approach significantly enhances the surgery process and improves patients post-operative quality of life. This study aims to highlight the advantages of utilizing the transcervical approach for thyroid tumor surgical procedures. Methods: We analyzed clinical data from both surgical techniques and formulated a risk model for thyroid tumors. This model was developed using the least absolute shrinkage and selection operator (LASSO) and logistic regression analytical methods. We established a thyroid tumor-related nomogram and validated the model using Receiver Operating Characteristics (ROC) and calibration curves. Results: Our research compared two types of thyroid surgery: traditional and transcervical approaches. The traditional method works well for patients with larger tumors and usually involves less bleeding during the operation. On the other hand, the transcervical approach is quicker and leads to better outcomes after the surgery. Also, it achieves similar surgical results as the traditional method. To sum up, the transcervical approach is often better than traditional thyroid surgery. Conclusions: The model was validated using ROC and calibration curves, demonstrating a satisfactory level of discrimination and calibration. This validated model enables swift differentiation between the two types of surgeries. The findings indicate that the transcervical approach is more suitable than traditional surgical techniques for treating thyroid tumors