ZNF26-Associated Genes as Prognostic Signatures in Colorectal Cancer with Broad Therapeutic Implications.

The identification of biomarkers correlated with colorectal cancer (CRC) prognosis holds substantial importance from both clinical and scientific perspectives. Zinc finger protein 26 (ZNF26) has not been previously investigated or documented in solid tumors; thus, further research is necessary to ascertain its prognostic value in CRC. Gene expression profiles and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA) database. Subsequently, expression correlation was assessed utilizing the TCGA CRC cohort. The prognostic value of ZNF26 was evaluated through Kaplan-Meier (KM) and ROC curve analyses. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to perform enrichment analysis between high- and low-ZNF26 expression groups. The association between immune cells, immune checkpoint genes, and ZNF26 expression levels was examined. Lastly, the research findings were further validated using CRC tissue samples. The results revealed that, in comparison to healthy controls, CRC significantly reduced ZNF26 expression. Elevated ZNF26 expression was associated with poorer overall survival in CRC patients. Additionally, high ZNF26 expression exhibited an inverse relationship with the immunological score and immune checkpoint gene expression in CRC patients. The findings from the TCGA data analysis were corroborated by the PCR results obtained from CRC tissue samples. ZNF26 is markedly upregulated in colorectal cancer tissues, potentially serving as a biomarker for CRC.

Antitumor Activity of Carboxymethyl Pachymaran with Different Molecular Weights Based on Immunomodulatory and Gut Microbiota.

Carboxymethyl pachymaran (CMP) was treated via high-temperature and cellulase hydrolysis to obtain HTCMP, HTEC-24, and HTEC-48. The chemical structure and in vivo antitumor activities of the four types of CMPs were investigated. Compared with CMP (787.9 kDa), the molecular weights of HTCMP, HTEC-24, and HTEC-48 were decreased to 429.8, 129.9, and 68.6 kDa, respectively. The viscosities and particle sizes of the CMPs could also decrease with the decline in the molecular weights. All the CMPs showed antitumor abilities, but HTEC-24 exhibited the best activity. In the animal study, when curing the spleen and thymus, CMPs displayed immunomodulatory effects by increasing the secretion of IFN-γ and IL2 in mice. The CMPs also exerted an antitumor ability by regulating the gut microbiota in tumor-bearing mice. Our results established a foundation to develop an antitumor drug with CMP.

Bioinformatics Analysis Build Autophagy Prognosis Model of Cremastra Intervention Breast Cancer and Explore the Prognostic Markers.

Objective: Autophagy is the catabolic process where the components of eukaryotes experience damage, and the affected or superfluous components undergo self-degradation. However autophagy can promote cancer cell apoptosis or facilitate cell growth. This work aimed to investigat the significance of autophagy-related genes (ARGs) in predicting the prognosis of breast cancer (BC) intervened with Cremastra. Methods: Active ingredients and action targets were obtained using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissTargetPrediction. Then, the BC transcriptome and clinical data were downloaded in The Cancer Genome Atlas (TCGA), whereas ARGs were collected in the Human Autophagy Database (HADb). Meanwhile, Perl and R software were used for data processing and analysis. Firstly, the transcriptome data of BC were mapped to ARGs to screen the BC-ARGs. Secondly, the above genes were mapped to the action targets of Cremastra, ARGs of Cremastra-intervened BC were then screened out. Moreover, an enrichment analysis of biological function was carried out. Univariate Cox regression was carried out on ARGs of BC for preliminarily selecting the independent prognostic genes and constructing the autophagy prognosis model. These genes were mapped to ARGs involved in Cremastra-intervened BC. Finally, those mapped genes were optimized by multi-factor Cox regression, and the key ARGs and potential compounds were obtained. Finally, all cases were classified as low- or high-risk group based on the median risk score. Receiver operating characteristic (ROC) curve, Kaplan-Meier (K-M) survival, independent prognosis and clinical correlation analyses were conducted for model evaluation and identification of factors to independently predict prognosis. Results: Altogether, 66 active components and 38 targets of the Cremastra-intervened autophagy of BC were screened and the autophagy prognosis model demonstrate good predictive performance. As suggested by the survival curve, low-risk patients had a markedly increased survival rate compared with high-risk patients (P < .01). Besides, the gene expression levels of the high-risk group increased with the increases in patients' risk scores. Upon univariate regression, 34 differentially expressed ARGs related to BC treatment were screened. Multivariate regression identified 4 key ARGs, which were mainly derived from glycosides, lignans, flavonoids, and dibenzyl compounds. Thereafter, key genes were subjected to correlation analysis between clinicopathological features and prognosis, among which BCL2 and TP63, showed independent prognostic value. Conclusions: In this study, an autophagy prognosis model was established, and BCL2 and TP63 were predicted for the Cremastra intervention of BC by Bioinformatics, which will be applied to further work.

Development of an immunogenic cell death prognostic signature for predicting clinical outcome and immune infiltration characterization in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD) is a common gastric histological cancer type with a high mortality rate. Immunogenic cell death (ICD) plays a key factor during carcinogenesis progress, whereas the prognostic value and role of ICD-related genes (ICDRGs) in STAD remain unclear. The MSigDB database collecting ICDRGs were selected by univariate Cox regression analysis and LASSO algorithm to establish a novel risk model. The Kaplan-Meier survival analysis indicated a significant difference of OS rate of patients by risk score stratification. ESTIMATE, CIBERSORT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape by risk stratification. Subgroup analysis and tumor mutation burden analysis were also analyzed to identify characteristics between groups. Differences in therapeutic responsiveness to chemotherapeutic drugs and targeted drugs were also analyzed between high-risk group and low-risk group. The impact of one ICDRG, GPX1, on the proliferation, migration and invasiveness of was confirmed by in vitro experiments in GC cells to test the reliability of bioinformatics results. This study gives evidence of the involvement of ICD process in STAD and provides a new perspective for further accurate assessment of prognosis and therapeutic efficacy in STAD patients. Stomach adenocarcinoma (STAD) is a common gastric histological cancer type with a high mortality rate. Immunogenic cell death (ICD) plays a key factor during carcinogenesis progress, whereas the prognostic value and role of ICD-related genes (ICDRGs) in STAD remains unclear. The MSigDB database collected ICDRGs were selected by univariate Cox regression analysis and LASSO algorithm to establish a novel risk model. The Kaplan-Meier survival analysis indicated a significant difference of OS rate of patients by risk score stratification. ESTIMATE, CIBERSORT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape by risk stratification. Subgroup analysis and tumor mutation burden analysis were also analyzed to identify characteristics between groups. Differences in therapeutic responsiveness to chemotherapeutic drugs and targeted drugs were also analyzed between high-risk group and low-risk group. The impact of one ICDRG, GPX1, on the proliferation, migration and invasiveness of was confirmed by in vitro experiments in GC cells to test the reliability of bioinformatics results. This study gives evidence of the involvement of ICD process in STAD and provides a new perspective for further accurate assessment of prognosis and therapeutic efficacy in STAD patients.

HPV16 infection promotes the malignant transformation of the esophagus and progression of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) may be correlated with HPV infection, and the mechanism underlying the ESCC formation induced by HPV16 infection remains elusive. Here, we overexpressed HPV16 E6 and E7 and coordinated the overexpression of these two genes in EPC2 and ESCC cells. We found that E7 and coordinated expression of E6 and E7 promoted the proliferation of EPC2 cells, and upregulation of shh was responsible for cell proliferation since the use of vismodegib led to the failure of organoid formation. Meanwhile, overexpression of E6 and E7 in ESCC cells promoted cell proliferation, migration, and invasion in vitro. Importantly, E6 and E7 coordinately increased the capability of tumor growth in nude mice, while vismodegib slowed the growth of tumors in NCG mice. Moreover, a series of genes and proteins changed in cell lines after overexpression of the E6 and E7 genes, the potential biological processes and pathways were systematically analyzed using a bioinformatics assay. Together, these findings suggest that the activation of the hedgehog pathway induced by HPV16 infection may initially transform basal cells in the esophagus and promote following malignant processes in ESCC cells. The application of hedgehog inhibitors may represent a therapeutic avenue for ESCC treatment.

Astragaloside II enhanced sensitivity of ovarian cancer cells to cisplatin via triggering apoptosis and autophagy.

Cisplatin (DDP) based chemotherapy occurs a reduced therapeutic effect on the later treatment of ovarian cancer (OC) due to DDP resistance. Astragaloside II (ASII), a natural product extracted from Radix Astragali, has shown promising anticancer effects. However, the effects of ASII on OC have not been clarified. In this study, we found that ASII inhibited cell growth and promoted cell apoptosis of DDP-resistant OC cells in vitro and in vivo. Further study showed that ASII downregulated multidrug resistance-related protein MDR1 and cell cycle-related protein Cyclin D1 and PCNA, and also upregulated apoptosis-related protein leaved PRAP and cleaved caspase-3. In addition, ASII induced autophagy, characterized by upregulation of LC3II expression, downregulation of p62 expression, and elevation of LC3 punctuation, may be associated with inhibition of the AKT/mTOR signaling pathway. Moreover, the messenger RNA-sequencing was used to identify potential molecules regulated by ASII. In conclusion, these findings indicated that ASII increased sensitivity of DDP in the treatment of OC.

Untargeted metabonomic analysis of non-alcoholic fatty liver disease with iron overload in rats via UPLC/MS.

BACKGROUND/AIMS: In recent years, many metabolites specific to nonalcoholic fatty liver disease (NAFLD) have been identified thanks to the application of metabolomics techniques. This study aimed to investigate the candidate targets and potential molecular pathways involved in NAFLD in the presence of iron overload. METHODS: Male Sprague Dawley rats were fed with control or high-fat diet with or without excess iron. After 8, 16, 20 weeks of treatment, urine samples of rats were collected for metabolomics analysis using ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). Blood and liver samples were also collected. RESULTS: High-fat, high-iron diet resulted in increased triglyceride accumulation and increased oxidative damage. A total of 13 metabolites and four potential pathways were identified. Compared to the control group, the intensities of adenine, cAMP, hippuric acid, kynurenic acid, xanthurenic acid, uric acid, and citric acid were significantly lower (p < 0.05) and the concentration of other metabolites was significantly higher in the high-fat diet group. In the high-fat, high-iron group, the differences in the intensities of the above metabolites were amplified. CONCLUSION: Our findings suggest that NAFLD rats have impaired antioxidant system and liver function, lipid disorders, abnormal energy, and glucose metabolism, and that iron overload may further exacerbate these disorders.

Phosphoglycerate kinase (PGK) 1 succinylation modulates epileptic seizures and the blood-brain barrier.

Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100ß in serum brain biomarkers' integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100ß in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.

MYBL2 alternative splicing-related genetic variants reduce the risk of triple-negative breast cancer in the Chinese population.

Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and studies have found an association between the Myb proto-oncogene like 2 (MYBL2) gene and TNBC development; however, the specific mechanisms underlying development remain unknown. Recent studies have reported the association of alternative splicing (AS) with cancer, providing new approaches to elucidate the carcinogenesis mechanism. This study aimed to identify MYBL2 AS-related genetic variants that influence the risk of developing TNBC, providing new ideas for probing the mechanism of TNBC and novel biomarkers for TNBC prevention. Methods: We conducted a case-control study of 217 patients with TNBC and 401 cancer-free controls. The CancerSplicingQTL database and HSF software were used to screen for MYBL2 AS-related genetic variants. The association of sample genotypes with the risk of TNBC development and with clinicopathological features was analysed via unconditional logistic regression. Combining multiple platforms, the candidate sites were subjected to biological function analysis. Results: Two AS-associated SNPs, rs285170 and rs405660, were identified using bioinformatics analysis. Logistic regression analysis showed that both rs285170 (OR = 0.541; 95% CI = 0.343-0.852; p = 0.008) and rs405660 (OR = 0.642; 95% CI = 0.469-0.879; p = 0.006) exhibited protective effects against TNBC under the additive model. Stratification analysis showed that these two SNPs had more significant protective effects in the Chinese population aged ≧50 years. Additionally, we found that rs405660 was associated with the risk of lymph node metastasis (OR = 0.396, 95% CI = 0.209-0.750, p = 0.005) in TNBC. Functional analysis revealed that both rs285170 and rs405660 are associated with splicing of exon 3 and that the exon 3-deleted spliceosome does not increase breast cancer risk. Conclusion: We found for the first time that MYBL2 AS-related genetic variants are associated with reduced TNBC susceptibility in the Chinese population, especially in women aged ≧50 years.

Functional variant rs10175368 which affects the expression of CYP1B1 plays a protective role against breast cancer in a Chinese Han population.

OBJECTIVE: Cytochrome P450 1B1 ( CYP1B1 ) genetic variants are relevant in the pathogenesis of breast cancer. Exploring the relationships between CYP1B1 functional variants and breast cancer could improve our understanding of breast cancer molecular pathophysiology. METHODS: This is a two-stage hospital-based case-control study of a Chinese Han population. Genotyping was performed to identify candidate gene variants. 3DSNP, ANNOVAR, and RegulomeDB were used to determine functional single nucleotide polymorphisms (SNPs). The relationship between candidate variants and breast cancer risk was evaluated through unconditional logistic regression analysis. The PancanQTL platform was used to perform cis and trans expression quantitative trait loci (eQTL) analysis of positive SNPs. The GSCA platform was then used to compare the gene expression levels of potential target genes between breast cancer tissue and normal tissue adjacent to the cancer. RESULTS: rs10175368-T acted as a protective factor against breast cancer based on an additive model [odds ratio (OR) = 0.722, 95% confidence interval (CI) = 0.613-0.850; P < 0.001], and was identified as a protective factor in the postmenopausal population (OR = 0.601; 95% CI, 0.474-0.764; P < 0.001). eQTL analysis and analysis of differential expression in carcinoma and paracancerous tissues revealed that the expression level of CYP1B1 - AS1 was associated with rs10175368 and that CYP1B1-AS1 had significantly higher expression levels in breast cancer tissues than in paracancerous tissues. CONCLUSION: We show, for the first time in a Chinese Han population, that the functional variant rs10175368 plays a protective role against breast cancer, especially in the postmenopausal population.

Association between Cystic Fibrosis exacerbations, lung function, T2 inflammation and microbiological colonization.

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) reports a high prevalence of asthma (34.6%) in people with Cystic Fibrosis (PwCF). While our current understanding of this relationship is limited, a type 2 inflammatory (T2) phenotype has often been identified in CF patients. RESEARCH QUESTION: This study aimed to evaluate the relationship between the eosinophilic CF T2 inflammatory phenotype and CF-related pulmonary outcomes and microbiological data. STUDY DESIGN AND METHODS: We conducted a retrospective chart review of adult patients with CF (18 and older; n = 93) receiving their care at University of Virginia Medical Center adult program from January, 2013 through December, 2018. Data collected included demographic data, CFTR (CF transmembrane conductance regulator) mutation, CF comorbidities, medications, Absolute Eosinophil Counts (AEC) in cells/µL and Immunoglobulin E (IgE) levels in IU/mL. RESULTS: Of 93 patients screened for study eligibility, 74 were included in the final analysis; 19 patients were excluded due to lack of longitudinal data across the study timeline. Lung function decline correlated with increased AEC (p < 0.001) and IgE (p < 0.001) even when adjusting for covariates: age, gender, presence of Pseudomonas spp., MRSA, other bacterial spp., Aspergillus spp., and other fungi (p < 0.001). Univariate analysis demonstrated that people with CF who experienced more than 2 exacerbations requiring hospitalizations and/or intravenous antibiotics a year were more likely to have high AEC (p = 0.018). Logistic regression showed that as AEC increases, the probability that the measurement was taken during a CF exacerbation increases (p = 0.0039). A linear mixed model showed that each additional annual exacerbation event increased on average the log IgE by 0.04. (p = 0.015). This finding remained stable in a multivariate model (p = 0.0145). When adjusted for atopy, log IgE increases as the number of exacerbation events increases (p = 0.022). There was no association between AEC and IgE and microbiological colonization. INTERPRETATION: This study has shown that in CF patients, T2 inflammation based on serum AEC and IgE correlated with pulmonary exacerbations requiring hospitalizations and/or intravenous antibiotics, independent of bacterial airway colonization. In addition, lung function decline correlated with increased IgE and AEC. Further studies are needed to explore these correlations and potential impact on treatment.

Biomechanical Properties of Bionic Collum Femoris Preserving Hip Prosthesis: A Finite Element Analysis.

OBJECTIVE: Compared with total hip replacement, conventional collum femoris preserving prosthesis has a better bone retention effect. However, damage to the trabecular bone of the proximal femur leads to inevitable abnormal stress distribution, which leads to increased risks of femoral neck bone absorption, periprosthetic fracture, prosthesis loosening, rotation, and sinking. Thus, we compare the biomechanical properties of collum femoris preserving (CFP) and bionic collum femoris preserving (BCFP) hip prostheses. METHODS: The Sawbone digital model (#3503, left, medium) was selected as the research object. We used the Mimics 21.0 software to reconstruct the digital model of the femur and the SolidWorks 2019 software to build and assemble the three-dimensional models of CFP and BCFP prostheses. With the ANSYS Workbench 2021R1 software, the models were meshed and assigned values to simulate the load of a single foot under slow walking. We measured the mechanical distribution of the whole model and obtained the stress nephogram. RESULTS: For CFP prosthesis, the peak stresses of the medial interface of the stem neck, the lateral interface of the stem neck, and the end of the stem were 64.894, 32.199, and 8.578 MPa, respectively; the peak stresses of the medial surface of the femoral shaft, the lateral surface of femoral shaft, the medial femoral neck bone-prosthesis interface (osteotomy interface), the lateral femoral neck bone-prosthesis interface (basal area), the lateral femoral neck bone-prosthesis interface (osteotomy interface), and the greater trochanter area were 28.093, 24.790, 14.388, 5.118, 4.179, and 8.245 MPa, respectively; the valley stress of the greater trochanter area was 1.134 MPa. For BCFP prosthesis, the peak stresses of the medial interface of the stem neck, the lateral interface of the stem neck, and the end of the stem were 47.015, 26.771, and 47.593 MPa, respectively; the peak stress of tension screw was 15.739 MPa; the peak stresses of the medial surface of the femoral shaft, the lateral surface of femoral shaft, the medial femoral neck bone-prosthesis interface (osteotomy interface), the lateral femoral neck bone-prosthesis interface (basal area), the lateral femoral neck bone-prosthesis interface (osteotomy interface) and the greater trochanter area were 28.581, 25.364, 15.624, 6.434, 4.986, and 8.796 MPa, respectively; the valley stress of the greater trochanter area was 1.419 MPa; the peak stress of bone-metal interface between the tension screw and the lateral surface of the femur was 5.858 MPa. CONCLUSION: Compared with the CFP prosthesis, the design of the BCFP prosthesis is based on the lever balance theory. With the bionic reconstruction of tension trabeculae, BCFP prosthesis makes up for the defects of CFP prosthesis design, optimizes the stress distribution, and reduces the stress shelter effect of the proximal femur, which has better biomechanical properties.

The Impact of Coronal Configuration of the Proximal Femur on its Mechanical Properties and the Validation of a New Theoretical Model: Finite Element Analysis and Biomechanical Examination.

OBJECTIVE: This study aims to establish the coronal configuration of the proximal femur as an independent factor for its mechanical properties and provide validation for the theoretical model "fulcrum-balance-reconstruction." METHODS: The digital 3D femur model constructed with the lower extremity high-resolution computed tomography of a senior subject was applied with the axial compression of 2100N under 5 different α angles of 10°, 5°, 0°, -5°, -10°. The equivalent stress distribution of the femoral geometric model under each angle were calculated. Under the same five α angles, fatigue test was performed on 15 composite artificial left femurs (three specimens in each angle group) to obtain the failure cycle and fracture site. The statistical analysis was accomplished using One-Way ANOVA. RESULTS: The maximum stress of the entire femur in physiological angle (α = 10°) occurred below femoral neck with a value of 63.91 MPa. When the proximal femur is in extreme abducted angle (α = -10°), the maximum stress shift to the lower medial cortex of femoral shaft with a value of 105.2 MPa. As the α angle changed from 10° to -10°, the greater trochanteric region had the largest increment in maximum stress (2.78 times for cortex and 1.67 times for cancellous bone) locally at the proximal femur. The failure cycles of the artificial femurs with a variety of abduction angle were averagely 9126 ± 2453.87 (α = -10°), 58,112.33 ± 1293.84 (α = -5°), 92,879.67 ± 2398.54 (α = 0°), 172,045.3 ± 11011.11 (α = 5°), and 264,949.3 ± 35,067.26 (α = 10°), and the statistical analysis revealed that the α angle of the group of concern is proportional to the P value of the corresponding group compared to the 10° group(α = 5° & α = 10°, P = 0.01; α = 0 & α = 10°, P = 0.001; α = -5°, -10° & α = 10°, P < 0.001). In fatigue test, the fracture appeared on femoral neck for the α angles of 10° (three subcapital), 5° (two basal; one transcervical), and 0° (one transcervical). Fracture sites located at trochanteric region were observed with the more abducted angles including 0° (two subtrochanteric) and -5° (two intertrochanteric; one subtrochanteric). The fracture line was only found on femoral shaft in the -10° group. CONCLUSION: With increasing hip abduction, the proximal femur shows declining mechanical properties, which suggests higher risk of hip fracture and increasement in the fraction of trochanteric fracture subtype. Furthermore, the hypothesis of "fulcrum-balance-reconstruction" was validated by our study to a certain extent.

Impact of elexacaftor/tezacaftor/ivacaftor on depression and anxiety in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is associated with worsening of depression and anxiety symptoms. Elexacaftor/tezacaftor/ivacaftor (Trikafta®), a cystic fibrosis transmembrane regulator (CFTR) modulator approved in 2019, significantly improves lung function, decreases pulmonary exacerbations, and improves quality of life. Studies are needed to evaluate the effects of Trikafta on symptoms of anxiety and depression. RESEARCH QUESTION: Do adults with CF report a change in depression and anxiety symptoms after Trikafta initiation? STUDY DESIGN AND METHODS: A retrospective chart review was conducted of patients with CF (n = 127) receiving care from January 2015 through February 2022. Data collected included demographics, annual PHQ-9 and GAD-7 scores, FEV1 percent predicted at each visit, BMI, consistency and timeline of Trikafta use, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of psychiatric medications, number of psychiatric emergency department visits and psychiatric hospital admissions, and sleep disturbances. RESULTS: Of the 127 patients screened for eligibility, 100 patients were included. Data collected yielded 563 PHQ-9, 563 GAD-7, and 560 ppFEV1 data points. No significant changes in average PHQ-9 or GAD-7 scores were found after Trikafta initiation or due to the COVID-19 pandemic. However, 22% of patients initiated or had a change in psychiatric medications, and patients with changes in psychiatric medications had significantly higher PHQ-9 and GAD-7 scores than patients not prescribed psychiatric medications. Trikafta use improved lung function by an average of 5.23% (p = 8.56e-08). Around a quarter (23%) of all patients reported sleep issues after initiating Trikafta. INTERPRETATION: No significant changes in average PHQ-9 and GAD-7 scores were found after Trikafta initiation. A quarter of patients required a change in psychiatric medications, and significant differences in depression and anxiety scores were found between patients with a change in psychiatric medications and those not prescribed medication. Twenty-three percent of patients reported a prevalence of sleep issues after Trikafta initiation.

MEF2C-AS1 regulates its nearby gene MEF2C to mediate cervical cancer cell malignant phenotypes in vitro.

Cervical cancer (CC) is the second most common malignancy among women. GEPIA demonstrated that MEF2C-AS1 and its nearby gene MEF2C present downregulation in CC tissues. We attempted to clarify molecular mechanism between MEF2C-AS1 and MEF2C underlying CC progression. RT-qPCR was used to measure expression levels and subcellular distribution of MEF2C-AS1 and MEF2C in CC cell lines. Gain-of-function assays were conducted to reveal roles of MEF2C-AS1 and MEF2C in CC cell behaviors. Bioinformatics, RNA pull down, and RIP assays were performed to assess association of MEF2C-AS1 or MEF2C with miR-20 b-5p in CC cells. Rescue assays were done to assess regulatory function of the MEF2C-AS1-miR-20 b-5p-MEF2C axis in CC cellular processes. MEF2C-AS1 and its nearby gene MEF2C showed downregulation and had a positive expression correlation in CC tissues. MEF2C-AS1 and MEF2C presented downregulation in CC cells, and they majorly distributed in CC cell cytoplasm. MEF2C-AS1 and MEF2C upregulation repressed CC cell proliferative, migratory, and angiogenic abilities. MEF2C-AS1 competitively bound with miR-20 b-5p to upregulate MEF2C in CC cells. The impacts of MEF2C-AS1 elevation on CC cell proliferative, migratory, and angiogenic capabilities were countervailed by miR-20 b-5p overexpression. The impacts of miR-20 b-5p inhibitor on CC cell proliferative, migratory and angiogenic capabilities were countervailed by MEF2C depletion. To sum up, MEF2C-AS1 and its nearby gene MEF2C present downregulation and serve as tumor suppressors in CC cells. MEF2C-AS1 suppresses CC cell malignancy in vitro through sponging miR-20 b-5p to upregulate MEF2C, which may provide a potential new direction for seeking therapeutic plans of CC.

Iron overload accelerated lipid metabolism disorder and liver injury in rats with non-alcoholic fatty liver disease.

Background/aims: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. Iron overload has been implicated in chronic non-communicable liver diseases, but its relationship with NAFLD remains unclear. This study aimed to investigate the underlying roles of iron overload in the development of NAFLD. Methods: Male Sprague Dawley rats were fed with a high-fat diet (HFD) and/or iron for 8, 12, and 20 weeks. Some rats fed with HFD plus iron also received intraperitoneal injection of deferoxamine (DFO) for 8 weeks. Liver steatosis, lipid metabolism and injury were evaluated. Results: A NAFLD model, including typical liver steatosis, was established by feeding rats with a HFD, while iron overload alone is not enough to induce severe NAFL. Compared with rats fed a HFD, excess iron further increased lipid accumulation, serum levels of lipids, enzymes of liver function, and expression levels of CD36 and FAS in rat liver. In addition, iron overload decreased the activities of antioxidative enzymes in liver compared with HFD rats. The levels of CPT1 and the ratios of p-ACC/ACC were also decreased by iron overload. DFO effectively reversed the abnormal lipid metabolism and liver damage induced by a high-fat, high-iron diet. Conclusion: A HFD plus iron overload might synergistically aggravate lipid metabolism disorders, liver injury, and oxidative damage, compared with a HFD alone. DFO might help to alleviate lipid metabolism dysfunction and improve the pathogenesis of NAFLD.

Finite Element Analysis of Proximal Femur Bionic Nail (PFBN) Compared with Proximal Femoral Nail Antirotation and InterTan in Treatment of Intertrochanteric Fractures.

OBJECTIVE: To compare the biomechanical properties of proximal femur bionic nail (PFBN), proximal femoral nail antirotation (PFNA) and InterTan in the treatment of elderly intertrochanteric fractures AO/OTA 31-A1.3 by finite element analysis. METHODS: We used Mimics, Unigraphics and other software to establish normal femur and AO/OTA 31-A1.3 fracture models, and reconstructed PFBN, PFNA and InterTan intramedullary nail models, and assembled them on the fracture model. The ANSYS software was used to compare the femoral von Mises stress distribution, deformation distribution, and internal fixation stress distribution of each group under a load of 2100 N. RESULTS: It could be seen that the femoral maximum stress, femoral maximum displacement, and maximum stress of internal fixation of the PFBN group were lower than those in the PFNA group and the InterTan group. The maximum femoral stress of the PFBN was 190.25 MPa, while the maximum stress of the femur of the PFNA and InterTan groups were 238.41 Mpa and 226.97 Mpa. The maximum femoral displacement of each group were located at the top of the femoral head, and the maximum displacement of the PFBN group was 14.373 mm, and the maximum displacement values of the PFNA and InterTan groups were 19.49 and 15.225 mm. For the stress distribution of intramedullary nail, the maximum stress of the three kinds of internal fixation was located on the main nail. The maximum stress of PFBN was 1191.8 MPa, compared with 2142.8 MPa for PFNA and 1702.3 MPa for InterTan. And the maximum stress on the PFBN pressure nail was 345.35 MPa, compared with 868.6 MPa for the PFNA spiral blade and 545.5 MPa for InterTan interlocking twin nails. CONCLUSION: Compared with PFNA and InterTan, PFBN has better mechanical properties. The biomechanical characteristics of PFBN are more advantageous than PFNA and InterTan internal fixation system in the treatment of femoral intertrochanteric fractures.

The Effect of Terpenoid Natural Chinese Medicine Molecular Compound on Lung Cancer Treatment.

Among all malignant tumors in the whole universe, the incidence and mortality of lung cancer disease rank first. Especially in the past few years, the occurrence of lung cancer in the urban population has continued to increase, which seriously threatens the lives and health of people. Among the many treatments for lung cancer, chemotherapy is the best one, but traditional chemotherapy has low specificity and drug resistance. To address the above issue, this study reviews the five biological pathways that common terpenoid compounds in medicinal plants interfere with the occurrence and development of lung cancer: cell proliferation, cell apoptosis, cell autophagy, cell invasion, metastasis, and immune mechanism regulation. In addition, the mechanism of the terpenoid natural traditional Chinese medicine monomer compound combined with Western medicine in the multipathway antilung cancer is summarized.

The Immune Infiltration in HNSCC and Its Clinical Value: A Comprehensive Study Based on the TCGA and GEO Databases.

BACKGROUND: Being potential field of research for tumor immunological therapy, the head and neck squamous cell carcinoma (HNSCC) is one of most discussed types of tumor. Recently, some clinical trials have also used immunological therapy and demonstrated a subset of HNSCC patients who have shown a clear longer survival time. OBJECTIVE: To conduct further studies and deeper research in the immunological oncology of HNSCC, a more detailed description and comprehending of the complicated landscape of immune infiltrative may be required. METHODS: Firstly, we have described the fraction of different infiltrating immune cells in the HNSCC tumor and then compared it to the normal tissue, and secondly, we have explored the clinical implications of various infiltrated immune cell fractions meticulously. The gene expression profiles of HNSCC tissue were obtained from databases of TCGA and GEO and utilized the deconvolution algorithm (CIBERSORT) to presume the fractions of 22 several immune sensitive cells. RESULTS: Our results indicated that the immune infiltrating cell fractions were considerably different between HNSCC tumor tissue and paired normal tissue, but at the same time, we found a potential internal correlation among the immune cells and also showed the association between immune infiltrating cells and their clinical characteristics. It is worth noting that the resting dendritic cells and M1 macrophages were linked with a favorable prognosis, while the CD4+ T cells with a poorer outcome. CONCLUSION: Fractions of immune cell percentage were also associated with tumors' pathological grade, age, and TNM stage.

Immunomodulatory Activity of Carboxymethyl Pachymaran on Immunosuppressed Mice Induced by Cyclophosphamide.

The effects of immunomodulatory activity of two types of carboxymethyl pachymaran (CMP-1 and CMP-2) on cyclophosphamide (CTX)-induced mice were investigated. Both CMP-1 and CMP-2 were found to restore the splenomegaly and alleviate the spleen lesions and the mRNA expressions of TLR4, MyD88, p65 and NF-κB in spleen were also increased. CMP-1 and CMP-2 could enhance the immunity by increasing the levels of TNF-α, IL-2, IL-6, IFN-γ, Ig-A and Ig-G in serum. In addition, CMP-1 could increase the relative abundance of Bacteroidetes and reduce the relative richness of Firmicutes at the phylum level. CMP-1 and CMP-2 could reduce the relative abundance Erysipelatoclostridum at the genus level. CMP-1 and CMP-2 might enhance the immune function of immunosuppression mice by regulating the gene expression in the TLR4/NF-κB signaling pathway and changing the composition and abundance of the intestinal microbiota. The results suggested that CMP-1 and CMP-2 would be as potential immunomodulatory agents in functional foods.