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BACKGROUND: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. MATERIALS AND METHODS: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. RESULTS: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p-PI3K and p-Akt were notably downregulated. CONCLUSION: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.
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Adenocarcinoma del Pulmón , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Medicamentos Herbarios Chinos/farmacología , Microambiente Tumoral/efectos de los fármacos , Ratones , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Humanos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Masculino , Pemetrexed/farmacología , Neovascularización Patológica/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Medicina Tradicional China/métodosRESUMEN
BACKGROUND: With continuous advancements in medical technology, neurosurgical nursing is constantly developing and improving to provide higher-quality nursing services. AIM: To explore the effects of different types of high-quality nursing care on clinical nursing quality and patient satisfaction in neurosurgical nursing. METHODS: Eighty patients who received neurosurgical treatment in the Affiliated Hospital of Southwest Medical University from June to December 2020 were selected as study participants and categorised into study and control groups. The study group comprised 40 patients who received 4 different types of high-quality nursing care, whereas the control group comprised 40 patients who received conventional nursing care. After a specific period, nursing satisfaction levels and adverse event and complication rates were compared between the two groups. RESULTS: Satisfaction with high-quality care was higher than that with conventional care, and high-quality health services and regional services showed the highest satisfaction levels, with an average score of 12 on the Glasgow scale. The satisfaction levels of the study and control groups were 75% and 57%, respectively, with a statistically significant difference (t = 7.314, P < 0.05). During the nursing period, the adverse event and complication rates were the highest in patients with level III pathology grade and those who underwent neurosurgery (40.02% and 85.93%, respectively), and the difference was statistically significant. CONCLUSION: In neurosurgical nursing, employing appropriate high-quality nursing methods can effectively reduce adverse event and complication rates in patients, thereby improving the quality of nursing care and increasing clinical nursing value.
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OBJECTIVE: To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients. METHODS: Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis. RESULTS: A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p = .025 for age; OR = 1.001, p = .037 for plasma concentration; and OR = 0.941, p = .003 for baseline Hb), with an AUC score of 0.859. CONCLUSIONS: Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.
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Insuficiencia Renal Crónica , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Resultado del Tratamiento , Glicina/uso terapéutico , Diálisis RenalRESUMEN
INTRODUCTION: Chronic systemic inflammation was proposed as a critical factor in the development of osteoporosis. We aim to investigate the effect of the DII on bone mineral density (BMD) in CKD patients. METHODS: 2276 participants from NHANES were enrolled. The DII score was calculated based on a single 24-h dietary recall. Total BMD was measured using Dual-energy x-ray absorptiometry. A multiple-stepwise linear regression model was used to determine associations between BMD and DII in CKD patients. RESULTS: When DII >0.35, a negative correlation was obtained between DII and BMD (all ß = -0.008 and p < 0.05). In subgroup analysis, BMD levels decreased across increasing tertiles of the DII for patients with non-osteoporosis, postmenopause, and low eGFR (p for trend ≤0.01). CONCLUSION: Higher consumption of pro-inflammatory diet correlates negatively with the BMD levels in CKD patients.
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Osteoporosis , Insuficiencia Renal Crónica , Femenino , Humanos , Densidad Ósea , Encuestas Nutricionales , Dieta , Absorciometría de Fotón , Osteoporosis/epidemiología , Osteoporosis/etiología , Inflamación , Insuficiencia Renal Crónica/complicacionesRESUMEN
OBJECTIVES: Multiple observational studies have shown that low serum level of 25-hydroxyvitamin D (25(OH)D) in patients with chronic kidney disease (CKD) have been associated with a faster progression of kidney disease and a higher risk of all-cause mortality. We aim to assess the association between dietary inflammatory index (DII) with Vitamin D in adults with CKD. METHOD: The National Health and Nutrition Examination Survey appropriated participants from 2009 to 2018 were enrolled. The patients who were under the age of 18, pregnant, and having incomplete data were excluded. DII score were calculated based on a single 24-h dietary recall interview for each participant. Mutivariable regression analysis and subgroup analysis were utilized to determine the independent associations between vitamin D with DII in CKD patients. RESULTS: In total, 4283 individuals were finally included. The results showed a negative association between DII scores and 25(OH)D with statistical significance (ß = - 1.83, 95% CI - 2.31, - 1.34, P < 0.001). In subgroup analysis stratified by gender, low eGFR, age and diabetes, the negative association between DII scores and 25(OH)D was still significant (all P for trend < 0.05). The results from interacion test indicated that the magnitude of the association was the same for the population with and without low eGFR (P for interacion = 0.464). CONCLUSION: Higher consumption of pro-inflammatory diet correlates negatively with the 25(OH)D level in CKD patients with and without low eGFR. Anti-inflammatory diet management may reduce the reduction of vitamin D in CKD patients.
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Insuficiencia Renal Crónica , Vitamina D , Adulto , Humanos , Encuestas Nutricionales , Dieta , Vitaminas , InflamaciónRESUMEN
Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated. Results: APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70-0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71-0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46-0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56-0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43-0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17-4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38-6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07-0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43-0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition. Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition.
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Introduction: Cancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs can be influenced by various factors, including the use of concomitant medications. Methods: We searched databases (PubMed, Embase, Cochrane Library, Web of Science) for systematic reviews and meta-analyses for systematic reviews and meta-analyses on the impact of concomitant medications on ICIs efficacy, published from inception to January 1, 2023. We evaluated the methodological quality of the included meta-analyses, and re-synthesized data using a random-effects model and evidence stratification. Results: We included 23 publications, comprising 11 concomitant medications and 112 associations. Class II-IV evidence suggested that antibiotics have a negative impact on ICIs efficacy. However, ICIs efficacy against melanoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma was not affected, this effect was related to the exposure window (class IV). Class III evidence suggested that proton pump inhibitors have a negative impact on ICIs efficacy; nevertheless, the efficacy against melanoma and renal cell carcinoma was not affected, and the effect was related to exposure before the initiation of ICIs therapy (class II). Although class II/III evidence suggested that steroids have a negative impact, this effect was not observed when used for non-cancer indications and immune-related adverse events (class IV). Class IV evidence suggested that opioids reduce ICIs efficacy, whereas statins and probiotics may improve ICIs efficacy. ICIs efficacy was not affected by histamine 2 receptor antagonists, aspirin, metformin, ß-blockers, and nonsteroidal anti-inflammatory agents. Conclusion: Current evidence suggests that the use of antibiotics, PPIs, steroids, and opioids has a negative impact on the efficacy of ICIs. However, this effect may vary depending on the type of tumor, the timing of exposure, and the intended application. Weak evidence suggests that statins and probiotics may enhance the efficacy of ICIs. Aspirin, metformin, ß-blockers, and NSAIDs do not appear to affect the efficacy of ICIs. However, caution is advised in interpreting these results due to methodological limitations. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO,identifier, CRD42022328681.
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Neoplasias Esofágicas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Renales , Neoplasias Hepáticas , Melanoma , Metformina , Humanos , Analgésicos Opioides , Antibacterianos , Antiinflamatorios no Esteroideos , Aspirina , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Esteroides , Revisiones Sistemáticas como Asunto , Metaanálisis como AsuntoRESUMEN
BACKGROUND: Metastasis, a leading cause of cancer-related deaths, involves complex mechanisms. The premetastatic niche (PMN) is a crucial contributor to this process. Myeloid-derived suppressor cells (MDSCs) play an important role in PMN formation and promote tumor progression and metastasis. The Xiaoliu Pingyi recipe (XLPYR), a traditional Chinese medicine, is effective in preventing postoperative recurrence and metastasis in cancer patients. OBJECTIVE: This study investigated the effects of XLPYR on MDSCs recruitment and on the expression of PMN markers and elucidated the mechanisms involved in the prevention of tumor metastasis. METHODS: C57BL/6 mice were subcutaneously injected with Lewis cells and treated with cisplatin and XLPYR. Tumors were resected after 14 days after the establishment of a model of lung metastasis, and tumor volume and weight were measured. Lung metastases were observed 21 days after resection. MDSCs in the lung, spleen, and peripheral blood were detected by flow cytometry. Western blotting, qRT-PCR and ELISA were used to detect the expression of S100A8, S100A9, MMP9, LOX, and IL-6/STAT3 in premetastatic lung tissue. RESULTS: XLPYR treatment inhibited tumor growth and prevented lung metastasis. Compared to mice without subcutaneous tumor cell transplantation, the model group had an increased proportion of MDSCs, higher expression of S100A8, S100A9, MMP9, and LOX in the premetastatic lung. XLPYR treatment reduced the proportion of MDSCs, S100A8, S100A9, MMP9, and LOX expression, and downregulated the IL-6/STAT3 pathway. CONCLUSIONS: XLPYR may prevent MDSCs recruitment and reduce the expression of S100A8, MMP9, LOX, and IL6/STAT3 in premetastatic lung tissue, thus reducing lung metastases.
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Neoplasias Pulmonares , Células Supresoras de Origen Mieloide , Animales , Ratones , Ratones Endogámicos C57BL , Metaloproteinasa 9 de la Matriz , Interleucina-6 , Neoplasias Pulmonares/tratamiento farmacológico , PulmónRESUMEN
Duchenne/Becker muscular dystrophy (DMD/BMD) is one of the most common progressive muscular dystrophy diseases with X-linked recessive inheritance. It is mainly caused by the deletion, duplication and point mutation of DMD gene. In rare cases, it is also caused by the destruction of DMD gene by chromosomal structural rearrangement. Here, we report a case of Duchenne/Becker Muscular dystrophy (DMD/BMD) with typical symptoms but unknown genetic defects after MLPA and next generation sequencing tests in other hospitals. Interestingly, we find a pericentric inversion of X chromosome (Chr.X: g. [31939463-31939465del; 31939466-131765063 inv; 131765064-131765067del]) in this patient. We then use the karyotyping, FISH, long-read sequencing and Sanger sequencing technologies to characterize the chromosome rearrangement. We find that this chromosomal aberration disrupt both the DMD gene and the HS6ST2 gene. The patient present with typical DMD symptoms such as muscle weakness, but no obvious symptoms of Paganini-Miozzo syndrome. Our results suggest that the destruction of DMD gene by structural rearrangement is also one of the important causes of DMD. Therefore, we suggest to provide further genetic testing for those DMD patients with unknown genetic defects through routine genetic testing. Cost-effective karyotyping and FISH should be considered firstly to identify chromosome rearrangements. Long-read sequencing followed by Sanger sequencing could be useful to locate the precise breakpoints. The genetic diagnosis of this case made it possible for reproductive intervention in the patient's family.
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Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/diagnóstico , Distrofina/genética , Pruebas Genéticas , Reordenamiento Génico/genética , Cromosoma X , Sulfotransferasas/genéticaRESUMEN
Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practice. However, there is no standard strategy for interpretation of the pathogenicity of DMD duplications during prenatal screening, especially for male fetuses, in which maternally inherited pathogenic DMD variants more frequently cause dystrophinopathies. Here, we report three non-contiguous DMD duplications identified in a woman and her male fetus during prenatal screening. Multiplex ligation probe amplification and long-read sequencing were performed on the woman and her family members to verify the presence of DMD duplications. Structural rearrangements in the DMD gene were mapped by long-read sequencing, and the breakpoint junction sequences were validated using Sanger sequencing. The woman and her father carried three non-contiguous DMD duplications. Long-read and Sanger sequencing revealed that the woman's father carried an intact DMD copy and a complex structural rearrangement of the DMD gene. Therefore, we reclassified these three non-contiguous DMD duplications, one of which is listed as pathogenic, as benign. We postulate that breakpoint analysis should be performed on identified DMD duplication variants, and the pathogenicity of the duplications found during prenatal screening should be interpreted cautiously for clinical prediction and genetic/reproductive counseling.
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Distrofia Muscular de Duchenne , Humanos , Embarazo , Femenino , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Diagnóstico Prenatal , Exones , Pruebas Genéticas , Reordenamiento GénicoRESUMEN
Purpose: Expanded carrier screening (ECS) is an effective method to identify at-risk couples (ARCs) and avoid birth defects. This study aimed to reveal the carrier spectrum in the Chinese population and to delineate an expanded carrier gene panel suitable in China. Methods: Medical exome sequencing (MES), including 4,158 disease-causing genes, was offered to couples at two reproductive centers. It was initially used as a diagnostic yield for potential patients and then used for ECS. Clinical information and ECS results were retrospectively collected. Results: A total of 2,234 couples, representing 4,468 individuals, underwent MES. In total, 254 individuals showed genetic disease symptoms, and 56 of them were diagnosed with genetic diseases by MES. Overall, 94.5% of them were carriers of at least one disease-causing variant. The most prevalent genes were GJB2 for autosomal recessive disorders and G6PD for X-linked diseases. The ARC rate was 9.80%, and couples were inclined to undergo preimplantation genetic testing when diseases were classified as "profound" or "severe." Conclusion: This study provided insight to establish a suitable ECS gene panel for the Chinese population. Disease severity significantly influenced reproductive decision-making. The results highlighted the importance of conducting ECS for couples before undergoing assisted reproductive technology.
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Background: As the main component of turmeric (Curcuma longa L.), curcumin is widely used in the treatment of various diseases. Previous studies have demonstrated that curcumin has great potential as a therapeutic agent, but the lack of understanding of the functional mechanism of the drug has hindered the widespread use of the natural product. In the present study, we used comprehensive bioinformatics analysis and in vitro experiments to explore the anti-tumor mechanism of curcumin. Materials and Methods: LUAD mRNA expression data were obtained from TCGA database and differentially expressed genes (DEGs) were identified using R software. Functional enrichment analysis was conducted to further clarify its biological properties and hub genes were identified by a protein-protein interaction (PPI) network analysis. Survival analysis and molecular docking were used to analyze the effectiveness of the hub genes. By an in vitro study, we evaluated whether curcumin could influence the proliferation, migration, and invasion activities of LUAD cells. Results: In this study, 1783 DEGs from LUAD tissue samples compared to normal samples were evaluated. Functional enrichment analysis and the PPI network revealed the characteristics of the DEGs. We performed a topological analysis and identified 10 hub genes. Of these, six genes (INS, GCG, SST, F2, AHSG, and NPY) were identified as potentially effective biomarkers of LUAD. The molecular docking results indicated that curcumin targets in regulating lung cancer may be INS and GCG. We found that curcumin significantly inhibited the proliferation, migration, and invasion of LUAD cells and significantly decreased the expression of the INS and GCG genes. Conclusion: The results of this study suggest that the therapeutic effects of curcumin on LUAD may be achieved through the intervention of INS and GCG, which may act as potential biomarkers for LUAD prevention and treatment.
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Adenocarcinoma del Pulmón , Curcumina , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor , Biología Computacional , Curcumina/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Simulación del Acoplamiento MolecularRESUMEN
PURPOSE: To evaluate the cytogenetic risk of assisted reproductive technology (ART) by comparing the incidence of de novo chromosomal abnormalities between fetuses conceived via in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) and natural conception. MATERIALS AND METHODS: Prenatal invasive diagnostic testing (amniocentesis and cytogenetic analysis) was performed on 1496 fetuses conceived via IVF/ICSI (IVF/ICSI group) and 1396 fetuses from natural conception (NC group). The incidence of de novo chromosomal abnormalities (including aneuploidy and chromosomal structure abnormalities) was used to evaluate the cytogenetic risk of ART. For statistical analysis, χ2-test was used for binary dependent variable. The significance level was P < 0.05 and confidence interval was 95%. RESULT(S): The IVF/ICSI group displayed a modest increase in the overall de novo chromosomal abnormality rate compared with that in the NC group but with no statistical significance (6.75% vs. 6.16%; χ2 = 0.42, P > 0.05). The incidence of abnormal karyotypes was also not significantly different between the IVF/ICSI and NC groups in different maternal ages, including ≥ 35 years group (7.55% vs. 9.60%, χ2 = 1.40, P > 0.05) and < 35 years group (6.20% vs. 4.54%, χ2 = 2.51, P > 0.05). Moreover, there was no difference in the proportion of aneuploid and structural abnormalities in detected karyotypes between the IVF/ICSI and NC groups. Logistic regression analysis showed no significant association between the method of pregnancy and de novo chromosomal abnormalities (odds ratio (OR) 1.03; 95% CI 0.71-1.50; P = 0.86) after adjusting for other confounding factors. CONCLUSION(S): Fetuses conceived via IVF/ICSI had a slight but not statistically significant increase in de novo abnormal karyotypes compared to those in naturally conceived fetuses. Our findings indicate no significant association between de novo fetal chromosomal abnormalities and the pregnancy method in high-risk pregnancies in the second trimester. For these pregnancies with a high risk but with a normal karyotype, further genetic testing is required for diagnosis.
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Semen , Inyecciones de Esperma Intracitoplasmáticas , Cariotipo Anormal , Adulto , Aneuploidia , Aberraciones Cromosómicas , Femenino , Fertilización In Vitro , Feto , Humanos , Masculino , Embarazo , Técnicas Reproductivas AsistidasRESUMEN
Almost all Echinococcus multilocularis (Em) infections occur in the liver of the intermediate host, causing a lethal zoonotic helminthic disease, alveolar echinococcosis (AE). However, the long non-coding RNAs (lncRNAs) expression profiles of the host and the potential regulatory function of lncRNA during Em infection are poorly understood. In this study, the profiles of lncRNAs and mRNAs in the liver of mice at different time points after Em infection were explored by microarray. Thirty-one differentially expressed mRNAs (DEMs) and 68 differentially expressed lncRNAs (DELs) were found continuously dysregulated. These DEMs were notably enriched in "antigen processing and presentation", "Th1 and Th2 cell differentiation" and "Th17 cell differentiation" pathways. The potential predicted function of DELs revealed that most DELs might influence Th17 cell differentiation and TGF-ß/Smad pathway of host by trans-regulating SMAD3, STAT1, and early growth response (EGR) genes. At 30 days post-infection (dpi), up-regulated DEMs were enriched in Toll-like and RIG-I-like receptor signaling pathways, which were validated by qRT-PCR, Western blotting and downstream cytokines detection. Furthermore, flow cytometric analysis and serum levels of the corresponding cytokines confirmed the changes in cell-mediated immunity in host during Em infection that showed Th1 and Th17-type CD4+ T-cells were predominant at the early infection stage whereas Th2-type CD4+ T-cells were significantly higher at the middle/late stage. Collectively, our study revealed the potential regulatory functions of lncRNAs in modulating host Th cell subsets and provide novel clues in understanding the influence of Em infection on host innate and adaptive immune response.
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Echinococcus multilocularis , ARN Largo no Codificante , Animales , Citocinas/metabolismo , Equinococosis , Hígado/metabolismo , Ratones , ARN Largo no Codificante/genética , ARN Mensajero/genéticaRESUMEN
Background: The advent of PD-1/L1 inhibitors has changed the landscape for patients with non-small-cell lung cancer (NSCLC). Meanwhile, the adverse events of PD-1/L1 inhibitors have been focused. Methods: The Cochrane Central Register of Controlled Trials, PubMed and Embase databases and ClinicalTrials.gov were searched from inception to February 2021. Results: 18 studies involving 11,394 patients with NSCLC were included. PD-1/L1 inhibitor monotherapy was associated (relative risk, 95% confidence interval) with an increased risk of pericardial effusion (2.72 [1.45-5.12]; p = 0.002) and cardiac tamponade (2.76 [1.15-6.62]; p = 0.023), whereas PD-1/L1 inhibitors combined with chemotherapy did not increase the risk of pericardial effusion and cardiac tamponade (3.08 [0.93-10.21]; p = 0.066 and 3.27 [0.37-28.94]; p = 0.288, respectively). Conclusion: For patients with NSCLC, treatment with PD-1/L1 inhibitor monotherapy increases the risk of pericardial effusion and cardiac tamponade, but PD-1/L1 inhibitors combined with chemotherapy do not.
In this study, the authors found that the incidence of pericardial effusion and cardiac tamponade in non-small-cell lung cancer patients treated with PD-1/L1 inhibitors was 0.63% and 0.35%, respectively, and in chemotherapy was 0.07% and less than 0.01%, respectively. The authors found that PD-1/L1 inhibitors combined with chemotherapy did not increase the risk of cardiac adverse events (AEs); however, the risk of cardiac AEs with PD-1/L1 inhibitor monotherapy should be considered, and the damage of pembrolizumab to the pericardium needs further attention. The mechanism of pericardial effusion and cardiac tamponade is not well understood, and pseudoprogression cannot be ruled out. Although the incidence of cardiac AEs is low, the prevention and management of immunotherapy should be paid attention to.
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Carcinoma de Pulmón de Células no Pequeñas , Taponamiento Cardíaco , Neoplasias Pulmonares , Derrame Pericárdico , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Taponamiento Cardíaco/tratamiento farmacológico , Taponamiento Cardíaco/epidemiología , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Derrame Pericárdico/tratamiento farmacológico , Derrame Pericárdico/epidemiología , Receptor de Muerte Celular Programada 1/uso terapéuticoRESUMEN
Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). Although a series of immunosuppressant agents are routinely used as the first-line prevention, the morbidity and mortality rate remains high in allo-HSCT recipients. Our previous work indicated that combining Xuebijing (XBJ) with Cyclosporin A (CSA) is superior to CSA alone in preventing aGVHD. However, it was not clear which compounds in XBJ may prevent aGVHD. Whether the effective compounds in XBJ can be safely combined with CSA to prevent GVHD remain to be evaluated. Here, we accessed whether the combination of four main components in XBJ (C0127) had the same efficacy as XBJ in preventing aGVHD. In addition, the effectiveness of a novel combination therapy (C0127â¯+â¯CSA) on aGVHD prophylaxis was evaluated using 16â¯s rRNA sequencing and RNA sequencing approaches in vitro and in vivo. In aGVHD mice, C0127 enhanced the preventive effects of CSA including decreasing mortality, maintaining weight, reducing GVHD score and reducing the expression of IL-6 and TNF-α in serum. Fatal GVHD is a frequent consequence of intestinal tract damage. We found combining C0127 with CSA alleviated the gut damage and maintained the normal physiological function of intestine by H&E staining, intestinal permeability and short chain fatty acid (SCFA) assays. Next, 16â¯S sequencing analysis of feces showed the combination treatment maintained the intestinal microbial diversity, normalized the intestinal microorganism and prevented flora disorder by reducing the relative abundances of Escherichia coli and Enterococcus. Further, RNA-seq analysis of colonic epithelium revealed C0127 combined with CSA chiefly regulated chemokines and cytokines in IL-17 signaling pathway. The combination treatment reduced the expression of G-CSF and its effector STAT3 (an axis that aggravated gut inflammation and flora disorder) in gut epithelium on mRNA and protein level. These findings indicated that C0127 improved the prevention of CSA in aGVHD mice partially by protecting the gut from damage through normalizing G-CSF signaling, which regulates the intestinal microbiota and the integrity of the epithelial barrier.
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Medicamentos Herbarios Chinos , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Aguda , Animales , Ciclosporina/farmacología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , RatonesRESUMEN
BACKGROUND: Numerous variants of uncertain significance (VUSs) have been identified by whole exome sequencing in clinical practice. However, VUSs are not currently considered medically actionable. OBJECTIVE: To assess the splicing patterns of 49 VUSs in 48 families identified clinically to improve genetic counselling and family planning. METHODS: Forty-nine participants with 49 VUSs were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Bioinformatic analysis was performed to preliminarily predict the splicing effects of these VUSs. RT-PCR and minigene analysis were used to assess the splicing patterns of the VUSs. According to the results obtained, couples opted for different methods of reproductive interventions to conceive a child, including prenatal diagnosis and preimplantation genetic testing (PGT). RESULTS: Eleven variants were found to alter pre-mRNA splicing and one variant caused nonsense-mediated mRNA decay, which resulted in the reclassification of these VUSs as likely pathogenic. One couple chose to undergo in vitro fertilisation with PGT treatment; a healthy embryo was transferred and the pregnancy is ongoing. Three couples opted for natural pregnancy with prenatal diagnosis. One couple terminated the pregnancy because the fetus was affected by short-rib thoracic dysplasia and harboured the related variant. The infants of the other two couples were born and were healthy at their last recorded follow-up. CONCLUSION: RNA splicing analysis is an important method to assess the impact of sequence variants on splicing in clinical practice and can contribute to the reclassification of a significant proportion of VUSs. RNA splicing analysis should be considered for genetic disease diagnostics.
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Precursores del ARN , Empalme del ARN , Femenino , Asesoramiento Genético , Pruebas Genéticas/métodos , Humanos , Embarazo , Diagnóstico Prenatal , Empalme del ARN/genéticaRESUMEN
OBJECTIVE: Studies in the general population suggest that central blood pressure (BP) may be superior to peripheral BP in risk assessment. Although ambulatory brachial BP is recognized as the most reliable BP measurement in the dialysis population, there is no comparison of office central BP with ambulatory BP regarding risk stratification in these patients. METHODS: In a multicenter prospective study of dialysis patients, central BP was measured noninvasively on a midweek nondialysis day, with interdialytic ambulatory BP and predialysis BP also collected. The primary outcomes were a composite of major adverse cardiovascular events (MACE) and all-cause mortality. Agreement between central and ambulatory BP was assessed using Cohen's Kappa index and Bland--Altman plot. Linear and nonlinear Cox regression models were used to determine the association of BP parameters with outcomes. RESULTS: A total of 368 patients were recruited and 366 underwent central BP measurement. Central BP had a moderate agreement with ambulatory BP in defining hypertension (κâ=â0.42) with wide limits of agreement in Bland--Altman analysis. After a median follow-up of 51.5âmonths, central pulse pressure, ambulatory SBP and ambulatory pulse pressure were associated with all-cause mortality, whereas all BP parameters, except for predialysis DBP, were significant predictors of MACE. However, whenever evaluated in a stepwise variable selection Cox model, only ambulatory pulse pressure, but not any central BP, was determined as the best candidate for prediction of both all-cause mortality and MACE. Nonlinear Cox models revealed no significant nonlinear trend of the association between central BP and outcomes. CONCLUSION: Central BP is predictive of all-cause mortality and cardiovascular events in dialysis patients but its prognostic value does not outperform ambulatory peripheral BP. Our data support the superiority of ambulatory BP in the dialysis population.
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Monitoreo Ambulatorio de la Presión Arterial , Hipertensión , Presión Sanguínea , Estudios de Cohortes , Humanos , Hipertensión/diagnóstico , Estudios Prospectivos , Diálisis RenalRESUMEN
Heat shock proteins (HSPs) are a large class of highly conserved chaperons, which play important roles in response to elevated temperature and other environmental stressors. In the present study, 5 HSP90 genes and 17 HSP70 genes were systematically characterized in spotted seabass (Lateolabrax maculatus). The evolutionary footprint of HSP genes was revealed via the analysis of phylogeny, chromosome location, and gene copy numbers. In addition, the gene structure features and the putative distribution of heat shock elements (HSEs) and hypoxia response elements (HREs) in the promoter regions were analyzed. The protein-protein interaction (PPI) network analyses results indicated the potential transcriptional regulation between the heat shock factor 1 (HSF1) and HSPs and a wide range of interactions among HSPs. Furthermore, quantitative (q)PCR was performed to detect the expression profiles of HSP90 and HSP70 genes in gill, liver, and muscle tissues after heat stress, meanwhile, the expression patterns in gills under alkalinity and hypoxia stresses were determined by analyzing RNA-Seq datasets. Results showed that after heat stress, most of the examined HSP genes were significantly upregulated in a tissue-specific and time-dependent manners, and hsp90aa1.1, hsp90aa1.2, hsp70.1, and hsp70.2 were the most intense responsive genes in all three tissues. In response to alkalinity stress, 11 out of 13 significantly regulated HSP genes exhibited suppressed expression patterns. Alternatively, among the 12 hypoxia-responsive-expressed HSP genes, 7 genes showed induced expressions, while hsp90aa1.2, hsp70.1, and hsp70.2 had more significant upregulated changes after hypoxic challenge. Our findings provide the essential basis for further functional studies of HSP genes in response to abiotic stresses in spotted seabass.
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INTRODUCTION: C-X-C motif chemokine ligand 16 (CXCL16) is an inflammatory marker that has been found to be predictive of outcomes in patients with cardiovascular disease. Our previous work has also demonstrated its relation to cardiac injury in dialysis patients. However, it is yet unclear whether there is an association between CXCL16 and adverse outcomes in dialysis patients. We aimed to evaluate its prognostic value along with several traditional inflammatory markers in the current study. METHODS: This is a multicenter longitudinal study of prevalent dialysis patients. Circulating inflammatory markers including CXCL16, C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 (IL-6) were measured using a multiplex assay. The primary outcomes were all-cause mortality and a composite of major adverse cardiovascular events (MACEs). The associations between biomarkers and outcomes were analyzed using Cox proportional hazards regression models. RESULTS: Of the 366 participants with available plasma samples, the average age was 52.5 (±12.1) years, and there were 160 (43.7%) female participants. For all-cause mortality, logarithmically transformed CXCL16, IL-6, and CRP were independent predictors after adjustment for covariates. When the 3 markers were included in the same model, CXCL16 was the only one remaining its significance. For MACEs, logarithmically transformed CXCL16 and IL-6 were significant predictors when analyzed separately and CXCL16 was an independent predictor even after adjustment for IL-6. When the biomarkers were analyzed as categorical variables, only CXCL16 was associated with both outcomes. Adding CXCL16 to established risk factors improved risk prediction as revealed by Net Reclassification Index (NRI). CONCLUSION: Using a multimarker approach, we determined that CXCL16 is a potent predictor of all-cause mortality and cardiovascular events in dialysis patients. Our data suggest CXCL16 may improve risk stratification and could be a potential interventional target.