ABSTRACT
BACKGROUND: This study aimed to use artificial intelligence (AI) to integrate various radiological and clinical pathological data to identify effective predictors of contralateral cervical lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC) and to establish a clinically applicable model to guide the extent of surgery. METHODS: This prospective cohort study included 603 patients with PTC from three centers. Clinical, pathological, and ultrasonographic data were collected and utilized to develop a machine learning (ML) model for predicting CCLNM. Model development at the internal center utilized logistic regression along with other ML algorithms. Diagnostic efficacy was compared among these methods, leading to the adoption of the final model (random forest). This model was subject to AI interpretation and externally validated at other centers. RESULTS: CCLNM was associated with multiple pathological factors. The Delphian lymph node metastasis ratio, ipsilateral cervical lymph node metastasis number, and presence of ipsilateral cervical lymph node metastasis were independent risk factors for CCLNM. Following feature selection, a Delphian lymph node-CCLNM (D-CCLNM) model was established using the Random forest algorithm based on five attributes. The D-CCLNM model demonstrated the highest area under the curve (AUC; 0.9273) in the training cohort and exhibited high predictive accuracy, with AUCs of 0.8907 and 0.9247 in the external and validation cohorts, respectively. CONCLUSIONS: We developed a new, effective method that uses ML to predict CCLNM in patients with PTC. This approach integrates data from Delphian lymph nodes and clinical characteristics, offering a foundation for guiding surgical decisions, and is conveniently applicable in clinical settings.
ABSTRACT
BACKGROUND: Ribosomal RNA Processing 8 (RRP8) is a nucleolar Rossman fold-like methyltransferase that exhibits increased expression in many malignant tumours. However, the role of RRP8 in hepatocellular carcinoma (HCC) is still uncertain. We explored the relationships between RRP8 and prognosis and immune infiltration, as well as the putative pathological function and mechanism of RRP8 in HCC. METHODS: Analysis of RRP8 expression across cancers was performed by using multiple databases. Associations between RRP8 expression and clinicopathological factors were further examined. Gene enrichment analysis was used to identify various putative biological activities and regulatory networks of RRP8 in HCC. The relationship between RRP8 expression and immune infiltration was confirmed by single-sample gene set enrichment analysis (ssGSEA). Univariate and multivariate Cox regression analyses were conducted to assess the impact of clinical variables on patient outcomes. Furthermore, a nomogram was constructed to estimate survival probability based on multivariate Cox regression analysis. Functional validation of RRP8 in HCC was performed with two different systems: doxycycline-inducible shRNA knockdown and CRISPR-Cas9 knockout. RESULTS: RRP8 was markedly overexpressed in HCC clinical specimens compared to adjacent normal tissues. Further analysis demonstrated that RRP8 was directly connected to multiple clinical characteristics and strongly associated with various immune markers in HCC. Moreover, elevated RRP8 expression indicated an unfavourable prognosis. Our functional studies revealed that both knockdown and knockout of RRP8 dramatically attenuated liver cancer cells to proliferate and migrate. Knockout of RRP8 decreased the phosphorylation of MEK1/2 and ß-catenin-(Y654) signalling pathway components; downregulated downstream signalling effectors, including Cyclin D1 and N-cadherin; and upregulated E-cadherin. CONCLUSIONS: RRP8 is strongly implicated in immune infiltration and could be a potential therapeutic target in HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Humans , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Methyltransferases/genetics , Methyltransferases/metabolism , Gene Expression Regulation, Neoplastic , Male , Female , Cell Proliferation , Cell Line, Tumor , Prospective StudiesABSTRACT
The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/ß-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.
Subject(s)
Homeostasis , Liver Regeneration , Liver , Wnt Signaling Pathway , Animals , Liver Regeneration/genetics , Mice , Liver/metabolism , Wnt Signaling Pathway/genetics , Hepatocytes/metabolism , Hepatocytes/cytology , Cell Proliferation/genetics , Single-Cell Analysis , Gene Regulatory Networks , Gene Expression Profiling/methods , Transcriptome , Mice, Inbred C57BL , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , MaleABSTRACT
PURPOSE: This study aimed to examine relationships between health-related quality of life (HRQOL), social determinants of health, and neighborhood socioeconomic disadvantage in individuals with early-stage breast cancer (ESBC) during chemotherapy. METHODS: This is a longitudinal study that recruited Black and White women with ESBC receiving chemotherapy. Participants completed questionnaires recording their sociodemographic information at baseline and the Functional Assessment of Cancer Therapy-General (FACT-G) to report their HRQOL before each chemotherapy cycle. Linear mixed modeling was employed to examine the associations between FACT-G scores, self-reported race, and area deprivation index (ADI) before and at the last chemotherapy cycle, with the duration of chemotherapy treatment as a covariate. RESULTS: A total of 84 Black and 146 White women with ESBC completed the surveys. Linear mixed modeling results suggested that women with ESBC who reported being Black experienced significantly worse physical well-being than those who reported being White throughout chemotherapy, with a 0.22-point lower average (p = 0.02). Both Black and White women with ESBC experienced decreased functional well-being over the chemotherapy, and Black women consistently reported lower scores than White women, with the change in functional well-being over time differing between racial groups (p = 0.03). Participants' ADI national percentiles were not significantly associated with their HRQOL throughout chemotherapy. CONCLUSIONS: These findings underscore possible racial differences in some dimensions of HRQOL during chemotherapy among women with ESBC. Future research should consider further assessing life stressors and past experiences of discrimination and racism that may contribute to these disparities and guide proactive interventions.
Subject(s)
Breast Neoplasms , Quality of Life , Female , Humans , Breast Neoplasms/drug therapy , Longitudinal Studies , Socioeconomic Disparities in Health , Social Determinants of HealthABSTRACT
BACKGROUND: Allogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively cleared by the recipient's immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies. METHODS: Here, we induced an acute inflammatory regenerative niche (3-96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment. RESULTS: The resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs. CONCLUSION: Overall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.
Subject(s)
Hematopoietic Stem Cell Transplantation , Kupffer Cells , Kupffer Cells/physiology , Liver , Hepatocytes/transplantation , Liver Regeneration/physiologyABSTRACT
Objective To investigate the effect of microglia activation regulated by C-X3-C motif chemokine ligand 1(CX3CL1)-C-X3-C motif chemokine receptor 1(CX3CR1)pathway on memory function in hemorrhagic shock/resuscitation rats.Methods The experiment was divided into two parts.In the first part,the rats were randomly divided into sham group,model-0.5 hour group,model-1.5 hour group,model-3 hour group,10 rats in each group.There were differences in the time of hemorrhagic shock among each group.In the second part,rats were randomly divided into control group and CX3CL1 group,10 rats in each group.The rats in CX3CL1 group were treated with CX3CL1 protein factor(intraventricular injection),and the rats in control group were treated with saline.All rats were trained in Morris water maze experiments before model construction,and tests of Morris water maze experiments were carried out after 4 days of model construction.After completion,the whole brains were taken for HE staining and immunohistochemical staining.Cerebrospinal fluid was taken for detection of inflammatory cytokines,and hippocampus tissues were taken for Real-time PCR detection and Western blotting detection.Results Compared with the sham group,the escape latency of rats in model group increased,the number of platform crossings and the resident time in the third quadrant decreased.The neuronal state was impaired in HE staining in model group.In addition,compared with the sham group,the expression of ionized calcium binding adaptor molecule-1(Iba1)in the brain of the rats in model group increased,the contents of tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 in the cerebrospinal fluid increased,and the M1-type microglia markers CD16,TNF-α,IL-1β and inducible nitric oxide synthase(iNOS)mRNA content increased.At the same time,compared with the sham group,the expressions of CX3CL1 and CX3CR1 in the brain of model group decreased,and the expressions of phosphorylated nuclear factor-κB(p-NF-κB)and nucleotide binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)increased.However,compared with the control group,rats in CX3CL1 group had reduced escape latency,increased platform crossing times and quadrantⅢresident time,and recovered neuronal states.In addition,the expression of Iba1 in the brain of CX3CL1 group decreased,the contents of TNF-α and IL-6 in the cerebrospinal fluid decreased,the mRNA contents of M1-type microglia markers like CD16,TNF-α,IL-1β and iNOS decreased,and the mRNA contents of markers of M2-type microglia glial like CD206,transforming growth factor-β(TGF-β),arginase-1(Arg1),Chitinase 3-like protein 1(Ym 1)increased.Conclusion CX3CL1 can help inhibit the excessive activation of microglia,induce the polarization of microglia to M2 type,inhibit the polarization of M1 type,reduce the release of inflammatory cytokines,and alleviate the memory function damage induced by hemorrhagic shock/resuscitation.
ABSTRACT
The polysaccharides extracted from Aspidopterys obcordata are thought to have anti-urolithiasis activity in Drosophila kidney stones. This study aimed to assess the effects of different extraction solvents on the yield, chemical composition, and bioactivity of polysaccharides from A. obcordata. A. obcordata polysaccharides were extracted by using four solutions: hot water, HCl solution, NaOH solution, and 0.1 M NaCl. The results revealed that the extraction solvents significantly influenced the extraction yields, molecular weight distribution, monosaccharide compositions, preliminary structural characteristics, and microstructures of polysaccharides. The NaOH solution's extraction yield was significantly higher than the other extraction methods. Vitro antioxidant activity assays revealed that the NaOH solution extracted exhibited superior scavenging abilities towards DPPH and ABTS radicals and higher FRAP values than other polysaccharides. The vitro assays conducted for calcium oxalate crystallization demonstrated that four polysaccharides exhibited inhibitory effects on the nucleation and aggregation of calcium oxalate crystals, impeded calcium oxalate monohydrate growth, and induced calcium oxalate dihydrate formation. The NaOH solution extracted exhibited the most pronounced inhibition of calcium oxalate crystal nucleation, while the hot water extracted demonstrated the most significant suppression of calcium oxalate crystal aggregation. Therefore, it can be inferred that polysaccharides extracted with NaOH solution exhibited significant potential as a viable approach for extracting polysaccharides from stems due to their superior yield and the remarkable bioactivity of the resulting products.
Subject(s)
Calcium Oxalate , Polysaccharides , Calcium Oxalate/chemistry , Solvents , Sodium Hydroxide , Polysaccharides/pharmacology , Polysaccharides/chemistry , WaterABSTRACT
PROBLEM IDENTIFICATION: To map key concepts underpinning work-related studies about nurses with cancer and identify knowledge gaps. LITERATURE REVIEW: A search was conducted in the PubMed®, CINAHL®, and PsycINFO® databases for articles about nurses with cancer and work-related topics published through March 2023. DATA EVALUATION: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews Checklist was used to report results, and the JBI critical appraisal tools were used to assess the quality of studies. Eleven articles were included. SYNTHESIS: The following four critical concepts were identified: role adjustments at work, cancer impacts on work, organizational support, and translating insights gained from cancer experience into work. Research gaps identified by the scoping review were a lack of theoretical or conceptual frameworks, lack of syntheses of main ideas, and lack of clear data about participants' socioeconomic status across studies. IMPLICATIONS FOR RESEARCH: Minimal research exists to map predictors, outcomes, or intervention targets to guide organizational strategies to support nurses' retention in the nursing workforce. A guiding framework, recruitment of diverse nurses, and focus on the four critical concepts identified in this scoping review are suggested for future research.
Subject(s)
Neoplasms , Nursing Staff , HumansABSTRACT
Aquatic plants are crucial for aquatic ecosystems and their species and distribution reflect aquatic ecosystem health. Remote sensing technology has been used to monitor plant distributions over large scales. However, the fine identification of the species of aquatic higher plants is challenging due to large temporal-spatial changes in optical water body properties and small spectral differences among plant species. Here, an aquatic plant identification method was developed by constructing a decision tree file in the C4.5 algorithm based on the canopy spectra of eight plants in the Changguangxi Wetland water area from hyperspectral remote sensing technology. The method was used to monitor the distribution of different plants in the Changguangxi Wetland area and two other water areas. The results showed that the spectral characteristics of plants were enhanced by calculating their spectral index, thereby improving the comparability among different species. The total recognition accuracy of the constructed decision tree file for eight types of plants was 85.02%. Nymphaea tetragona, Pontederia cordata, and Nymphoides peltatum had the highest recognition accuracy and Eichhornia crassipes was the lowest. The specific species and distributions of aquatic plants were consistent with the water quality in the area. The results can provide a reference for the accurate identification of aquatic plants in the same type of water area.
Subject(s)
Ecosystem , Environmental Monitoring , Environmental Monitoring/methods , Lakes , Hyperspectral Imaging , Wetlands , Plants , Remote Sensing TechnologyABSTRACT
Background: Radiotherapy is the mainstay of treatment for nasopharyngeal carcinoma. Radiation-induced temporal lobe injury (TLI) can regress or resolve in the early phase, but it is irreversible at a later stage. However, no study has proposed a risk-based follow-up schedule for its early detection. Planning evaluation is difficult when dose-volume histogram (DVH) parameters are similar and optimization is terminated. Methods: This multicenter retrospective study included 6065 patients between 2014 and 2018. A 3D ResNet-based deep learning model was developed in training and validation cohorts and independently tested using concordance index in internal and external test cohorts. Accordingly, the patients were stratified into risk groups, and the model-predicted risks were used to develop risk-based follow-up schedules. The schedule was compared with the Radiation Therapy Oncology Group (RTOG) recommendation (every 3 months during the first 2 years and every 6 months in 3-5 years). Additionally, the model was used to evaluate plans with similar DVH parameters. Findings: Our model achieved concordance indexes of 0.831, 0.818, and 0.804, respectively, which outperformed conventional prediction models (all P < 0.001). The temporal lobes in all the cohorts were stratified into three groups with discrepant TLI-free survival. Personalized follow-up schedules developed for each risk group could detect TLI 1.9 months earlier than the RTOG recommendation. According to a higher median predicted 3-year TLI-free survival (99.25% vs. 99.15%, P < 0.001), the model identified a better plan than previous models. Interpretation: The deep learning model predicted TLI more precisely. The model-determined risk-based follow-up schedule detected the TLI earlier. The planning evaluation was refined because the model identified a better plan with a lower risk of TLI. Funding: The Sun Yat-sen University Clinical Research 5010 Program (2015020), Guangdong Basic and Applied Basic Research Foundation (2022A1515110356), Medical Scientific Research Foundation of Guangdong Province (A2022367), and Guangzhou Science and Technology Program (2023A04J1788).
ABSTRACT
Obstructive sleep apnea (OSA) and obesity can increase the risk of hypertension, but the combined effects of these two conditions on hypertension are not yet known. We collected the basic characteristics, sleep parameters, and glucose levels of subjects with a polysomnography test and divided them into four groups, according to whether they had severe OSA and obesity or not. The main effects of severe OSA and obesity and the interactions of the two on systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels were detected using analysis of covariance. The association between obesity and severe OSA and abnormal blood pressure and their combined effects were detected with logistic regression. In total, 686 subjects were included. After adjusting for multiple confounding factors, the strong main effects of obesity and severe OSA were detected in the SBP and DBP levels, with no combined effects from the two conditions on SBP or DBP. Obesity was independently associated with the presence of hyper-systolic blood pressure (hyper-SBP) and hypertension, and severe OSA was independently associated with the presence of hyper diastolic blood pressure (hyper-DBP) and hypertension. No effects of the interaction between severe OSA and obesity on the presence of abnormal blood pressure were observed. Both severe OSA and obesity were associated with hypertension, while obesity was closely associated with hyper-SBP, and severe OSA was associated with hyper-DBP. No effects of the interaction between these two on hypertension were observed.
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Diet, High-Fat , Hepatocytes , Intercellular Signaling Peptides and Proteins , Lipid Metabolism/genetics , Liver Cirrhosis , Non-alcoholic Fatty Liver Disease/genetics , CD36 Antigens/metabolismABSTRACT
Serum amyloid A (SAA) is an acute response protein that mainly produced by hepatocytes, and it can promote endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. Overdose of Acetaminophen (APAP) will cause hepatotoxicity accompany with hepatocyte necrosis, liver sinusoidal endothelial cells (LSECs) damage and thrombosis in liver. However, whether SAA plays a role in APAP-induced liver toxicity remains unclear. Here, we evaluated the Saa1/2 expression in APAP-induced liver injury, and found that Saa1/2 production was significantly increased in an autocrine manner in APAP injury model. Moreover, we used neutralizing antibody (anti-SAA) to block the function of serum Saa1/2. We found that neutralizing serum Saa1/2 protected against APAP-induced liver injuries and increased the survival rate of mice that were treated with lethal dose APAP. Further investigations showed that blocking Saa1/2 reduced APAP-induced sinusoidal endothelium damage, hemorrhage and thrombosis. In addition, in vitro experiments showed that Saa1/2 augmented the toxic effect of APAP on LSECs, and Saa1/2 promoted platelets aggregation on LSECs cell membrane. Taken together, this study suggests that Saa1/2 may play a critical role in APAP-induced liver damages through platelets aggregation and sinusoidal damage. Therefore, we conceptually demonstrate that inhibition of SAA may be a potential intervention for APAP-directed acute liver injuries.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Mice , Animals , Acetaminophen/toxicity , Serum Amyloid A Protein/metabolism , Platelet Aggregation , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Endothelial Cells , Liver/metabolism , Hepatocytes/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/metabolism , Mice, Inbred C57BLABSTRACT
The hemodynamic characteristics of venous reflux are associated with infertility in patients with varicocele; however, an effective method for quantifying the structural distribution of the reflux is lacking. This study aimed to predict surgical outcomes using a new software for venous reflux quantification. This was a retrospective cohort study of a consecutive series of 105 patients (age range: 22-44 years) between July 2017 and September 2019. Venous reflux of the varicocele was obtained using the Valsalva maneuver during scrotal Doppler ultrasonography before microsurgical varicocelectomy. Using this software, the colored reflux signals were segmented, and the gray scale of the color pixels representing the reflux velocity was comprehensively quantified into the mean reflux velocity of the green layer (MRVG) and the reflux velocity standard deviation of the green layer (RVSDG). Spontaneous pregnancy and changes from baseline in the semen parameters were assessed during a 12-month follow-up period. Data were analyzed using logistic regression analysis. An association of the high MRVG group with impaired progressive motility (odds ratio [OR] = 2.868, 95% confidence interval [CI]: 1.133-7.265) and impaired sperm concentration (OR = 2.943, 95% CI: 1.196-7.239) was found during multivariate analysis. High MRVG (OR = 2.680, 95% CI: 1.086-6.614) and high RVSDG (OR = 2.508, 95% CI: 1.030-6.111) were found to be independent predictors of failure to achieve pregnancy following microsurgical repair. In summary, intense venous reflux is an independent predictor of impaired progressive motility, sperm concentration, and pregnancy outcomes after microsurgical varicocelectomy.
Subject(s)
Infertility, Male , Varicocele , Pregnancy , Female , Humans , Male , Young Adult , Adult , Varicocele/complications , Varicocele/diagnostic imaging , Varicocele/surgery , Retrospective Studies , Semen , Veins/surgery , Sperm Count , Infertility, Male/diagnostic imaging , Infertility, Male/etiology , Infertility, Male/surgery , Microsurgery/methods , Sperm MotilityABSTRACT
BACKGROUND: Women with advanced cancer experience significant barriers to achieving high-quality care and maximizing their physical and emotional health. Our novel serious game, Strong Together, aims to teach women with advanced cancer self-advocacy skills needed to improve their symptom burden, quality of life, and patient-centered care. METHODS: This is a single-center, multi-site randomized clinical trial of the Strong Together intervention among 336 women within three months of an advanced breast or gynecologic cancer diagnosis. Randomization occurs to the 3-month Strong Together serious game or enhanced care as usual group. The aims are to: (1) evaluate the effects of the intervention on patient self-advocacy (primary outcome); (2) evaluate the effects of the intervention on quality of life, symptom burden, and patient-centered care (secondary outcomes); and (3) evaluate the behavioral and game mechanisms that influence the efficacy of the intervention. ELIGIBILITY CRITERIA: female, age ≥ 18 years; diagnosis of advanced breast or gynecologic cancer within the past 3 months; Eastern Cooperative Oncology Group score of 0-2; English literacy; and ≥ 6-month life expectancy. Patient-reported outcome measures are collected at baseline, 3-months, and 6-months. CONCLUSION: This protocol is the first large-scale intervention aimed at promoting self-advocacy in women with advanced cancer. Understanding the ability of serious games to impact patient outcomes provides critical information for researchers, clinicians, and stakeholders aiming to improve patient-centered care. TRIAL REGISTRATION: NCT04813276.
Subject(s)
Breast Neoplasms , Games, Experimental , Genital Neoplasms, Female , Self Care , Adolescent , Female , Humans , Quality of Life , Randomized Controlled Trials as Topic , Adult , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Genital Neoplasms, Female/pathology , Genital Neoplasms, Female/therapy , Treatment OutcomeABSTRACT
Many strategies have been adopted to constructin vitromyocardium models, which are of great value to both drug cardiotoxicity evaluation and cardiovascular drug development. In particular, the recent rapid development of human-induced pluripotent stem cell (hiPSC) technology and the rise of the organ-on-a-chip technique have provided great potential to achieve more physiologically relevantin vitromodels. However, recapitulating the key role of the vasculature endothelial layer in drug action on myocardium in the models is still challenging. In this work, we developed an openable heart-on-a-chip system using highly purified functional hiPSC-derived cardiomyocytes (hiPSC-CMs) with an integrated vascular endothelial layer based on our previously proposed culture-patch method. The purity and functionality of the differentiated hiPSC-CMs were characterized, which were applied into the lower chamber of the sandwich-structured device to form the CM layer. The integrity and cell morphology of the endothelial layer on the culture patch as well as the influence of fluid shear force were studied, which was integrated in between the upper and lower chambers. The constructed heart-on-a-chip was finally applied for drug testing. The effect of two cardiac targeting drugs (isoproterenol and E-4031) directly on the hiPSC-CMs or after penetrating through the endothelial layer under static or dynamic conditions was evaluated. The results demonstrated the significance of a vascular layer inin vitromyocardium models for drug testing, as well as the advantage and potential of the proposed platform for cardiovascular drug evaluation with more human physiological relevance.
Subject(s)
Cardiovascular Agents , Induced Pluripotent Stem Cells , Humans , Myocytes, Cardiac , Drug Evaluation , Lab-On-A-Chip Devices , Action Potentials/physiology , Cardiovascular Agents/pharmacologyABSTRACT
Seven new sesquiterpenes, named croargoid A-G (1-7), were isolated from the bark of Croton argyratus. Compounds 1-4 were the first examples of eudesmane sesquiterpene lactones containing C5-OH group. Compound 7 was a highly degraded eudesmane sesquiterpene possessing a rare eleven-carbon skeleton. Their structures with stereochemistry were mainly elucidated by NMR analyses in combination with MS and ECD data. Cytotoxicities and NO inhibitions of all isolates were evaluated and only compound 5 showed moderate NO inhibitory activity.
Subject(s)
Croton , Sesquiterpenes, Eudesmane , Sesquiterpenes , Carbon , Lactones/pharmacology , Molecular Structure , Plant Bark , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Sesquiterpenes, Eudesmane/chemistry , Sesquiterpenes, Eudesmane/pharmacologyABSTRACT
Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by mutations in the MEN1 gene encoding a nuclear protein menin. Among those different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) are life-threatening and frequently implicated. Since there are uncertainties in genotype and phenotype relationship and there are species differences between humans and mice, it is worth it to replenish the mice model with human cell resources. Here, we tested whether the patient-origin induced pluripotent stem cell (iPSC) lines could phenocopy some defects of MEN1. In vitro ß-cell differentiation revealed that the percentage of insulin-positive cells and insulin secretion were increased by at least two-fold in MEN1-iPSC derived cells, which was mainly resulted from significantly higher proliferative activities in the pancreatic progenitor stage (Day 7-13). This scenario was paralleled with increased expressions of prohormone convertase1/3 (PC1/3), glucagon-like peptide-1 (GLP-1), GLP-1R, and factors in the phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway, and the GLP-1R was mainly expressed in ß-like cells. Blockages of either GLP-1R or PI3K significantly reduced the percentages of insulin-positive cells and hypersecretion of insulin in MEN1-derived cells. Furthermore, in transplantation of different stages of MEN1-derived cells into immune-deficient mice, only those ß-like cells produced tumors that mimicked the features of the PNETs from the original patient. To the best of our knowledge, this was the first case using patient-origin iPSCs modeling most phenotypes of MEN1, and the results suggested that GLP-1R may be a potential therapeutic target for MEN1-related hyperinsulinemia.
Subject(s)
Induced Pluripotent Stem Cells , Multiple Endocrine Neoplasia Type 1 , Neuroectodermal Tumors, Primitive , Animals , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Insulin/metabolism , Insulin, Regular, Human , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene ProteinsABSTRACT
Aspidopterys obcordata vine is a Chinese Dai ethnic herb used to treat urolithiasis. However, the material basis and underlying mechanisms remain undefined. In this study, a 2.3 kD inulin-like A. obcordata fructan (AOFOS) was isolated by size exclusion column chromatography and characterized by ultrahigh-performance liquid chromatography-ion trap-time of flight mass spectrometry (UPLC-IT-TOF-MS), nuclear magnetic resonance (NMR) spectroscopy, gas chromatography mass spectrometry (GC-MS) and high-performance gel permeation chromatography (HGPC). In addition, AOFOS showed unique anti-urolithiasis activity in Drosophila kidney stone models. Mechanism study indicated that AOFOS reduced the size of calcium oxalate crystals by inhibiting the formation of large size crystals and the generation rate of calcium oxalate crystals as well as the crystal form conversion from calcium oxalate monohydrate (COM) to calcium oxalate dihydrate (COD).
Subject(s)
Kidney Calculi , Malpighiaceae , Calcium Oxalate/chemistry , Crystallization , Fructans , Inulin , Kidney Calculi/chemistryABSTRACT
Heavy metal ions in contaminated water, such as hexavalent chromium, are harmful to humans. Bacterial biosorption is an ideal method for the treatment of hexavalent chromium. However, hexavalent chromium in solution causes bacteria to produce reactive oxygen species, which leads to bacterial death and affects biosorption. We developed a microfluidics-based biomimetic mineralization method to encapsulate bacteria (e.g., Escherichia coli and Bacillus subtilis) with zeolitic imidazolate framework-8 (ZIF-8), thus allowing the bacteria to form a continuous and homogeneous shell. The artificial shells endowed bacteria with the ability to tolerate harsh environments, which was significant during the treatment of contaminated water. The adsorption of hexavalent chromium was a two-step process: first the fast physical adsorption of ZIF-8 and biosorption by bacteria (up to 30-50% adsorption in 1 day), followed by secondary biosorption after decomposition of the system. The maximum adsorption of hexavalent chromium by the encapsulated bacteria reached 90%. The microfluidic device developed in this study provides a simple method to encapsulate bacteria mildly and enable cell survival in extreme environments, offering the possibility of future microbial applications in environmental and other fields.