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Understanding Sorafenib-Induced Cardiovascular Toxicity: Mechanisms and Treatment Implications.
Li, J, Zhang, L, Ge, T, Liu, J, Wang, C, Yu, Q
Drug design, development and therapy. 2024;:829-843
Abstract
Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.
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MicroRNA-specific therapeutic targets and biomarkers of apoptosis following myocardial ischemia-reperfusion injury.
Ge, T, Ning, B, Wu, Y, Chen, X, Qi, H, Wang, H, Zhao, M
Molecular and cellular biochemistry. 2023
Abstract
MicroRNAs are single-stranded non-coding RNAs that participate in post-transcriptional regulation of gene expression, it is involved in the regulation of apoptosis after myocardial ischemia-reperfusion injury. For example, the alteration of mitochondrial structure is facilitated by MicroRNA-1 through the regulation of apoptosis-related proteins, such as Bax and Bcl-2, thereby mitigating cardiomyocyte apoptosis. MicroRNA-21 not only modulates the expression of NF-κB to suppress inflammatory signals but also activates the PI3K/AKT pathway to mitigate ischemia-reperfusion injury. Overexpression of MicroRNA-133 attenuates reactive oxygen species (ROS) production and suppressed the oxidative stress response, thereby mitigating cellular apoptosis. MicroRNA-139 modulates the extrinsic death signal of Fas, while MicroRNA-145 regulates endoplasmic reticulum calcium overload, both of which exert regulatory effects on cardiomyocyte apoptosis. Therefore, the article categorizes the molecular mechanisms based on the three classical pathways and multiple signaling pathways of apoptosis. It summarizes the targets and pathways of MicroRNA therapy for ischemia-reperfusion injury and analyzes future research directions.
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Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
Zheng, Y, Yao, Y, Ge, T, Ge, S, Jia, R, Song, X, Zhuang, A
Journal of experimental & clinical cancer research : CR. 2023;(1):291
Abstract
Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.
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Experimental evidence for the impact of phages on mineralization of soil-derived dissolved organic matter under different temperature regimes.
Wang, S, Yu, S, Zhao, X, Zhao, X, Mason-Jones, K, Zhu, Z, Redmile-Gordon, M, Li, Y, Chen, J, Kuzyakov, Y, et al
The Science of the total environment. 2022;:157517
Abstract
Microbial mineralization of dissolved organic matter (DOM) plays an important role in regulating C and nutrient cycling. Viruses are the most abundant biological agents on Earth, but their effect on the density and activity of soil microorganisms and, consequently, on mineralization of DOM under different temperatures remains poorly understood. To assess the impact of viruses on DOM mineralization, we added soil phage concentrate (active vs. inactive phage control) to four DOM extracts containing inoculated microbial communities and incubated them at 18 °C and 23 °C for 32 days. Infection with active phages generally decreased DOM mineralization at day one and showed accelerated DOM mineralization later (especially from day 5 to 15) compared to that with the inactivated phages. Overall, phage infection increased the microbially driven CO2 release. Notably, while higher temperature increased the total CO2 release, the cumulative CO2 release induced by phage infection (difference between active phages and inactivated control) was not affected. However, higher temperatures advanced the response time of the phages but shortening its active period. Our findings suggest that bacterial predation by phages can significantly affect soil DOM mineralization. Therefore, higher temperatures may accelerate host-phage interactions and thus, the duration of C recycling.
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Towards subpercentage uncertainty proton stopping-power mapping via dual-energy CT: Direct experimental validation and uncertainty analysis of a statistical iterative image reconstruction method.
Medrano, M, Liu, R, Zhao, T, Webb, T, Politte, DG, Whiting, BR, Liao, R, Ge, T, Porras-Chaverri, MA, O'Sullivan, JA, et al
Medical physics. 2022;(3):1599-1618
Abstract
PURPOSE To assess the potential of a joint dual-energy computerized tomography (CT) reconstruction process (statistical image reconstruction method built on a basis vector model (JSIR-BVM)) implemented on a 16-slice commercial CT scanner to measure high spatial resolution stopping-power ratio (SPR) maps with uncertainties of less than 1%. METHODS JSIR-BVM was used to reconstruct images of effective electron density and mean excitation energy from dual-energy CT (DECT) sinograms for 10 high-purity samples of known density and atomic composition inserted into head and body phantoms. The measured DECT data consisted of 90 and 140 kVp axial sinograms serially acquired on a Philips Brilliance Big Bore CT scanner without beam-hardening corrections. The corresponding SPRs were subsequently measured directly via ion chamber measurements on a MEVION S250 superconducting synchrocyclotron and evaluated theoretically from the known sample compositions and densities. Deviations of JSIR-BVM SPR values from their theoretically calculated and directly measured ground-truth values were evaluated for our JSIR-BVM method and our implementation of the Hünemohr-Saito (H-S) DECT image-domain decomposition technique for SPR imaging. A thorough uncertainty analysis was then performed for five different scenarios (comparison of JSIR-BVM stopping-power ratio/stopping power (SPR/SP) to International Commission on Radiation Measurements and Units benchmarks; comparison of JSIR-BVM SPR to measured benchmarks; and uncertainties in JSIR-BVM SPR/SP maps for patients of unknown composition) per the Joint Committee for Guides in Metrology and the Guide to Expression of Uncertainty in Measurement, including the impact of uncertainties in measured photon spectra, sample composition and density, photon cross section and I-value models, and random measurement uncertainty. Estimated SPR uncertainty for three main tissue groups in patients of unknown composition and the weighted proportion of each tissue type for three proton treatment sites were then used to derive a composite range uncertainty for our method. RESULTS Mean JSIR-BVM SPR estimates deviated by less than 1% from their theoretical and directly measured ground-truth values for most inserts and phantom geometries except for high-density Delrin and Teflon samples with SPR error relative to proton measurements of 1.1% and -1.0% (head phantom) and 1.1% and -1.1% (body phantom). The overall root-mean-square (RMS) deviations over all samples were 0.39% and 0.52% (head phantom) and 0.43% and 0.57% (body phantom) relative to theoretical and directly measured ground-truth SPRs, respectively. The corresponding RMS (maximum) errors for the image-domain decomposition method were 2.68% and 2.73% (4.68% and 4.99%) for the head phantom and 0.71% and 0.87% (1.37% and 1.66%) for the body phantom. Compared to H-S SPR maps, JSIR-BVM yielded 30% sharper and twofold sharper images for soft tissues and bone-like surrogates, respectively, while reducing noise by factors of 6 and 3, respectively. The uncertainty (coverage factor k = 1) of the DECT-to-benchmark values comparison ranged from 0.5% to 1.5% and is dominated by scanning-beam photon-spectra uncertainties. An analysis of the SPR uncertainty for patients of unknown composition showed a JSIR-BVM uncertainty of 0.65%, 1.21%, and 0.77% for soft-, lung-, and bony-tissue groups which led to a composite range uncertainty of 0.6-0.9%. CONCLUSIONS Observed JSIR-BVM SPR estimation errors were all less than 50% of the estimated k = 1 total uncertainty of our benchmarking experiment, demonstrating that JSIR-BVM high spatial resolution, low-noise SPR mapping is feasible and is robust to variations in the geometry of the scanned object. In contrast, the much larger H-S SPR estimation errors are dominated by imaging noise and residual beam-hardening artifacts. While the uncertainties characteristic of our current JSIR-BVM implementation can be as large as 1.5%, achieving < 1% total uncertainty is feasible by improving the accuracy of scanner-specific scatter-profile and photon-spectrum estimates. With its robustness to beam-hardening artifact, image noise, and variations in phantom size and geometry, JSIR-BVM has the potential to achieve high spatial-resolution SPR mapping with subpercentage accuracy and estimated uncertainty in the clinical setting.
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Microbial community changes in different underground compartments of potato affected yield and quality.
Chen, G, Wu, C, Wang, F, Lyu, H, Lu, Y, Yan, C, Chen, J, Deng, Y, Ge, T
3 Biotech. 2022;(5):106
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Abstract
UNLABELLED Soil microbial communities are critical to plant health and productivity. Crop-associated microbial diversity may exhibit spatial specificity across regions and soil compartments. However, we lack sound evidence for the impact of variation in soil microbial diversity on plant productivity caused by regional differences. The main aims of this study are to explore the structure and functionality of the belowground (potato tuber surface and rhizosphere) microbial communities in three compartments and assess whether these communities contribute to potato productivity. Significant differences in alpha and beta diversities of belowground microbiota were detected in different compartments and regions, mainly due to differences in available soil nutrients and pH. Changes to microbial diversity between bulk soil and rhizosphere or tuber surface soil were significantly negatively correlated with potato yield and nutrient content and positively correlated with starch content. We further found some bacterial (Mucilaginibacter, Dokdonella, and Salinispora) and fungal (Solicoccozyma, Scytalidium, and Humicola) genera closely associated with potato yield and quality. Aggregated boosted tree prediction revealed that soil physicochemical properties and microbial diversity of tuber surface soil contributed more to potato yield; tuber surface soil bacterial contributed more to potato starch and nutrient content. Our findings provide experimental evidence that the significant differences in soil microbial diversity and specific microbial taxa enrichment may potentially influence crop productivity under soil physicochemical property change scenarios in the agricultural ecosystem. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s13205-022-03167-6.
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Clinical features and prognostic factors in patients with bone metastases from non-small cell lung cancer.
Wu, XT, Zhou, JW, Pan, LC, Ge, T
The Journal of international medical research. 2020;(5):300060520925644
Abstract
OBJECTIVE To investigate the clinical features and evaluate the prognostic factors in patients with bone metastases from non-small cell lung cancer (NSCLC). METHODS We retrospectively investigated 356 patients with NSCLC with bone metastases from January 2012 to December 2017. The overall survival (OS) and 1-year survival rate were calculated by Kaplan-Meier analysis and compared by univariate analysis using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS A total of 694 sites of bone metastases were determined among the 356 patients. The most common site of bone metastases was the ribs. The median OS was 12.5 months and the 1-year survival was 50.8% in the overall population. Univariate analysis revealed that histological type, number of bone metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), bisphosphonate therapy, and serum calcium, lactate dehydrogenase, and alkaline phosphatase were significantly correlated with prognosis. Multivariate analysis identified multiple bone metastases, ECOG PS ≥2, lactate dehydrogenase ≥225 U/L, and alkaline phosphatase ≥140 U/L as independent negative prognostic factors. CONCLUSION Multiple bone metastases, high ECOG PS, and high serum alkaline phosphatase and lactate dehydrogenase are independent negative prognostic factors for bone metastases from NSCLC.
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Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials.
Wang, Y, Li, X, Ge, T, Xiao, Y, Liao, Y, Cui, Y, Zhang, Y, Ho, W, Yu, G, Zhang, T
Medicine. 2016;95(31):e4509
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Plain language summary
Respiratory tract infections (RTIs) are a leading cause of morbidity and mortality among children worldwide. Probiotics are thought to be able to balance the gut microbiota and interact with the immune system, which may promote resistance against pathogens. There are conflicting results from studies investigating the effect of probiotics on RTI infection. The aim of this systematic review and meta-analysis was to provide the latest and convincing evidence of the effect of probiotic consumption on RTIs in children. 32 studies were included in the qualitative analysis, and 23 in the quantitative meta-analysis. All trials were randomised, double-blinded, and placebo-controlled. Probiotic supplementation had a significant effect on the reduction of number of subjects having at least 1 respiratory symptom episode, on the number of days the children were ill and the number of days absent from day care/school. There was no significant statistical difference of illness episode duration. There was statistical heterogeneity among the trials, and subgroup analysis did not highlight the source of this. It was noted, however, that the probiotic strain, the duration of regimens, administration forms, doses, and follow-up times differed across the included studies, as did the age of children. The authors conclude that probiotic consumption may decrease the incidence and illness duration of RTIs, and that further research is needed to establish optimal probiotic strains, dosing, administration form, time of intervention, and long-time follow-up.
Abstract
BACKGROUND Respiratory tract infections (RTIs) represent one of the main health problems in children. Probiotics are viable bacteria that colonize the intestine and affect the host intestinal microbial balance. Accumulating evidence suggests that probiotic consumption may decrease the incidence of or modify RTIs. The authors systematically reviewed data from randomized controlled trials (RCTs) to investigate the effect of probiotic consumption on RTIs in children. METHODS MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for RCTs regarding the effect of probiotics on RTIs in children. The outcomes included number of children experienced with at least 1 RTI episode, duration of illness episodes, days of illness per subject, and school/day care absenteeism due to infection. A random-effects model was used to calculate pooled relative risks, or mean difference (MD) with the corresponding 95% confidence interval (CI). RESULTS A total of 23 trials involving 6269 children were eligible for inclusion in the systematic review. None of the trials showed a high risk of bias. The quality of the evidence of outcomes was moderate. The age range of subjects was from newborn to 18 years. The results of meta-analysis showed that probiotic consumption significantly decreased the number of subjects having at least 1 RTI episode (17 RCTs, 4513 children, relative risk 0.89, 95% CI 0.82-0.96, P = 0.004). Children supplemented with probiotics had fewer numbers of days of RTIs per person compared with children who had taken a placebo (6 RCTs, 2067 children, MD -0.16, 95% CI -0.29 to 0.02, P = 0.03), and had fewer numbers of days absent from day care/school (8 RCTs, 1499 children, MD -0.94, 95% CI -1.72 to -0.15, P = 0.02). However, there was no statistically significant difference of illness episode duration between probiotic intervention group and placebo group (9 RCTs, 2817 children, MD -0.60, 95% CI -1.49 to 0.30, P = 0.19). CONCLUSION Based on the available data and taking into account the safety profile of RCTs, probiotic consumption appears to be a feasible way to decrease the incidence of RTIs in children.
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Propensity score and proximity matching using random forest.
Zhao, P, Su, X, Ge, T, Fan, J
Contemporary clinical trials. 2016;:85-92
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Abstract
In order to derive unbiased inference from observational data, matching methods are often applied to produce balanced treatment and control groups in terms of all background variables. Propensity score has been a key component in this research area. However, propensity score based matching methods in the literature have several limitations, such as model mis-specifications, categorical variables with more than two levels, difficulties in handling missing data, and nonlinear relationships. Random forest, averaging outcomes from many decision trees, is nonparametric in nature, straightforward to use, and capable of solving these issues. More importantly, the precision afforded by random forest (Caruana et al., 2008) may provide us with a more accurate and less model dependent estimate of the propensity score. In addition, the proximity matrix, a by-product of the random forest, may naturally serve as a distance measure between observations that can be used in matching. The proposed random forest based matching methods are applied to data from the National Health and Nutrition Examination Survey (NHANES). Our results show that the proposed methods can produce well balanced treatment and control groups. An illustration is also provided that the methods can effectively deal with missing data in covariates.
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Single-component versus multicomponent dietary goals for the metabolic syndrome: a randomized trial.
Ma, Y, Olendzki, BC, Wang, J, Persuitte, GM, Li, W, Fang, H, Merriam, PA, Wedick, NM, Ockene, IS, Culver, AL, et al
Annals of internal medicine. 2015;(4):248-57
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Abstract
BACKGROUND Few studies have compared diets to determine whether a program focused on 1 dietary change results in collateral effects on other untargeted healthy diet components. OBJECTIVE To evaluate a diet focused on increased fiber consumption versus the multicomponent American Heart Association (AHA) dietary guidelines. DESIGN Randomized, controlled trial from June 2009 to January 2014. (ClinicalTrials.gov: NCT00911885). SETTING Worcester, Massachusetts. PARTICIPANTS 240 adults with the metabolic syndrome. INTERVENTION Participants engaged in individual and group sessions. MEASUREMENTS Primary outcome was weight change at 12 months. RESULTS At 12 months, mean change in weight was -2.1 kg (95% CI, -2.9 to -1.3 kg) in the high-fiber diet group versus -2.7 kg (CI, -3.5 to -2.0 kg) in the AHA diet group. The mean between-group difference was 0.6 kg (CI, -0.5 to 1.7 kg). During the trial, 12 (9.9%) and 15 (12.6%) participants dropped out of the high-fiber and AHA diet groups, respectively (P = 0.55). Eight participants developed diabetes (hemoglobin A1c level ≥6.5%) during the trial: 7 in the high-fiber diet group and 1 in the AHA diet group (P = 0.066). LIMITATIONS Generalizability is unknown. Maintenance of weight loss after cessation of group sessions at 12 months was not assessed. Definitive conclusions cannot be made about dietary equivalence because the study was powered for superiority. CONCLUSION The more complex AHA diet may result in up to 1.7 kg more weight loss; however, a simplified approach to weight reduction emphasizing only increased fiber intake may be a reasonable alternative for persons with difficulty adhering to more complicated diet regimens. PRIMARY FUNDING SOURCE National Heart, Lung, and Blood Institute.