Characterization of T/B cell antigen specific-engineered tumors for studying T cell and GC B cell function in a murine model of NSCLC

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Targeting VEGF/VEGFRs Pathway in the Antiangiogenic Treatment of Human Cancers by Traditional Chinese Medicine

Bearing in mind the doctrine of tumor angiogenesis hypothesized by Folkman several decades ago, the fundamental strategy for alleviating numerous cancer indications may be the strengthening application of notable antiangiogenic therapies to inhibit metastasis-related tumor growth. Under physiological conditions, vascular sprouting is a relatively infrequent event unless when specifically stimulated by pathogenic factors that contribute to the accumulation of angiogenic activators such as the vascular endothelial growth factor (VEGF) family and basic fibroblast growth factor (bFGF). Since VEGFs have been identified as the principal cytokine to initiate angiogenesis in tumor growth, synthetic VEGF-targeting medicines containing bevacizumab and sorafenib have been extensively used, but prominent side effects have concomitantly emerged. Traditional Chinese medicines (TCM)–derived agents with distinctive safety profiles have shown their multitarget curative potential by impairing angiogenic stimulatory signaling pathways directly or eliciting synergistically therapeutic effects with anti-angiogenic drugs mainly targeting VEGF-dependent pathways. This review aims to summarize ( a ) the up-to-date understanding of the role of VEGF/VEGFR in correlation with proangiogenic mechanisms in various tissues and cells; ( b ) the elaboration of antitumor angiogenesis mechanisms of 4 representative TCMs, including Salvia miltiorrhiza, Curcuma longa , ginsenosides, and Scutellaria baicalensis ; and ( c ) circumstantial clarification of TCM-driven therapeutic actions of suppressing tumor angiogenesis by targeting VEGF/VEGFRs pathway in recent years, based on network pharmacology

Successful use of retrograde branched extension limb assembling technique in endovascular repair of pararenal abdominal aortic aneurysm

Surgeon-modified retrograde branched extension limb assembling technique and bridged endografts were successfully used to exclude an asymptomatic pararenal abdominal aortic aneurysm and to reconstruct the superior mesenteric artery and bilateral renal arteries in a case with high-grade celiac artery stenosis, nondilated aorta above the superior mesenteric artery, and large lumen below the renal arteries. In patient-specific models for hemodynamics analysis, enhanced flow diversion to visceral arteries up to 6-month follow-up confirmed treatment feasibility; however, endograft configurations could be improved to avoid sharp corners at bifurcations, thereby ensuring smooth flow transport and possibly reducing risk for endograft narrowing or the development of thrombosis

Association of Matrix Metalloproteinase 9 C-1562T Polymorphism with Genetic Susceptibility to Myocardial Infarction: A Meta-Analysis

Background: Myocardial infarction (MI) is the major cause of death by disease in the world. Many studies have identified the associations between matrix metalloproteinase 9 (MMP9) C-1562T polymorphisms and MI. However, the results remain inconclusive. To clarify the role of MMP9 C-1562T polymorphism in MI risk, we conducted a systematic review and large-scale meta-analysis. Methods: Studies published between January 2005 and March 2014 were obtained from the electronic databases PubMed, Medline, and Embase. The odds ratios (ORs) with 95% CIs were calculated for comparisons of the alleles and genotypes in the overall population and in ethnicity subgroups to measure the strength of genetic associations. Results: A total of 7 related studies, including 3952 MI cases and 4977 healthy control subjects were included in our meta-analysis. Our results show a statistically significant association between T allele and MI in the overall population (OR = 1.23; 95% CI, 1.02–1.48; P = 0.03). The risk of MI was also significantly higher in patients carrying the T allele (TC + TT genotypes) than in those with the CC genotype (P < 0.05). In stratified analysis by ethnicity, we found the T allele was strongly associated with MI in white populations, whereas in Asian populations there appeared no significant association. Conclusions: Our data show that the MMP9 C-1562T polymorphism is a risk factor associated with increased MI susceptibility in the total population and white populations, although no significant association was observed in Asians populations. Further studies with larger sample sizes and assessing gene–gene and gene–environment interactions are required

Effects of ambient PM1 air pollution on daily emergency hospital visits in China: an epidemiological study

Background: China is experiencing severe ambient air pollution. However, few studies anywhere have examined the health effects of PM1 (particulate matter with aerodynamic diameter <1 μm), which are a major part of PM2·5 (particulate matter with aerodynamic diameter <2·5 μm) and even potentially more harmful than PM2·5. We aimed to estimate the effects of ambient daily PM1 and PM2·5 concentrations on emergency hospital visits in China. Methods: In this epidemiological study, we collected daily counts of emergency hospital visits from the 28 largest hospitals in 26 Chinese cities from Sept 9, 2013, to Dec 31, 2014. Ground-based monitoring data for PM1 and PM2·5 and meteorological data were also collected. Hospital-specific emergency hospital visits associated with PM1 or PM2·5 were evaluated with a time-series Poisson regression. The effect estimates were then pooled at the country level using a random-effects meta-analysis. Findings: The mean daily concentration of PM1 in all cities was 42·5 μg/m3 (SD 34·6) and of PM2·5 was 51·9 μg/m3 (41·5). The mean daily number of emergency hospital visits in all hospitals was 278 (SD 173). PM1 and PM2·5 concentrations were significantly associated with an increased risk of emergency hospital visits at lag 0–2 days (cumulative relative risk [RRs] 1·011 [95% CI 1·006–1·017] for a 10 μg/m3 increase in PM1 and 1·010 [1·005–1·016] for a 10 μg/m3 increase in PM2·5). Slightly higher RRs of ambient PM1 and PM2·5 pollution were noted among women and children than among men and adults, respectively, but without statistical significance. Given a cause-effect association, 4·47% (95% CI 2·05–6·79) and 5·05% (2·23–7·75) of daily emergency hospital visits in China could be attributed to ambient PM1 and PM2·5 pollution, respectively. Interpretation: Exposure to both ambient PM1 and PM2·5 were significantly associated with increased emergency hospital visits. The results suggest that most of the health effects of PM2·5 come from PM1. Funding: None

Role of Plasma methylated SEPT9 for Predicting Microvascular Invasion and Tumor Proliferation in Hepatocellular Carcinoma

Background: Methylated SEPT9 (mSEPT9) has a role in the occurrence and development of hepatocellular carcinoma (HCC). Here, we studied the significance of plasma mSEPT9 for predicting prognosis-associated pathological parameters in patients with HCC. Methods: We retrospectively analyzed data from 205 subjects, including 111 HCC patients, 53 patients with at-risk liver disease (ARD) and 41 healthy donors (HDs). Analysis of plasma mSEPT9 was performed using methylation-specific polymerase chain reaction. Levels of mSEPT9 among different groups were compared using a nonparametric Mann-Whitney U test or a one-way ANOVA test. Correlations between pretreatment plasma mSEPT9 and clinicopathological characteristics were analyzed using the Chi-square. Univariate and multivariate analyses were used to identify factors related to microvascular invasion (MVI). Performance of variables for MVI prediction was evaluated by receiver operating characteristics curve. Results: A specific increase of plasma mSEPT9 in HCC was found when compared with ARD and HDs (HCC vs ARD, P   =  1.1  ×  10 −5 and HCC vs HDs, P    =   3.7  ×  10 −10 ). Pretreatment plasma mSEPT9 was significantly correlated tumor number ( P   =  .004), tumor size ( P   =  4.6  ×  10 −5 ), MVI ( P   =  .002) and Barcelona Clinic Liver Cancer stage ( P   =  .012). Levels of plasma mSEPT9 correlated significantly with Ki67 expression in tumor ( r   =  0.356, P   =  1.3  ×  10 −4 ). Univariate and multivariate analyses showed that plasma mSEPT9 and serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) were independent predictors for MVI. A combination of these 2 markers exhibited a larger areas under the curve (areas under the curve [AUC]  =  0.72) than mSEPT9 or PIVKA alone (AUC  =  0.67 and 0.65), especially in early-stage HCC. Conclusions: Plasma mSEPT9 is a promising noninvasive biomarker for predicting MVI and tumor proliferation in HCC. Integration plasma mSEPT9 detection into clinical settings might facilitate the patient management

Clinical Features Associated with ‘Normal Range’ Fibrin D-Dimer Levels in Atrial Fibrillation Patients with Left Atrial Thrombus

Background Left atrial thrombus (LAT) often complicates with atrial fibrillation (AF). The evidence whether fibrin D-dimer levels could be used as a predictive biomarker for LAT is contradictory. This study firstly investigated the relationship between ‘normal range’ D-dimer and prevalent LAT. Second, we explored factors contributing to normal D-dimer levels in the presence of LAT. Methods We studied 244 AF patients with LAT (mean age: 59.9 years, SD:11.7; 53.3% female): of these, 103 (42.2%) had normal D-dimer, 25 (10.2%) had atrial thrombus exclusion score (ATE score) of 0 19 (16.7%) males had CHA 2 DS 2 -VASc score of 0, 21(16.2%) females had CHA 2 DS 2 -VASc score of 1 and 16 had overlapped ATE score of 0 and CHA 2 DS 2 -VASc score of 0 (N = 8 if male) or CHA 2 DS 2 -VASc score of 1(N = 8 if female). Using multivariate binary analysis, larger left atrial diameter (LAD; adjusted OR: 1.06, 1.03−1.10, p = 0.001) were associated with increased D-dimer. Patients with high body mass index (BMI), hypertension history and previous anticoagulation were more likely to show normal range D-dimer levels in the presence of LAT. Conclusions A high prevalence (42.2%) of ‘normal range’ D-dimer levels was found in AF patients with LAT, especially in those with hypertension, high BMI and prior anticoagulation. D-dimer levels of those patients with larger LAD were more likely to be increased

Aged Human Multipotent Mesenchymal Stromal Cells Can Be Rejuvenated by Neuron-Derived Neurotrophic Factor and Improve Heart Function After Injury

Reduced regenerative capacity of aged stem cells hampers the benefits of autologous cell therapy for cardiac regeneration. This study investigated whether neuron-derived neurotrophic factor (NDNF) could rejuvenate aged human bone marrow (hBM)- multipotent mesenchymal stromal cells (MSCs) and whether the rejuvenated hBM-MSCs could improve cardiac repair after ischemic injury. Over-expression of NDNF in old hBM-MSCs decreased cell senescence and apoptosis. Engraftment of NDNF over-expressing old hBM-MSCs into the ischemic area of mouse hearts resulted in improved cardiac function after myocardial infarction, while promoting implanted stem cell survival. Our findings suggest NDNF could be a new factor to rejuvenate aged stem cells and improve their capability to repair the aged heart after injury

Pharmacogenomics of Gemcitabine Metabolism: Functional Analysis of Genetic Variants in Cytidine Deaminase andDeoxycytidine Kinase.DrugMetab. Dispos

Abstract Gemcitabine (dFdC) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK) but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type (WT) enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from E. coli and enzyme kinetic parameters estimated for cytarabine (ara-C), dFdC and its metabolite 2&apos;,2&apos;-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K m and V max for ara-C and dFdC deamination, except for CDA70Thr which had a 2.5-fold lower K m and 6-fold lower V max for ara-C deamination. All four DCK proteins yielded comparable metabolic activity for ara-C and dFdC monophosphorylation, except for DCK24Val which demonstrated an approximately 2-fold increase (p&lt;0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K m (p &lt;0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity towards dFdC and therefore would not contribute to inter-individual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val towards dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. DMD #48769