Publications by authors named "Ge Tao"

60 Publications

The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.

Cell Rep 2021 Nov;37(8):110030

Department of Molecular Medicine, College of Veterinary Medicine, Cornell, Ithaca, NY 14853, USA. Electronic address:

Intestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer ASE alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.
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http://dx.doi.org/10.1016/j.celrep.2021.110030DOI Listing
November 2021

Prognostic value of surgical intervention in advanced lung adenocarcinoma: a population-based study.

J Thorac Dis 2021 Oct;13(10):5942-5953

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Surgical intervention is generally not considered as a treatment option in patients with advanced non-small cell lung cancer (NSCLC). Accumulating data suggest that surgery may have beneficial effects for these advanced patients. However, no evidence supports the significance of primary tumor resection (PTR) and metastatic tumor resection (MTR) in patients with stage IV lung adenocarcinoma (LUAD).

Methods: A total of 32,497 patients diagnosed with primary stage IV LUAD were selected through the Surveillance, Epidemiology, and End Results (SEER) database. Possible confounders were eliminated by propensity score matching (PSM). The overall survival (OS) and lung cancer-specific survival (LCSS) were estimated as the primary endpoints. Furthermore, the independent prognostic factors of patients with the surgical intervention were retrospectively analyzed.

Results: Patients underwent surgical intervention had better OS and LCSS than those who did not (P=0.001 for OS; P<0.001 for LCSS). Meanwhile, patients who underwent surgery combined with lymph node dissection had better survival outcomes (P<0.001 for OS and LCSS) in the K-M analysis. For different metastatic sites, PTR was beneficial to the survival of patients with isolated lung metastases (LUM) and multiple organ metastases (MOM) (LUM: P=0.041; MOM: P=0.003). As for metastatic surgery, no patients were found to benefit from resection of metastatic tumor [bone metastasis (BOM): P=0.696; brain metastasis (BRM): P=0.951; LUM: P=0.402; MOM: P=0.365].

Conclusions: Surgical intervention strategies can prolong survival to some extent, depending on different sites of metastasis and highly selected patients.
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http://dx.doi.org/10.21037/jtd-21-997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575796PMC
October 2021

Editorial: Cardiomyocyte Maturation: Novel Insights for Regenerative Medicine.

Front Cell Dev Biol 2021 2;9:730622. Epub 2021 Aug 2.

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States.

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http://dx.doi.org/10.3389/fcell.2021.730622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365607PMC
August 2021

A novel transgenic Cre allele to label mouse cardiac conduction system.

Dev Biol 2021 10 8;478:163-172. Epub 2021 Jul 8.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Texas Heart Institute, Houston, TX 77030, USA. Electronic address:

The cardiac conduction system is a network of heterogeneous cell population that initiates and propagates electric excitations in the myocardium. Purkinje fibers, a network of specialized myocardial cells, comprise the distal end of the conduction system in the ventricles. The developmental origins of Purkinje fibers and their roles during cardiac physiology and arrhythmia have been reported. However, it is not clear if they play a role during ischemic injury and heart regeneration. Here we introduce a novel tamoxifen-inducible Cre allele that specifically labels a broad range of components in the cardiac conduction system while excludes other cardiac cell types and vital organs. Using this new allele, we investigated the cellular and molecular response of Purkinje fibers to myocardial injury. In a neonatal mouse myocardial infarction model, we observed significant increase in Purkinje cell number in regenerating myocardium. RNA-Seq analysis using laser-captured Purkinje fibers showed a unique transcriptomic response to myocardial infarction. Our finds suggest a novel role of cardiac Purkinje fibers in heart injury.
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http://dx.doi.org/10.1016/j.ydbio.2021.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482537PMC
October 2021

Comprehensive genomic profiling of combined small cell lung cancer.

Transl Lung Cancer Res 2021 Feb;10(2):636-650

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Combined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC.

Methods: The clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC.

Results: There were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that and were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components.

Conclusions: There were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations.
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http://dx.doi.org/10.21037/tlcr-20-1099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947408PMC
February 2021

Early diagnosis of lung cancer: which is the optimal choice?

Aging (Albany NY) 2021 02 11;13(4):6214-6227. Epub 2021 Feb 11.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.

The prognosis of lung cancer patients with different clinical stages is significantly different. The 5-year survival of stage IA groups can exceed 90%, while patients with stage IV can be less than 10%. Therefore, early diagnosis is extremely important for lung cancer patients. This research focused on various diagnosis methods of early lung cancer, including imaging screening, bronchoscopy, and emerging potential liquid biopsies, as well as volatile organic compounds, autoantibodies, aiming to improve the early diagnosis rate and explore feasible and effective early diagnosis strategies.
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http://dx.doi.org/10.18632/aging.202504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950268PMC
February 2021

The prevalent I686T human variant and loss-of-function mutations in the cardiomyocyte-specific kinase gene TNNI3K cause adverse contractility and concentric remodeling in mice.

Hum Mol Genet 2021 01;29(21):3504-3515

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.

TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling, characterized by ventricular wall thickening and substantial reduction of cardiomyocyte aspect ratio. This pathology occurs in mice carrying a Tnni3k null allele, a K489R point mutation rendering the protein kinase-dead, or an allele corresponding to human I686T, the most common human non-synonymous TNNI3K variant, which is hypomorphic for kinase activity. Mutant mice develop these conditions in the absence of fibrosis or hypertension, implying a primary cardiomyocyte etiology. In culture, mutant cardiomyocytes were impaired in contractility and calcium dynamics and in protein kinase A signaling in response to isoproterenol, indicating diminished contractile reserve. These results demonstrate a beneficial function of TNNI3K in the adult heart that might explain its evolutionary conservation and imply that human TNNI3K variants, in particular the widespread I686T allele, may convey elevated risk for altered heart geometry and hypertrophy.
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http://dx.doi.org/10.1093/hmg/ddaa234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788294PMC
January 2021

Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer.

Genome Biol 2020 06 24;21(1):152. Epub 2020 Jun 24.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.

Background: Malignant transformation and progression of cancer are driven by the co-evolution of cancer cells and their dysregulated tumor microenvironment (TME). Recent studies on immunotherapy demonstrate the efficacy in reverting the anti-tumoral function of T cells, highlighting the therapeutic potential in targeting certain cell types in TME. However, the functions of other immune cell types remain largely unexplored.

Results: We conduct a single-cell RNA-seq analysis of cells isolated from tumor tissue samples of non-small cell lung cancer (NSCLC) patients, and identify subtypes of tumor-infiltrated B cells and their diverse functions in the progression of NSCLC. Flow cytometry and immunohistochemistry experiments on two independent cohorts confirm the co-existence of the two major subtypes of B cells, namely the naïve-like and plasma-like B cells. The naïve-like B cells are decreased in advanced NSCLC, and their lower level is associated with poor prognosis. Co-culture of isolated naïve-like B cells from NSCLC patients with two lung cancer cell lines demonstrate that the naïve-like B cells suppress the growth of lung cancer cells by secreting four factors negatively regulating the cell growth. We also demonstrate that the plasma-like B cells inhibit cancer cell growth in the early stage of NSCLC, but promote cell growth in the advanced stage of NSCLC. The roles of the plasma-like B cell produced immunoglobulins, and their interacting proteins in the progression of NSCLC are further validated by proteomics data.

Conclusion: Our analysis reveals versatile functions of tumor-infiltrating B cells and their potential clinical implications in NSCLC.
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http://dx.doi.org/10.1186/s13059-020-02064-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315523PMC
June 2020

The effect of environmental regulation intensity deviation on China's inclusive growth.

Authors:
Tao Ge Jinye Li

Environ Sci Pollut Res Int 2020 Sep 16;27(27):34158-34171. Epub 2020 Jun 16.

School of Economics and Management, Xinjiang University, Urumqi, 830046, China.

This is the first attempt to explore the impact of environmental regulation intensity deviation on inclusive growth. An analysis framework in which the deviation between actual intensity and optimal intensity affects inclusive growth is constructed. Based on this analytical framework, this study uses panel data from 281 prefecture-level cities in China during the period 2004-2016 to investigate environmental regulation intensity deviation, as well as the feature, heterogeneity, and mechanisms of environmental regulation intensity deviation affecting inclusive growth. The empirical findings show that (i) environmental regulation has an inverted U-shaped effect on inclusive growth, but the actual intensity of environmental regulation in China is lower than the optimal intensity, which makes it difficult to give full play to its incentive role on inclusive growth; (ii) further grouping tests show that environmental regulation intensity deviation will inhibit inclusive growth within regions but promote inclusive growth between regions due to the difference in deviation; (iii) technological innovation, industrial transformation, and foreign investment have a partial mediating effect, which may be important mechanisms for environmental regulation intensity deviation to restrain inclusive growth; and (iv) the robustness test of informal environmental regulation supports the findings of formal environmental regulation and finds that the deviation of informal environmental regulation is more severe than that of formal environmental regulation. The empirical findings therefore suggest that policymakers should scientifically improve the environmental regulation intensity and optimize the environmental regulatory structure.
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http://dx.doi.org/10.1007/s11356-020-09574-7DOI Listing
September 2020

The impact of environmental regulation efficiency loss on inclusive growth: Evidence from China.

J Environ Manage 2020 Aug 6;268:110700. Epub 2020 May 6.

School of Economics and Management, Xinjiang University, Urumchi, 830046, Xinjiang, China.

This study uses panel data from 281 cities in China during the period 2004-2016 and the two-regime spatial Durbin model to investigate the strategic interactions of environmental regulation efficiency loss between cities. It adopts the spatial lag of X model and the mediating effect model to analyze the effect and mechanisms of environmental regulation efficiency loss on inclusive growth. The results show that there are asymmetric strategic interactions in the form of imitative competition and upward competition between geographically neighboring cities, which exacerbates the environmental regulation efficiency loss. The environmental regulation efficiency loss of local and neighboring cities inhibits inclusive growth at both the national and regional levels. At the regional level, the local and neighbor effects are the strongest in the central and western regions. The results also show that the inhibition of the neighbor effect is more obvious within 500 km and is relatively stable after 2007. Revenue decentralization, fiscal autonomy, and promotion pressure have a partial mediating effect, which may be important channels for the environmental regulation efficiency loss to restrain inclusive growth. However, expenditure decentralization plays a masking effect, which mitigates the inhibition of the environmental regulation efficiency loss on inclusive growth. In addition, the robustness test of the informal environmental regulation efficiency loss supports the conclusions of the formal environmental regulation efficiency loss. Moreover, the inhibitions of the two are similar at the national level but are different at the regional level. This study therefore suggests that policymakers should adopt a series of measures to improve environmental regulation efficiency, in addition to increasing environmental regulation intensity.
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http://dx.doi.org/10.1016/j.jenvman.2020.110700DOI Listing
August 2020

Familial assimilation in transmission of raw-freshwater fish-eating practice leading to clonorchiasis.

PLoS Negl Trop Dis 2020 04 30;14(4):e0008263. Epub 2020 Apr 30.

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, China.

Clonorchiasis is caused by raw-freshwater fish-eating practice and causes high burden in Asia. Transmission mechanism of this behavior hasn't been illuminated, which hinders the adoption of sustainable control activities. A cross-sectional survey was implemented in students from four endemic provinces in China. Data with 23,222 students aged 9-18 and their parents were eligible. Familial clustering of raw-eating practice, impact of parents' practice on children, interaction of spouses' practice was analyzed. Raw-eating practice met β-binomial distribution (χ2 = 0.8, p>0.05). Clustering coefficient increased by students' age (R2 = 0.82, p<0.001) and was higher in those families with boys compared to girls (t = 4.1, p<0.01). The proportion of students with raw-eating practice increased yearly by 8.9% in girls and 10.5% in boys. Compared to those without parents' raw-eating practice, adjusted odds ratio of students' raw-eating practice was 10.5 (95% confidential intervals (95% CI): 9.4-11.7) in those with fathers' practice, 33.6 (95% CI: 26.3-42.9) in those with mothers' practice and 47.1 (95% CI: 42.0-52.8) in those with both parents' practice. There existed interaction between spouses' practice (χ2 = 6713.1, p<0.001) and the impact from husband on his wife was higher than that from wife on her husband. Familial assimilation characterizes the transmission of raw-freshwater fish-eating practice, consisted of vertical intergenerational assimilation from parents to their children and horizontal martial assimilation between spouses. A sustainable strategy against clonorchiasis should interrupt the transmission of raw-freshwater fish-eating practice. Additionally, further studies are expected to explore more information, e.g. the frequency in raw-eating practice and type of raw freshwater fish, infection status of C. sinensis in participants, as well as direct collection of parents' eating information from themselves.
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http://dx.doi.org/10.1371/journal.pntd.0008263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233597PMC
April 2020

Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling.

Elife 2020 03 13;9. Epub 2020 Mar 13.

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States.

Injury to the newborn mouse heart is efficiently regenerated, but this capacity is lost by one week after birth. We found that IGF2, an important mitogen in heart development, is required for neonatal heart regeneration. IGF2 originates from the endocardium/endothelium and is transduced in cardiomyocytes by the insulin receptor. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry during the early part of the first postnatal week. Consequently, regeneration failed despite the later presence of additional cell cycle-inducing activities 7 days following injury. Most cardiomyocytes transition from mononuclear diploid to polyploid during the first postnatal week. Regeneration was rescued in Igf2-deficient neonates in three different contexts that elevate the percentage of mononuclear diploid cardiomyocytes beyond postnatal day 7. Thus, IGF2 is a paracrine-acting mitogen for heart regeneration during the early postnatal period, and IGF2-deficiency unmasks the dependence of this process on proliferation-competent mononuclear diploid cardiomyocytes.
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http://dx.doi.org/10.7554/eLife.53071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105374PMC
March 2020

Rapid screening of Clonorchis sinensis infection: Performance of a method based on raw-freshwater fish-eating practice.

Acta Trop 2020 Jul 30;207:105380. Epub 2020 Jan 30.

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, China; National Center for International Research on Tropical Diseases, Ministry of Science and Technology, Shanghai, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China. Electronic address:

Clonorchis sinensis infection is caused by ingestion of raw freshwater fish containing the infective larvae of Clonorchis sinensis. It is highly endemic in East Asia, especially in China. Selective chemotherapy of people who report habitual eating of raw freshwater fish is a control measure. As the performance of this screening technique has not yet been fully evaluated in China, a cross-sectional study was conducted, covering 17 counties in four major clonorchiasis-endemic provinces. About 1 000 participants were enrolled from each county. Fecal samples were collected and examined for helminth eggs and each person enrolled was asked about their practice with respect to eating raw freshwater fish. In total, 16 230 participants from 16 counties were finally included. The overall prevalence of C. sinensis infection was 10.8%, ranging from 0 to 53.7% in the 16 counties, while the percentage of inhabitants eating raw freshwater fish was 26.5%, ranging from 0 to 79.1%. The overall sensitivity and specificity of screening for C. sinensis infection in this approach was 82.3% and 80.3%, respectively, yielding a Youden's index of 0.6. The overall positive and negative likelihood ratios were 4.2 and 0.2, respectively, while the overall positive and negative predictive values were 33.5% and 97.4%, respectively. Furthermore, the sensitivity was higher with regard to high-intensity infections compared to light infections.
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http://dx.doi.org/10.1016/j.actatropica.2020.105380DOI Listing
July 2020

Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency.

PLoS Genet 2019 10 7;15(10):e1008354. Epub 2019 Oct 7.

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.

Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2-10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy.
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http://dx.doi.org/10.1371/journal.pgen.1008354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797218PMC
October 2019

A Fast Sparse Recovery Algorithm for Compressed Sensing Using Approximate ₀ Norm and Modified Newton Method.

Materials (Basel) 2019 Apr 15;12(8). Epub 2019 Apr 15.

The State Key Laboratory of Heavy Duty AC Drive Electric Locomotive Systems Integration, CRRC Zhuzhou Locomotive Co., Ltd., Zhuzhou 412001, China.

In this paper, we propose a fast sparse recovery algorithm based on the approximate ₀ norm (FAL0), which is helpful in improving the practicability of the compressed sensing theory. We adopt a simple function that is continuous and differentiable to approximate the ₀ norm. With the aim of minimizing the ₀ norm, we derive a sparse recovery algorithm using the modified Newton method. In addition, we neglect the zero elements in the process of computing, which greatly reduces the amount of computation. In a computer simulation experiment, we test the image denoising and signal recovery performance of the different sparse recovery algorithms. The results show that the convergence rate of this method is faster, and it achieves nearly the same accuracy as other algorithms, improving the signal recovery efficiency under the same conditions.
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http://dx.doi.org/10.3390/ma12081227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515327PMC
April 2019

SNHG20 serves as a predictor for prognosis and promotes cell growth in oral squamous cell carcinoma.

Oncol Lett 2019 Jan 15;17(1):951-957. Epub 2018 Nov 15.

Department of Stomatology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) serve important roles in various tumor types, including colorectal cancer and gastric cancer. The present study aimed to investigate the contribution of the lncRNA small nucleolar RNA host gene 20 (SNHG20) in oral squamous cell carcinoma (OSCC) progression. It was demonstrated that SNHG20 expression was significantly increased in OSCC tissue specimens, compared with in adjacent non-tumor tissue specimens. The increased SNHG20 expression in OSCC tissue specimens was associated with tumor differentiation and Tumor-Node-Metastasis stage. Kaplan-Meier analysis and log-rank tests indicated that Higher SNHG20 expression predicted a poor overall survival (OS) rate in patients with OSCC. Multivariate Cox proportional hazards regression analysis demonstrated that increased SNHG20 expression was an independent predictor for the OS of patients with OSCC. Knockdown of SNHG20 expression in OSCC cells suppressed proliferation. The cell proliferation-associated proteins proliferating cell nuclear antigen and Ki67 expression levels were reduced when SNHG20 was knocked down in OSCC cells; thus, the results indicated that SHNG20 may serve as a predictor and potential target for OSCC treatment.
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http://dx.doi.org/10.3892/ol.2018.9709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312994PMC
January 2019

Study on dielectric properties of high organic sulfur coking coal and modeling sulfur compounds.

PLoS One 2019 3;14(1):e0208125. Epub 2019 Jan 3.

Department of Material Science and Engineering, Anhui University of Science and Technology, Huainan, PR China.

Coking coal is geologically scarce resource and most of them cannot be directly used in steel making due to their higher sulfur content. One desulfurization method that has great potential for massive application is microwave desulfurization, which removes the relatively stubborn organic sulfur under mild conditions. The dielectric properties of coals determine the efficiency of the microwave energy absorption. The key to describing the mechanism of microwave desulfurization and further improvement of the desulfurization efficiency is the dielectric response of organic sulfur compounds in coal to microwave. This study focuses on existing formand microwave response of organic sulfur components of three typical coking coal in China. Resultsshowed that the major organic sulfur in selected coals is thiophene which has a stable structure and is the most difficult to be removed. Several dielectric peaks (dielectric loss)andsignificant differencesofeach selected coal samples are observed. The microwave absorption peaks of the model sulfur compounds are identified to be within 9-11GHz. The real parts of the relative dielectric constants (hereinafter referred to as ε') shows a decreasing trend as: diphenyl sulfoxide > diphenyl sulfone > diphenyl sulfide > dibenzothiophene > Octadecane thiol. Response to microwaveare observed to be distinctively different between sulfur-containing and sulfur-free model compounds. The dielectric polarization of mixture (coal mixed with model sulfur compounds) is greater than pure coal. Meanwhile the higher the sulfur content of the coal, the greater the ε' is. Sulfur componentsin coal can significantly influence its polarization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317830PMC
September 2019

maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Development 2018 09 26;145(18). Epub 2018 Sep 26.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA

Loss of the paired-like homeodomain transcription factor 2 () in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in conditional-knockout ( CKO) mice. We found adipose-like tissue in CKO hearts 60 days after MI induced surgically at postnatal day 2 but not at day 8. Molecular and cellular analyses showed the onset of adipogenic signaling in mutant hearts after MI. Lineage tracing experiments showed a non-cardiomyocyte origin of the adipose-like tissue. Interestingly, we found that promotes mitochondrial function through its gene regulatory network, and that the knockdown of a key mitochondrial target gene, , also leads to the accumulation of myocardial fat tissue. Single-nuclei RNA-seq revealed that -deficient hearts were oxidatively stressed. Our findings reveal a role for in maintaining proper cardiac cellular composition during heart regeneration via the maintenance of proper mitochondrial structure and function.
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http://dx.doi.org/10.1242/dev.168609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176932PMC
September 2018

PEGylated liposomes as delivery systems for Gambogenic acid: Characterization and in vitro/in vivo evaluation.

Colloids Surf B Biointerfaces 2018 Dec 16;172:26-36. Epub 2018 Aug 16.

School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China. Electronic address:

Gambogenic acid (GNA), which possesses diverse anti-tumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. However, the excessive irritation to the blood vessel, short elimination half-life and poor aqueous solubility restricted its clinical application. In this study, Gambogenic acid-loaded PEGylated liposomes (GNA-PEG-LPs) were developed to reduce toxicity, prolong the half-life and enhance anticancer efficacy both in vitro and in vivo. The average particle size of GNA-PEG-LPs was 90.13 ± 0.16 nm and their polydispersity index (PDI) was 0.092 ± 0.003. The encapsulation efficiency, drug loading and zeta potential of GNA-PEG-LPs were 88.13 ± 1.31%, 3.72 ± 0.04%, -22.10 ± 0.20 mV, respectively. Compared to free GNA, GNA-PEG-LPs showed enhanced cytotoxicity and apoptosis induction effect against A549, SGC-7901 and HepG2 cells. Mechanistically, western blot analysis revealed that up-regulation of Bax, down-regulation of Bcl-2 and activation of caspase-3 contributed to apoptosis. In addition, the blood vessel irritation test showed that the vascular irritation of GNA could be reduced by liposomal encapsulation. The hemolysis assay revealed that good hemocompatibility of the liposomes. Furthermore, pharmacokinetic study showed that the t and the AUC of GNA-PEG-LPs were higher than GNA solution approximately 2.84-fold and 2.97-fold, respectively. In vivo antitumor efficacy demonstrated that GNA-PEG-LPs significantly inhibited the tumor growth in LLC tumor-bearing C57BL/6 mouse model. Results of Immunohistochemistry indicated that GNA-PEG-LPs significantly suppressed the expression of Bcl-2 and increased the expression of Bax and caspase-3 compared with free GNA. Collectively, PEGylated liposomes could be a potential nanocarrier to prolong half-life, reduce toxicity and enhance anticancer efficacy both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.colsurfb.2018.08.022DOI Listing
December 2018

Effect of Gambogenic Acid on Cytochrome P450 1A2, 2B1 and 2E1, and Constitutive Androstane Receptor in Rats.

Eur J Drug Metab Pharmacokinet 2018 Dec;43(6):655-664

Pharmacokinetics Lab, School of Pharmacy, Anhui University of Chinese Medicine, 001 Qianjiang Road, Hefei, 230012, Anhui, China.

Background And Objectives: Gambogenic acid (GNA), which possesses diverse antitumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. Cytochrome P450 (CYP) enzymes play an important role in the metabolism of most xenobiotics; constitutive androstane receptor (CAR), a nuclear receptor that might be activated by xenobiotics and associated with the expression of some CYPs. In this study, we determined the effect of GNA on multiple rat liver CYP isoforms (CYP1A2, 2B1, and 2E1) and CAR as well as the potential of GNA to interact with co-administered drugs.

Methods: Male SD rats were randomly divided into the control, and the low (5 mg/kg)-, medium (25 mg/kg)-, and high- (100 mg/kg) dose GNA groups. After the intragastric administration of GNA for 14 consecutive days, a cocktail method was adopted to evaluate the activities of CYP1A2, 2B1, and 2E1. The liver expression of CYP1A2, 2B1, and 2E1 and CAR was analyzed by Western blotting (WB) and quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR).

Results: The 14-day administration of GNA significantly increased both the mRNA and protein expressions and the activity of CYP2E1. Additionally, the mRNA and protein expressions of CYP1A2 were clearly induced, while only the high GNA dose increased the activity of liver CYP1A2. Moreover, the mRNA expression levels of CYP2B1 and CAR were increased, but their protein levels and the activity parameters of CYP2B1 did not show significant changes.

Conclusions: The obtained results suggest that the CYP1A2 and CYP2E1 enzymes could be induced in rats after treatment with GNA. Therefore, when GNA is administrated with other drugs, potential drug-drug interactions (DDI) mediated by CYP1A2 and CYP2E1 induction should be taken into consideration.
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http://dx.doi.org/10.1007/s13318-018-0477-7DOI Listing
December 2018

Ambient ozone and asthma hospital admissions in Texas: a time-series analysis.

Asthma Res Pract 2017 1;3. Epub 2017 Aug 1.

Texas Commission on Environmental Quality, 12100 Park 35 Circle, Austin, TX USA.

Background: Many studies have evaluated associations between asthma emergency department (ED) visits, hospital admissions (HAs), and ambient ozone (O) across the US, but not in Texas. We investigated the relationship between O and asthma HAs, and the potential impacts of outdoor pollen, respiratory infection HAs, and the start of the school year in Texas.

Methods: We obtained daily time-series data on asthma HAs and ambient O concentrations for Dallas, Houston, and Austin, Texas for the years 2003-2011. Relative risks (RRs) and 95% confidence intervals (CIs) of asthma HAs per 10-ppb increase in 8-h maximum O concentrations were estimated from Poisson generalized additive models and adjusted for temporal trends, meteorological factors, pollen, respiratory infection HAs, day of the week, and public holidays. We conducted a number of sensitivity analyses to assess model specification.

Results: We observed weak associations between total asthma HAs and O at lags of 1 day (RR = 1.012, 95% CI: 1.004-1.021), 2 days (RR = 1.011, 95% CI: 1.002-1.019), and 0-3 days (RR = 1.017, 95% CI: 1.005-1.030). The associations were primarily observed in children aged 5-14 years (e.g., for O at lag 0-3 days, RR = 1.037, 95% CI: 1.011-1.064), and null in individuals 15 years or older. The effect estimates did not change significantly with adjustment for pollen and respiratory infections, but they attenuated considerably and lost statistical significance when August and September data were excluded. A significant interaction between time around the start of the school year and O at lag 2 day was observed, with the associations with pediatric asthma HAs stronger in August and September (RR = 1.040, 95% CI: 1.012-1.069) than in the rest of the year (October-July) (RR = 1.006, 95% CI: 0.986-1.026).

Conclusions: We observed small but statistically significant positive associations between total and pediatric asthma HAs and short-term O exposure in Texas, especially in August and September. Further research is needed to determine how the start of school could modify the observed association between O and pediatric asthma HAs.
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http://dx.doi.org/10.1186/s40733-017-0034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540296PMC
August 2017

Divergent Requirements for EZH1 in Heart Development Versus Regeneration.

Circ Res 2017 Jul 16;121(2):106-112. Epub 2017 May 16.

From the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (S.A., Y.L., C.L., Y.Y., C.L., A.H.); Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (X.Y., Y.P., A.H.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX (G.T.); Department of Cardiology, Boston Children's Hospital, MA (W.T.P.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.).

Rationale: Polycomb repressive complex 2 is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are 2 alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown.

Objective: We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration.

Methods And Results: Heart development was normal in Ezh1 (1 knockout) and Ezh2::cTNT (2 knockout) embryos. Ablation of both genes in Ezh1::Ezh2::cTNT embryos caused lethal heart malformations, including hypertrabeculation, compact myocardial hypoplasia, and ventricular septal defect. Epigenome and transcriptome profiling showed that derepressed genes were upregulated in a manner consistent with total EZH dose. In neonatal heart regeneration, Ezh1 was required, but Ezh2 was dispensable. This finding was further supported by rescue experiments: cardiac myocyte-restricted re-expression of EZH1 but not EZH2 restored neonatal heart regeneration in 1 knockout. In myocardial infarction performed outside of the neonatal regenerative window, EZH1 but not EZH2 likewise improved heart function and stimulated cardiac myocyte proliferation. Mechanistically, EZH1 occupied and activated genes related to cardiac growth.

Conclusions: Our work unravels divergent mechanisms of EZH1 in heart development and regeneration, which will empower efforts to overcome epigenetic barriers to heart regeneration.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527745PMC
July 2017

Concentration-response of short-term ozone exposure and hospital admissions for asthma in Texas.

Environ Int 2017 07 23;104:139-145. Epub 2017 Apr 23.

Gradient, 20 University Road, Cambridge, MA, United States. Electronic address:

Background: Short-term exposure to ozone has been associated with asthma hospital admissions (HA) and emergency department (ED) visits, but the shape of the concentration-response (C-R) curve is unclear.

Methods: We conducted a time series analysis of asthma HAs and ambient ozone concentrations in six metropolitan areas in Texas from 2001 to 2013. Using generalized linear regression models, we estimated the effect of daily 8-hour maximum ozone concentrations on asthma HAs for all ages combined, and for those aged 5-14, 15-64, and 65+years. We fit penalized regression splines to evaluate the shape of the C-R curves.

Results: Using a log-linear model, estimated risk per 10ppb increase in average daily 8-hour maximum ozone concentrations was highest for children (relative risk [RR]=1.047, 95% confidence interval [CI]: 1.025-1.069), lower for younger adults (RR=1.018, 95% CI: 1.005-1.032), and null for older adults (RR=1.002, 95% CI: 0.981-1.023). However, penalized spline models demonstrated significant nonlinear C-R relationships for all ages combined, children, and younger adults, indicating the existence of thresholds. We did not observe an increased risk of asthma HAs until average daily 8-hour maximum ozone concentrations exceeded approximately 40ppb.

Conclusion: Ozone and asthma HAs are significantly associated with each other; susceptibility to ozone is age-dependent, with children at highest risk. C-R relationships between average daily 8-hour maximum ozone concentrations and asthma HAs are significantly curvilinear for all ages combined, children, and younger adults. These nonlinear relationships, as well as the lack of relationship between average daily 8-hour maximum and peak ozone concentrations, have important implications for assessing risks to human health in regulatory settings.
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http://dx.doi.org/10.1016/j.envint.2017.04.006DOI Listing
July 2017

Pleural plaques and lung function in the Marysville worker cohort: a re-analysis.

Inhal Toxicol 2016 09;28(11):514-9

a Gradient , Cambridge , MA , USA.

Background: In the 2014 Integrated Risk Information System (IRIS) assessment for Libby amphibole asbestos (LAA), US EPA calculated a reference concentration (RfC) based on the prevalence of pleural plaques in a group of vermiculite workers in Marysville, Ohio. This RfC is based on the assumption that pleural plaques are associated with adverse lung function. In this study, we evaluated the association between pleural plaques and lung function in the Marysville worker cohort to determine whether they are associated with adverse effects or, rather, are more likely a biomarker of cumulative exposure to LAA.

Methods: We obtained the dataset on the Marysville worker cohort from University of Cincinnati, which included information on demographics, occupational exposures and results of chest high-resolution computed tomography (HRCT)/computed tomography (CT) scans and pulmonary function tests (PFTs). We used multivariate linear regression to estimate mean differences in several lung function parameters, and logistic regression to evaluate the odds of abnormal ventilatory patterns, among men with different pulmonary findings on HRCT/CT scans.

Results: No statistically significant differences in FEV1, FVC, FEV1/FVC, TLC, RV or DLCO were observed between workers with normal scans and those with pleural plaques but no other abnormalities. In contrast, workers with other abnormal findings had statistically significant lower FEV1, FVC, TLC and DLCO, compared with those with normal scans.

Conclusions: This study does not indicate that pleural plaques have a significant effect on lung function when past asbestos exposure is accounted for.
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http://dx.doi.org/10.1080/08958378.2016.1210704DOI Listing
September 2016

Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury.

Nature 2016 06 25;534(7605):119-23. Epub 2016 May 25.

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity. Reactivating primitive reparative ability in the mature mammalian heart requires knowledge of the mechanisms that promote early heart repair. By testing an established Hippo-deficient heart regeneration mouse model for factors that promote renewal, here we show that the expression of Pitx2 is induced in injured, Hippo-deficient ventricles. Pitx2-deficient neonatal mouse hearts failed to repair after apex resection, whereas adult mouse cardiomyocytes with Pitx2 gain-of-function efficiently regenerated after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo pathway effector Yap. Furthermore, Nrf2, a regulator of the antioxidant response, directly regulated the expression and subcellular localization of Pitx2. Pitx2 mutant myocardium had increased levels of reactive oxygen species, while antioxidant supplementation suppressed the Pitx2 loss-of-function phenotype. These findings reveal a genetic pathway activated by tissue damage that is essential for cardiac repair.
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http://dx.doi.org/10.1038/nature17959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999251PMC
June 2016

Comment on "Exposure-response modeling of non-cancer effects in humans exposed to Libby Amphibole Asbestos; update" by Benson et al. (2015).

Regul Toxicol Pharmacol 2016 10 25;80:268-9. Epub 2016 May 25.

Gradient, 20 University Road, Cambridge, MA 02138, USA. Electronic address:

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http://dx.doi.org/10.1016/j.yrtph.2016.05.014DOI Listing
October 2016

PEGylated niosomes-mediated drug delivery systems for Paeonol: preparation, pharmacokinetics studies and synergistic anti-tumor effects with 5-FU.

J Liposome Res 2017 Jun 30;27(2):161-170. Epub 2016 Jun 30.

a Anhui University of Chinese Medicine , Hefei , Anhui , PR China.

This work describes the preparation of a PEGylated niosomes-mediated drug delivery systems for Paeonol, thereby improving the bioavailability and chemical stability of Paeonol, prolonging its cellular uptake and enhancing its synergistic anti-cancer effects with 5-Fu. PEGylated niosomes, which are prepared from biocompatible nonionic surfactant of Spans 60 and cholesterol, and modified with PEG-SA. Pae-PEG-NISVs were evaluated in vitro and in vivo. The cytotoxicity of Pae-PEG-NISVs was investigated against HepG2 cells. Fluorescence microscope was used to detect the apoptotic morphological changes. Growth inhibition assays were carried out to investigate whether Pae-PEG-NISVs could enhance the antiproliferative effects of Pae co-treated with 5-FU on HepG2 cells. The optimized Pae-PEG-NISVs had mean diameters of approximately 166 nm and entrapment efficiency (EE) of 61.8%. Furthermore, the in vitro release study of Paeonol from PEGylated niosomes exhibited a relatively prolonged release profile for 12 h. Pharmacokinetic studies in rats after i.v. injection showed that Pae-PEG-NISVs had increased elimination half-lives (t, 87.5 versus 17.0 min) and increased area under the concentration-time curve (AUC, 38.0 versus 19.48 μg/ml*min) compared to Paeonol solution. Formulated Paeonol had superior cytotoxicity versus the free drug with IC values of 22.47 and 85.16 μg/mL at 24 h on HepG2 cells, respectively, and we found that low concentration of Pae-PEG-NISVs and 5-Fu in conjunction had obviously synergistic effect. Our results indicate that the PEG-NISVs system has the potential to serve as an efficient carrier for Paeonol by effectively solubilizing, stabilizing and delivering the drug to the cancer cells.
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http://dx.doi.org/10.1080/08982104.2016.1191021DOI Listing
June 2017

Long-range fine particulate matter from the 2002 Quebec forest fires and daily mortality in Greater Boston and New York City.

Air Qual Atmos Health 2016;9:213-221. Epub 2015 Feb 28.

Gradient, 20 University Road, Cambridge, MA 02138 USA.

During July 2002, forest fires in Quebec, Canada, blanketed the US East Coast with a plume of wood smoke. This "natural experiment" exposed large populations in northeastern US cities to significantly elevated concentrations of fine particulate matter (PM), providing a unique opportunity to test the association between daily mortality and ambient PM levels that are uncorrelated with societal activity rhythms. We obtained PM measurement data and mortality data for a 4-week period in July 2002 for the Greater Boston metropolitan area (which has a population of over 1.7 million people) and New York City (which has a population of over 8 million people). Daily average PM concentrations were markedly increased for 3 days over this period, reaching as high as 63 μg/m for Greater Boston and 86 μg/m for New York City from background ambient levels of 4-48 μg/m in the non-smoke days. We examined temporal patterns of natural-cause deaths and 24-h ambient PM concentrations in July 2002 and did not observe any discernible increase in daily mortality subsequent to the dramatic elevation in ambient PM levels. Comparison to mortality rates over the same time periods in 2001 and 2003 showed no evidence of impact. Results from Poisson regression analyses suggest that 24-h ambient PM concentrations were not associated with daily mortality. In conclusion, substantial short-term elevation in PM concentrations from forest fire smoke were not followed by increased daily mortality in Greater Boston or New York City.
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http://dx.doi.org/10.1007/s11869-015-0332-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837205PMC
February 2015

Evaluation of Acute Nonlymphocytic Leukemia and Its Subtypes With Updated Benzene Exposure and Mortality Estimates: A Lifetable Analysis of the Pliofilm Cohort.

J Occup Environ Med 2016 Apr;58(4):414-20

Gradient, Cambridge (Drs Rhomberg, Goodman, Tao, Zu); Affectiva, Waltham, Massachusetts (Chandalia); E Risk Sciences, LLP, Boulder, Colorado (Dr Williams); and Independent Consultant, Chapel Hill, North Carolina (Mr Allen).

Objective: US Environmental Protection Agency (EPA) based its benzene carcinogenicity assessment on the Pliofilm cohort. We evaluated associations between benzene exposure and acute nonlymphocytic leukemia (ANLL) and acute myelocytic leukemia (AML) risks using this cohort's updated exposure estimates and mortality data.

Methods: We calculated standardized mortality ratios (SMRs) for ANLL/AML using lifetable analyses, with various exposure quantile categories and lag times.

Results: Workers in the highest exposure categories had significantly elevated risks of ANLL and AML; no leukemia cases occurred in lower exposure categories. Exposure within 10 years of cancer onset appears most relevant for leukemia induction.

Conclusions: Our results confirmed the association between high-level benzene exposures and leukemia risks, and provided further evidence of a threshold effect and relevant exposure window. Our findings call for an updated risk assessment for benzene carcinogenicity using updated exposure estimates and mortality data.
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http://dx.doi.org/10.1097/JOM.0000000000000689DOI Listing
April 2016
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