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  • 1
    Publication Date: 2018-10-02
    Description: Purpose: Triple-negative breast cancer (TNBC) is a clinically aggressive disease with poor prognosis. Conventional chemotherapeutics are generally able to shrink the tumor mass, but often fail to completely eradicate cancer stem–like cells (CSCs) that are responsible for high risk of relapse and frequent metastases. In this study, we examined thermal sensibility of CSCs, developed an approach that enabled concurrent elimination of both the bulk of cancer cells and CSCs, and investigated the underlying mechanism. Experimental Design: We designed a platform consisting of gold nanoparticle-coated porous silicon microparticle (AuPSM) that was also loaded with docetaxel micelles (mDTXs) to enable concurrent killing of the bulk of cancer cells by released mDTX and CSCs by mild hyperthermia upon stimulation of AuPSM with near infrared. In addition, we examined the role of heat shock proteins in sensitizing CSC killing. Finally, we applied mDTX-loaded AuPSM to treat mice with SUM159 and 4T1 orthotopic tumors and evaluated tumor growth and tumor metastasis. Results: MDA-MB-231 and SUM159 TNBC cells treated with mDTX-loaded AuPSM and mild hyperthermia displayed significantly reduced efficiencies in mammosphere formation than those treated with mDTX alone or mild hyperthermia alone. Combination treatment also completely inhibited SUM159 orthotopic tumor growth and 4T1 tumor metastasis. Mechanistically, DTX treatment suppressed expression of heat shock protein 27 in cancer cells including the CSCs, rendering cells sensitive to mild hyperthermia. Conclusions: Our results indicate that chemotherapy sensitizes CSC to mild hyperthermia. We have developed an effective therapeutic approach to eliminate therapy-resistant cells in TNBC. Clin Cancer Res; 24(19); 4900–12. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Keywords: SUSCEPTIBILITY LOCUS ; WOMEN ; CHINESE
    Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 x 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 x 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 x 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 x 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 x 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 x 10(-7), p(heterogeneity) = 5.1 x 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
    Type of Publication: Journal article published
    PubMed ID: 22879957
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  • 3
    Abstract: Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001〉 P 〉 5x10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6x10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1x10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4x10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05x10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16x10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
    Type of Publication: Journal article published
    PubMed ID: 26363033
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  • 4
    Keywords: CANCER ; POLYMORPHISMS ; BRCA1 ; GLUCOSE ; MUTATION CARRIERS ; METAANALYSIS ; ALLELES ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; 6Q25.1
    Abstract: A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER) positive tumors. Using data from the Breast Cancer Association Consortium(BCAC) we sought to determine if risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)=0.98) at 14q24.1 (RAD51L1), for up to 46,036 invasive breast cancer cases and 46,930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25,458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per allele- odds ratio (OR) for ER-positive tumors was 1.13, 95%CI=1.10 to 1.16, and for ER-negative tumors OR was 1.03, 95%CI=0.98 to 1.07, case only P-heterogeneity = 7.6x10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P=6.7 x10(-3)) and lobular histology (case-only P =0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 21852249
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 387 (1980), S. 147-164 
    ISSN: 1432-2307
    Keywords: Lead encephalopathy ; Mitochondria ; Respiration ; Elemental microanalysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The toxic effects of inorganic lead feedings on the immature brain were studied in the rat pup. Beginning when litters were two weeks old, PbCO3 was fed to nursing mothers and then to pups directly after weaning. Results in lead-fed pups were compared to age-matched controls and to lead-fed young adult males (60 days old). Anaemia and growth failure developed in both pups and adults. In the second week, more than half the pups developed an encephalopathy, with haemorrhage and oedema predominately in the cerebellum and lead-containing densities in the cerebellar molecular layer. The latter were confirmed by X-ray microanalysis. No lead-fed adults showed signs of an encephalopathy. Cerebellar mitochondria from lead-fed pups, studied polarographically, showed a very early loss of respiratory control and a subsequent inhibition of phosphorylation-coupled respiration with NAD-linked substrates but not with succinate. Compared to the pup cerebellum, these changes were much less marked in immature cerebral mitochondria and were not found in adult cerebral or cerebellar mitochondria. Cerebral and cerebellar homogenates from immature and mature lead-fed animals showed large increases in lead content measured by atomic absorption spectrophotometry. Immature cerebellar mitochondrial lead contents were increased to the same extent as in the homogenates. Mitochondria from immature cerebrum and from both regions in the mature brain showed less immediate and smaller increases in lead content. In conclusion, altered mitochondrial respiration occurs early in regional and age-dependent association with lead encephalopathy in the rat pup. The development of lead encephalopathy also is associated with increased mitochondrial lead concentrations.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-6903
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of lead acetate on respiration in cerebral and cerebellar mitochondria from immature and adult rats were studied polarographically. With all substrates low lead concentrations produced an increase in respiration. Higher concentrations produced an inhibition of both this lead-induced respiration and ADP-dependent (State 3) respiration. Lead-induced respiration required inorganic phosphate and was inhibited by oligomycin, suggesting a coupling to oxidative phosphorylation. Inhibition of respiration was produced by much lower lead concentrations with NAD-linked citric acid cycle substrates than with succinate or α-glycerophosphate. In partially disrupted mitochondria, NAD-linked substrate oxidation was inhibited at lead concentrations which did not affect NADH oxidation. Thus, in brain mitochondria the NAD-linked dehydrogenases, located in the matrix space, were more sensitive to inhibition by lead than were inner membrane enzymes. All in vitro lead effects on mitochondrial respiration were comparable in cerebral and cerebellar mitochondria isolated from both immature and adult rats.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2011-08-06
    Description: The modern Indian summer monsoon (ISM) is characterized by exceptionally strong interhemispheric transport, indicating the importance of both Northern and Southern Hemisphere processes driving monsoon variability. Here, we present a high-resolution continental record from southwestern China that demonstrates the importance of interhemispheric forcing in driving ISM variability at the glacial-interglacial time scale as well. Interglacial ISM maxima are dominated by an enhanced Indian low associated with global ice volume minima. In contrast, the glacial ISM reaches a minimum, and actually begins to increase, before global ice volume reaches a maximum. We attribute this early strengthening to an increased cross-equatorial pressure gradient derived from Southern Hemisphere high-latitude cooling. This mechanism explains much of the nonorbital scale variance in the Pleistocene ISM record.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉An, Zhisheng -- Clemens, Steven C -- Shen, Ji -- Qiang, Xiaoke -- Jin, Zhangdong -- Sun, Youbin -- Prell, Warren L -- Luo, Jingjia -- Wang, Sumin -- Xu, Hai -- Cai, Yanjun -- Zhou, Weijian -- Liu, Xiaodong -- Liu, Weiguo -- Shi, Zhengguo -- Yan, Libin -- Xiao, Xiayun -- Chang, Hong -- Wu, Feng -- Ai, Li -- Lu, Fengyan -- New York, N.Y. -- Science. 2011 Aug 5;333(6043):719-23. doi: 10.1126/science.1203752.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Loess and Quaternary Geology, Institute of Earth Environment, Chinese Academy of Sciences, Xi'an 710075, China. anzs@loess.llqg.ac.cn〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21817044" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-05-19
    Description: Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319976/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319976/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nelson, Matthew R -- Wegmann, Daniel -- Ehm, Margaret G -- Kessner, Darren -- St Jean, Pamela -- Verzilli, Claudio -- Shen, Judong -- Tang, Zhengzheng -- Bacanu, Silviu-Alin -- Fraser, Dana -- Warren, Liling -- Aponte, Jennifer -- Zawistowski, Matthew -- Liu, Xiao -- Zhang, Hao -- Zhang, Yong -- Li, Jun -- Li, Yun -- Li, Li -- Woollard, Peter -- Topp, Simon -- Hall, Matthew D -- Nangle, Keith -- Wang, Jun -- Abecasis, Goncalo -- Cardon, Lon R -- Zollner, Sebastian -- Whittaker, John C -- Chissoe, Stephanie L -- Novembre, John -- Mooser, Vincent -- T32 HG002536/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Jul 6;337(6090):100-4. doi: 10.1126/science.1217876. Epub 2012 May 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA. matthew.r.nelson@gsk.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22604722" target="_blank"〉PubMed〈/a〉
    Keywords: African Americans/genetics ; Asian Continental Ancestry Group ; Disease/*genetics ; European Continental Ancestry Group/genetics ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; *Genetic Variation ; *Genome, Human ; Geography ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Targeted Therapy ; Multifactorial Inheritance ; Mutation Rate ; Pharmacogenetics ; Phenotype ; Polymorphism, Single Nucleotide ; Population Growth ; Sample Size ; Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-03-16
    Description: The quantized version of the anomalous Hall effect has been predicted to occur in magnetic topological insulators, but the experimental realization has been challenging. Here, we report the observation of the quantum anomalous Hall (QAH) effect in thin films of chromium-doped (Bi,Sb)2Te3, a magnetic topological insulator. At zero magnetic field, the gate-tuned anomalous Hall resistance reaches the predicted quantized value of h/e(2), accompanied by a considerable drop in the longitudinal resistance. Under a strong magnetic field, the longitudinal resistance vanishes, whereas the Hall resistance remains at the quantized value. The realization of the QAH effect may lead to the development of low-power-consumption electronics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Cui-Zu -- Zhang, Jinsong -- Feng, Xiao -- Shen, Jie -- Zhang, Zuocheng -- Guo, Minghua -- Li, Kang -- Ou, Yunbo -- Wei, Pang -- Wang, Li-Li -- Ji, Zhong-Qing -- Feng, Yang -- Ji, Shuaihua -- Chen, Xi -- Jia, Jinfeng -- Dai, Xi -- Fang, Zhong -- Zhang, Shou-Cheng -- He, Ke -- Wang, Yayu -- Lu, Li -- Ma, Xu-Cun -- Xue, Qi-Kun -- New York, N.Y. -- Science. 2013 Apr 12;340(6129):167-70. doi: 10.1126/science.1234414. Epub 2013 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Low-Dimensional Quantum Physics, Department of Physics, Tsinghua University, Beijing, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23493424" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-02-22
    Description: China is experiencing intense air pollution caused in large part by anthropogenic emissions of reactive nitrogen. These emissions result in the deposition of atmospheric nitrogen (N) in terrestrial and aquatic ecosystems, with implications for human and ecosystem health, greenhouse gas balances and biological diversity. However, information on the magnitude and environmental impact of N deposition in China is limited. Here we use nationwide data sets on bulk N deposition, plant foliar N and crop N uptake (from long-term unfertilized soils) to evaluate N deposition dynamics and their effect on ecosystems across China between 1980 and 2010. We find that the average annual bulk deposition of N increased by approximately 8 kilograms of nitrogen per hectare (P 〈 0.001) between the 1980s (13.2 kilograms of nitrogen per hectare) and the 2000s (21.1 kilograms of nitrogen per hectare). Nitrogen deposition rates in the industrialized and agriculturally intensified regions of China are as high as the peak levels of deposition in northwestern Europe in the 1980s, before the introduction of mitigation measures. Nitrogen from ammonium (NH4(+)) is the dominant form of N in bulk deposition, but the rate of increase is largest for deposition of N from nitrate (NO3(-)), in agreement with decreased ratios of NH3 to NOx emissions since 1980. We also find that the impact of N deposition on Chinese ecosystems includes significantly increased plant foliar N concentrations in natural and semi-natural (that is, non-agricultural) ecosystems and increased crop N uptake from long-term-unfertilized croplands. China and other economies are facing a continuing challenge to reduce emissions of reactive nitrogen, N deposition and their negative effects on human health and the environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xuejun -- Zhang, Ying -- Han, Wenxuan -- Tang, Aohan -- Shen, Jianlin -- Cui, Zhenling -- Vitousek, Peter -- Erisman, Jan Willem -- Goulding, Keith -- Christie, Peter -- Fangmeier, Andreas -- Zhang, Fusuo -- England -- Nature. 2013 Feb 28;494(7438):459-62. doi: 10.1038/nature11917. Epub 2013 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉College of Resources & Environmental Sciences, China Agricultural University, Beijing 100193, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23426264" target="_blank"〉PubMed〈/a〉
    Keywords: Air Pollutants/*analysis/metabolism/supply & distribution ; Air Pollution/*analysis/statistics & numerical data ; Animals ; China ; *Ecosystem ; Environmental Monitoring/*statistics & numerical data ; Greenhouse Effect ; Human Activities ; Humans ; Nitrates/analysis/metabolism ; Nitrogen/*analysis/metabolism ; Plants/chemistry/metabolism ; Quaternary Ammonium Compounds/analysis/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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