bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycobacterium tuberculosis Requires Phosphate-Responsive Gene Regulation To Resist Host Immunity
Authors: Tischler Anna D. , Leistikow Rachel L. , Kirksey Meghan A. , Voskuil Martin I. , McKinney John D. 
Published: November 2012

ABSTRACT

Mycobacterium tuberculosis
persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the
M. tuberculosis
phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A Δ
pstA1
mutant was fully virulent in IFN-γ
−/−
mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that Δ
pstA1
bacteria are sensitized to an IFN-γ-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In
M. tuberculosis
, we found that Δ
pstA1
bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the
regX3
gene suppressed the replication and virulence defects of Δ
pstA1
bacteria in NOS2
−/−
mice, suggesting that
M. tuberculosis
requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate
in vivo
. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling
M. tuberculosis
gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.
Exploring the Parallel Development of Microbial Systems in Neonates with Cystic Fibrosis
Authors: Rogers Geraint B. , Bruce Kenneth D. 
Published: November 2012

ABSTRACT
Recent studies have greatly extended our understanding of the microbiota present in and on the human body. Here, advanced sequencing strategies have provided unprecedented analytical power. The important implications that the emerging data have for human health emphasize the need to intensify research in this area (D. A. Relman, Nature 486:194-195, 2012). It is already clear from these studies that the microbiotas characterized in different body locations of healthy individuals are both complex and diverse (The Human Microbiome Project Consortium, Nature 486:215-221). These studies also provide a point of contrast for investigations that aim to characterize the microbiota present in disease conditions. In this regard, Madan et al. (mBio 3(4):e00251-12, 2012) monitored the development over time of microbiota in the oropharynges and feces of neonates with cystic fibrosis and explored the potential for interactions between these complex microbial systems.
Human Disease Isolates of Serotype M4 and M22 Group A Streptococcus Lack Genes Required for Hyaluronic Acid Capsule Biosynthesis
Authors: Flores Anthony R. , Jewell Brittany E. , Fittipaldi Nahuel , Beres Stephen B. , Musser James M. 
Published: November 2012

ABSTRACT

Group A streptococcus (GAS) causes human pharyngitis and invasive infections and frequently colonizes individuals asymptomatically. Many lines of evidence generated over decades have shown that the hyaluronic acid capsule is a major virulence factor contributing to these infections. While conducting a whole-genome analysis of the
in vivo
molecular genetic changes that occur in GAS during longitudinal human pharyngeal interaction, we discovered that serotypes M4 and M22 GAS strains lack the
hasABC
genes necessary for hyaluronic acid capsule biosynthesis. Using targeted PCR, we found that all 491 temporally and geographically diverse disease isolates of these two serotypes studied lack the
hasABC
genes. Consistent with the lack of capsule synthesis genes, none of the strains produced detectable hyaluronic acid. Despite the lack of a hyaluronic acid capsule, all strains tested multiplied extensively
ex vivo
in human blood. Thus, counter to the prevailing concept in GAS pathogenesis research, strains of these two serotypes do not require hyaluronic acid to colonize the upper respiratory tract or cause abundant mucosal or invasive human infections. We speculate that serotype M4 and M22 GAS have alternative, compensatory mechanisms that promote virulence.

IMPORTANCE
A century of study of the antiphagocytic hyaluronic acid capsule made by group A streptococcus has led to the concept that it is a major virulence factor contributing to human pharyngeal and invasive infections. However, the discovery that some strains that cause abundant human infections lack hyaluronic acid biosynthetic genes and fail to produce this capsule provides a new stimulus for research designed to understand the group A streptococcus factors contributing to pharyngeal infection and invasive disease episodes.
Multivariate amortized resource analysis
Authors: Hoffmann Jan , Aehlig Klaus , Hofmann Martin 
Published: November 2012

We study the problem of automatically analyzing the worst-case resource usage of procedures with several arguments. Existing automatic analyses based on amortization or sized types bound the resource usage or result size of such a procedure by a sum of unary functions of the sizes of the arguments.

In this article we generalize this to arbitrary multivariate polynomial functions thus allowing bounds of the form
mn
which had to be grossly overestimated by
m
2
+
n
2
before. Our framework even encompasses bounds like ∑

i,j≤ n
m
i
m
j

where the

m
i

are the sizes of the entries of a list of length
n
.

This allows us for the first time to derive useful resource bounds for operations on matrices that are represented as lists of lists and to considerably improve bounds on other superlinear operations on lists such as longest common subsequence and removal of duplicates from lists of lists. Furthermore, resource bounds are now closed under composition which improves accuracy of the analysis of composed programs when some or all of the components exhibit superlinear resource or size behavior.
The analysis is based on a novel multivariate amortized resource analysis. We present it in form of a type system for a simple first-order functional language with lists and trees, prove soundness, and describe automatic type inference based on linear programming.
We have experimentally validated the automatic analysis on a wide range of examples from functional programming with lists and trees. The obtained bounds were compared with actual resource consumption. All bounds were asymptotically tight, and the constants were close or even identical to the optimal ones.
Evaluating Genetic Risk for Prostate Cancer among Japanese and Latinos
Authors: Cheng Iona , Chen Gary K. , Nakagawa Hidewaki , He Jing , Wan Peggy , Laurie Cathy C. , Shen Jess , Sheng Xin , Pooler Loreall C. , Crenshaw Andrew T. , Mirel Daniel B. , Takahashi Atsushi , Kubo Michiaki , Nakamura Yusuke , Al Olama Ali Amin , Benlloch Sara , Donovan Jenny L. , Guy Michelle , Hamdy Freddie C. , Kote-Jarai Zsofia , Neal David E. , Wilkens Lynne R. , Monroe Kristine R. , Stram Daniel O. , Muir Kenneth , Eeles Rosalind A. , Easton Douglas F. , Kolonel Laurence N. , Henderson Brian E. , Le Marchand Loïc , Haiman Christopher A. 
Published: November 2012

Abstract
Background: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.
Methods: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P &lt; 1.0 × 10−4) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894).
Results: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10−6) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10−5 and stage II: OR = 1.58; P = 3.05 × 10−7). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10−25 and OR = 1.07; P = 1.02 × 10−16 for Japanese and Latinos, respectively).
Conclusion and Impact: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos. Cancer Epidemiol Biomarkers Prev; 21(11); 2048–58. ©2012 AACR.
Biomarkers for Screening, Diagnosis, and Monitoring of Ovarian Cancer
Authors: Kobayashi Eiji , Ueda Yutaka , Matsuzaki Shinya , Yokoyama Takuhei , Kimura Toshihiro , Yoshino Kiyoshi , Fujita Masami , Kimura Tadashi , Enomoto Takayuki 
Published: November 2012

Abstract
Serum tumor markers have a major role in the screening, diagnosis, and monitoring of most of the gynecologic cancers. Ovarian cancer is one of the deadliest of the group because it is so frequently asymptomatic until it has advanced to an untreatable stage. Even serum cancer antigen-125 (CA-125), clinically one of the most reliable serum markers for ovarian cancer, is elevated in only half of early-stage still-treatable tumors. Because of the very low prevalence of ovarian cancer in the general population, at present, there is no cost-effective imaging or simple microscopic screening test for ovarian cancer as there is for breast and cervical cancers. However, recent proteomics and nucleic acid–based analyses have shown great promise for the discovery of new and more useful serum biomarkers, which cumulatively might provide such a screening tool. In this review, we will discuss both the currently used serum tumor markers for screening, diagnosis, monitoring of ovarian cancer, and the novel biomarkers that are now under investigation and validation. Cancer Epidemiol Biomarkers Prev; 21(11); 1902–12. ©2012 AACR.
The Association between NSAID Use and Colorectal Cancer Mortality: Results from the Women's Health Initiative
Authors: Coghill Anna E. , Phipps Amanda I. , Bavry Anthony A. , Wactawski-Wende Jean , Lane Dorothy S. , LaCroix Andrea , Newcomb Polly A. 
Published: November 2012

Abstract
Background: Randomized trial evidence shows that nonsteroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC).
Methods: We examined the association between NSAID use and CRC mortality among 160,143 postmenopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Reported CRC cases were locally confirmed and centrally adjudicated; cause of death was determined according to centralized medical record and death certificate review. Cox regression was used to investigate the association between NSAID use and CRC mortality.
Results: Overall, NSAID use at baseline was not associated with CRC mortality [HR: 0.93; 95% confidence interval (CI) 0.76, 1.14]. However, women who reported NSAID use at both baseline and year 3 experienced reductions in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared with nonusers.
Conclusion: Results suggest that NSAID use is associated with lower CRC mortality among postmenopausal women who use these medications more consistently over time.
Impact: Our results support prolonged NSAID use in postmenopausal women for the prevention of poor CRC outcomes. Cancer Epidemiol Biomarkers Prev; 21(11); 1966–73. ©2012 AACR.
A Pooled Analysis of Smoking and Colorectal Cancer: Timing of Exposure and Interactions with Environmental Factors
Authors: Gong Jian , Hutter Carolyn , Baron John A. , Berndt Sonja , Caan Bette , Campbell Peter T. , Casey Graham , Chan Andrew T. , Cotterchio Michelle , Fuchs Charles S. , Gallinger Steven , Giovannucci Edward , Harrison Tabitha , Hayes Richard , Hsu Li , Jiao Shuo , Lin Yi , Lindor Noralane M. , Newcomb Polly , Pflugeisen Bethann , Phipps Amanda I. , Rohan Thomas , Schoen Robert , Seminara Daniela , Slattery Martha L. , Stelling Deanna , Thomas Fridtjof , Warnick Greg , White Emily , Potter John , Peters Ulrike 
Published: November 2012

Abstract
Background: Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer (CRC). What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for CRC modify this association.
Methods: We conducted a pooled analysis of eight studies, including 6,796 CRC cases and 7,770 controls, to evaluate the association between cigarette smoking history and CRC risk and to investigate potential effect modification by other risk factors.
Results: Current smokers [OR, 1.26; 95% confidence interval (CI), 1.11–1.43] and former smokers (OR, 1.18; 95% CI, 1.09–1.27), relative to never smokers, showed higher risks of CRC. Former smokers remained at higher CRC risk, relative to never smokers, for up to about 25 years after quitting. The impact of time since quitting varied by cancer subsite: The excess risk due to smoking decreased immediately after quitting for proximal colon and rectal cancer but not until about 20 years post-quitting for distal colon cancer. Furthermore, we observed borderline statistically significant additive interactions between smoking status and body mass index [BMI; relative excess risk due to interaction (RERI]), 0.15; 95% CI, −0.01 to 0.31; P = 0.06] and significant additive interaction between smoking status and fruit consumption (RERI, 0.16; 95% CI, 0.01–0.30; P = 0.04).
Conclusion: CRC risk remained increased for about 25 years after quitting smoking, and the pattern of decline in risk varied by cancer subsite. BMI and fruit intake modified the risk associated with smoking.
Impact: These results contribute to a better understanding of the mechanisms through which smoking impacts CRC etiology. Cancer Epidemiol Biomarkers Prev; 21(11); 1974–85. ©2012 AACR.
Bile Acid Promotes Intestinal Metaplasia and Gastric Carcinogenesis
Authors: Tatsugami Masana , Ito Masanori , Tanaka Shinji , Yoshihara Masaharu , Matsui Hirofumi , Haruma Ken , Chayama Kazuaki 
Published: November 2012

Abstract
Background: Bile acid and Helicobacter pylori (H. pylori) are important toxic factors for gastric mucosal injury. We examined the role of bile acid in promoting histologic gastritis and gastric carcinoma in Japanese patients.
Methods: A total of 767 patients (452 men, mean age 51.1 years) were studied. Gastric juice was collected by gastro-endoscopic examination, and the bile acid concentration was examined by enzymatic method. The grade of histologic gastritis was evaluated by gastric biopsies, and the relationship between the bile acid concentration and the gastritis score was examined. The occurrence of gastric cancer was examined by a retrospective cohort study. CDX2/CINC1 expression in RGM-1 cells was evaluated by real-time PCR.
Results: In H. pylori–positive patients, we found significant positive correlation between the bile acid concentration and the grades of atrophy/intestinal metaplasia (P &lt; 0.01). However, we found significant negative associations between the bile acid concentrations and the histologic scores of mononuclear cell/neutrophil infiltrations (P &lt; 0.01). Patients with a high concentration of bile acid developed gastric cancer more frequently than those with a low concentration (P &lt; 0.05). Cholic acid treatment significantly increased CDX2 expression in RGM-1 cells. CINC1 expression in RGM-1 cell was significantly induced by coculture with H. pylori, and the induction was reduced by glycochenodeoxycholic acid treatment.
Conclusion: The bile acid in gastric juice contributes to the progression of histologic atrophy and intestinal metaplasia without inflammatory cell infiltration, followed by carcinogenesis in H. pylori–positive patients.
Impact: Bile acid promotes intestinal metaplasia and gastric carcinogenesis without inflammatory cell infiltration. Cancer Epidemiol Biomarkers Prev; 21(11); 2101–7. ©2012 AACR.
Stichoposide C Induces Apoptosis through the Generation of Ceramide in Leukemia and Colorectal Cancer Cells and Shows In Vivo Antitumor Activity
Authors: Yun Seong-Hoon , Park Eun-Seon , Shin Sung-Won , Na Yong-Woo , Han Jin-Yeong , Jeong Jin-Sook , Shastina Valeria V. , Stonik Valentin A. , Park Joo-In , Kwak Jong-Young 
Published: November 2012

Abstract
Purpose: Marine triterpene glycosides that are physiologically active natural compounds isolated from sea cucumbers (holothurians) and sponges have antifungal, cytotoxic, and antitumor activities, whose specific molecular mechanisms remain to be elucidated. In this study, we examined if and through which mechanisms stichoposide C (STC) from Thelenota anax (family Stichopodidae) induces apoptosis in leukemia and colorectal cancer cells.
Experimental Design: We examined STC-induced apoptosis in human leukemia and colorectal cancer cells in the context of mitochondrial injury and signaling pathway disturbances, and investigated the antitumor effect of STC in mouse CT-26 subcutaneous tumor and HL-60 leukemia xenograft models.
Results: We found that STC induces apoptosis in these cells in a dose-dependent manner and leads to the activation of Fas and caspase-8, cleavage of Bid, mitochondrial damage, and activation of caspase-3. STC activates acid sphingomyelinase (SMase) and neutral SMase, which resulted in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase and siRNA knockdown experiments partially blocked STC-induced apoptosis. Moreover, STC markedly reduced tumor growth of HL-60 xenograft and CT-26 subcutaneous tumors and increased ceramide generation in vivo.
Conclusions: Ceramide generation by STC, through activation of acid and neutral SMase, may in part contribute to STC-induced apoptosis and antitumor activity. Thus, STC may have therapeutic relevance for human leukemia and colorectal cancer. Clin Cancer Res; 18(21); 5934–48. ©2012 AACR.
Reversing Effect of Ring Finger Protein 43 Inhibition on Malignant Phenotypes of human Hepatocellular Carcinoma
Authors: Xing Chunyang , Zhou Wuhua , Ding Songming , Xie Haiyang , Zhang Wu , Yang Zhe , Wei Bajin , Chen Kangjie , Su Rong , Cheng Jun , Zheng Shusen , Zhou Lin 
Published: November 2012

Abstract
It has been shown that Ring finger protein 43 (RNF43) is overexpressed in colorectal cancer and mediates cancer cell proliferation; however, its role in hepatocellular carcinoma (HCC) remains unknown. In this study, we found that RNF43 was frequently overexpressed in HCCs, and this overexpression was correlated with positive vascular invasion, poor tumor differentiation, and advanced tumor stage. Functional studies showed that knockdown of RNF43 could induce apoptosis and inhibit proliferation, invasion, colony formation, and xenograft growth of HCCs. Microarray-based gene profiling showed a total of 229 genes differentially expressed after RNF43 knockdown, many of which are involved in oncogenic processes such as cell proliferation, cell adhesion, cell motility, cell death, DNA repair, and so on. These results suggest that RNF43 is involved in tumorigenesis and progression of HCCs and that antagonism of RNF43 may be beneficial for HCC treatment. Mol Cancer Ther; 12(1); 94–103. ©2012 AACR.
Multiple Functions of Sushi Domain Containing 2 (SUSD2) in Breast Tumorigenesis
Authors: Watson Allison P. , Evans Rick L. , Egland Kristi A. 
Published: November 2012

Abstract
Routinely used therapies are not adequate to treat the heterogeneity of breast cancer, and consequently, more therapeutic targets are desperately needed. To identify novel targets, we generated a breast cancer cDNA library enriched for genes that encode membrane and secreted proteins. From this library we identified SUSD2 (Sushi Domain Containing 2), which encodes an 822-amino acid protein containing a transmembrane domain and functional domains inherent to adhesion molecules. Previous studies describe the mouse homolog, Susd2, but there are no studies on the human gene associated with breast cancer. Immunohistochemical analysis of human breast tissues showed weak or no expression of SUSD2 in normal epithelial cells, with the endothelial lining of vessels staining positive for SUSD2. However, staining was observed in pathologic breast lesions and in lobular and ductal carcinomas. SUSD2 interacts with galectin-1 (Gal-1), a 14-kDa secreted protein that is synthesized by carcinoma cells and promotes tumor immune evasion, angiogenesis, and metastasis. Interestingly, we found that localization of Gal-1 on the surface of cells is dependent on the presence of SUSD2. Various phenotype assays indicate that SUSD2 increases the invasion of breast cancer cells and contributes to a potential immune evasion mechanism through induction of apoptosis of Jurkat T cells. Using a syngeneic mouse model, we observed accelerated tumor formation and decreased survival in mice with tumors expressing Susd2. We found significantly fewer CD4 tumor infiltrating lymphocytes in mice with tumors expressing Susd2. Together, our findings provide evidence that SUSD2 may represent a promising therapeutic target for breast cancer. Mol Cancer Res; 11(1); 74–85. ©2012 AACR.