bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sitamaquine Overcomes ABC-Mediated Resistance to Miltefosine and Antimony inLeishmania
Authors: Pérez-Victoria José M. , Bavchvarov Boris I. , Torrecillas Iván R. , Martínez-García Marta , López-Martín Carmen , Campillo Mercedes , Castanys Santiago , Gamarro Francisco 
Published: June 2011

ABSTRACTAlthough oral miltefosine represented an important therapeutic advance in the treatment of leishmaniasis, the appearance of resistance remains a serious threat. LMDR1/LABCB4, a P-glycoprotein-like transporter included in theLeishmaniaABC (ATP-binding cassette) family, was the first molecule shown to be involved in experimental miltefosine resistance. LMDR1 pumps drugs out of the parasite, thereby decreasing their intracellular accumulation. Sitamaquine, another promising oral drug for leishmaniasis, is currently in phase 2b clinical trials. The physicochemical features of this drug suggested to us that it could be considered for use as an LMDR1 inhibitor. Indeed, we report herein that nonleishmanicidal concentrations of sitamaquine reverse miltefosine resistance in a multidrug resistanceLeishmania tropicaline that overexpresses LMDR1. This reversal effect is due to modulation of the LMDR1-mediated efflux of miltefosine. In addition, sitamaquine is not a substrate of LMDR1, as this transporter does not affect sitamaquine accumulation or sensitivity in the parasite. Likewise, we show that ketoconazole, another oral leishmanicidal drug known to interact with ABC transporters, is also able to reverse LMDR1-mediated miltefosine resistance, although with a lower efficiency than sitamaquine. Molecular docking on a three-dimensional homology model of LMDR1 showed different preferential binding sites for each substrate-inhibitor pair, thus explaining this different behavior. Finally, we show that sitamaquine is also able to modulate the antimony resistance mediated by MRPA/LABCC3, another ABC transporter involved in experimental and clinical antimony resistance in this parasite. Taken together, these data suggest that the combination of sitamaquine with miltefosine or antimony could avoid the appearance of resistance mediated by these membrane transporters inLeishmania.
Susceptibility of Vertilmicin to Modifications by Three Types of Recombinant Aminoglycoside-Modifying Enzymes
Authors: Yuan Min , Han Hui , Li Cong-Ran , Yang Xin-Yi , Li Guo-Qing , Cen Shan , Kang Xi-Xiong , Si Shu-Yi , Jiang Jian-Dong , You Xue-Fu 
Published: June 2011

ABSTRACT
The susceptibilities of vertilmicin and seven reference aminoglycosides to modifications by six recombinant aminoglycoside-modifying enzymes, AAC(6′)-Ie, APH(2′′)-Ia, AAC(6′)-Ie-APH(2′′)-Ia, ANT(2′′)-Ia, AAC(6′)-Ib, and AAC(6′)-Ib-cr, were studied by coupled spectrophotometric assays in microtiter plates. In comparison to other aminoglycosides, the susceptibility of vertilmicin was 45.8- to 250.0-fold lower for AAC(6′)-Ie acetylation, 39.2- to 116.7-fold lower for AAC(6′)-Ie-APH(2′′)-Ia acetylation, and 1.8- to 7.5-fold lower for ANT(2′′)-Ia adenylation (except that shown by amikacin) while relatively comparable for AAC(6′)-Ib acetylation, AAC(6′)-Ib-cr acetylation, APH(2′′)-Ia phosphorylation, and AAC(6′)-Ie-APH(2′′)-Ia phosphorylation.
Is ischaemia-modified albumin a test for venous thromboembolism?
Authors: Hogg Kerstin , Hinchliffe Edward , Halsam Shonagh , Valkov Alex , Lecky Fiona 
Published: June 2011

ObjectivePatients with symptoms of deep vein thrombosis (DVT) and pulmonary embolism (PE) commonly present to the emergency department (ED). The aim of this study was to assess the role of ischaemia-modified albumin (IMA) testing in the diagnosis of venous thromboembolism (VTE).MethodsThis was a prospective diagnostic cohort study. Inpatients and ED patients >16 years of age investigated for PE or DVT at a single hospital were eligible for study consent. Blinded IMA analysis was performed on the first blood sample taken from each patient. Patients underwent reference standard investigation for PE or DVT, including 3-month follow-up. Receiver operating characteristic (ROC) curves were constructed for IMA and the IMA:albumin ratio in the diagnosis of all VTE, PE and DVT. A sensitivity analysis was performed.Results452 patients were consented and investigated for DVT, and 354 patients were consented and investigated for PE (806 in total). 348 patients investigated for PE had IMA testing as did 195 of the first 199 DVT patients. VTE prevalence was 19.7%. The IMA:albumin ratio performed better than IMA alone. The area under the ROC curve (AUC) for IMA:albumin in all VTE was 0.60 (95% CI 0.54 to 0.66), in DVT 0.56 (95% CI 0.46 to 0.65) and in PE 0.63 (95% CI 0.56 to 0.71). In ED patients with symptoms of PE, the AUC for IMA:albumin was 0.69 (95% CI 0.60 to 0.78).ConclusionsIMA testing cannot be used alone to diagnose DVT or PE, although there is a moderate association with PE in ED patients.
Effect of ON 01910.Na, an Anticancer Mitotic Inhibitor, on Cell-Cycle Progression Correlates with RanGAP1 Hyperphosphorylation
Authors: Oussenko Irina A. , Holland James F. , Reddy E. Premkumar , Ohnuma Takao 
Published: June 2011

Abstract
The benzyl styryl sulfone, ON 01910.Na, is a novel anticancer agent that inhibits mitotic progression and induces apoptosis in most cancer cell lines. We examined the effect of ON 01910.Na on DNA damage–signaling molecules upstream of Cdc25C (Chk1, Chk2, and H2AX), as well as on Ran GTPase-activating protein 1 conjugated to small ubiquitin-related modifier 1 (RanGAP1·SUMO1), a mitosis coordinator. Prostate cancer, lymphoma, and leukemic cells were incubated with the drug for 4, 16, or 24 hours. Cell lysates were resolved on SDS-PAGE and analyzed by Western blot. Camptothecin and doxorubicin treatment caused activation/phosphorylation of DNA damage-responsive molecules by 4 hours, whereas ON 01910.Na did not do so. ON 01910.Na caused hyperphosphorylation of RanGAP1·SUMO1 within 4 hours that was sustained for more than 24 hours. Mild phosphorylation of Chk2 was observed only after 24-hour exposure, indicating that DNA damage response was not an initial effect of ON 01910.Na. MOLT-3 cells, synchronized by double-thymidine block, when released into a medium containing ON 01910.Na, accumulated mitotic cell number with a peak from 10 to 14 hours and remained near plateau for 20 hours, which corresponded with the time of RanGAP phosphorylation. ON 01910.Na had minimal effects on tubulin polymerization. These findings imply that ON 01910.Na neither induces DNA damage directly nor acts as a tubulin toxin. Its biological activity appears to rely on prolonged phosphorylation/hyperphosphorylation of RanGAP1·SUMO1. M-phase arrest and the consequent induction of apoptosis that follows could possibly be attributed to it. ON 01910.Na may act as an inhibitor of a RanGAP1·SUMO1 phosphatase or a stimulant of a new kinase. RanGAP1·SUMO1 appears to be a new target pathway for cancer chemotherapy. Cancer Res; 71(14); 4968–76. ©2011 AACR.
Notch Signaling in CD66+ Cells Drives the Progression of Human Cervical Cancers
Authors: Bajaj Jeevisha , Maliekal Tessy Thomas , Vivien Eric , Pattabiraman Chitra , Srivastava Sweta , Krishnamurthy H. , Giri V. , Subramanyam Deepa , Krishna Sudhir 
Published: June 2011

Abstract
Human epithelial tumor progression and metastasis involve cellular invasion, dissemination in the vasculature, and regrowth at metastatic sites. Notch signaling has been implicated in metastatic progression but its roles have yet to be fully understood. Here we report the important role of Notch signaling in maintaining cells expressing the carcinoembryonic antigen cell adhesion molecule CEACAM (CD66), a known mediator of metastasis. CD66 and Notch1 were studied in clinical specimens and explants of human cervical cancer, including specimens grown in a pathophysiologically relevant murine model. Gene expression profiling of CD66+ cells from primary tumors showed enhanced features of Notch signaling, metastasis, and stemness. Significant differences were also seen in invasion, colony formation, and tumor forming efficiency between CD66+ and CD66− cancer cells. Notably, CD66+ cells showed a marked sensitivity to a Notch small molecule inhibitor. In support of studies in established cell lines, we documented the emergence of a tumorigenic CD66+ cell subset within a metastatic lesion-derived cervical-cancer cell line. Similar to primary cancers, CD66 expression in the cell line was blocked by chemical and genetic inhibitors of ligand-dependent nuclear Notch signaling. Collectively, our work on the oncogenic properties of CD66+ cells in epithelial cancers provides insights into the nature of tumor progression and offers a mechanistic rationale to inhibit the Notch signaling pathway as a generalized therapeutic strategy to treat metastatic cancers. Cancer Res; 71(14); 4888–97. ©2011 AACR.
Metabolites of a Tobacco-Specific Lung Carcinogen in Children Exposed to Secondhand or Thirdhand Tobacco Smoke in Their Homes
Authors: Thomas Janet L. , Guo Hongfei , Carmella Steven G. , Balbo Silvia , Han Shaomei , Davis Andrew , Yoder Andrea , Murphy Sharon E. , An Larry C. , Ahluwalia Jasjit S. , Hecht Stephen S. 
Published: June 2011

Abstract
Background: People exposed to secondhand tobacco smoke (SHS) inhale the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) which is metabolized to NNAL and its glucuroniders. These urinary metabolites, termed total NNAL, can be quantified. A related compound, iso-NNAL, has been proposed as a biomarker for exposure to smoke constituent residues on surfaces (thirdhand tobacco smoke). There is limited information in the literature on levels of total NNAL in children exposed to SHS.
Methods: We recruited 79 parent–child dyads from homes where the enrolled parent was a cigarette smoker and visited their homes. Parents were asked questions, home ambient air quality was evaluated, and children provided urine samples. Urine was analyzed for total NNAL, total cotinine, total nicotine, and iso-NNAL.
Results: Ninety percent of the children had detectable total NNAL in urine; total nicotine and total cotinine were also detected in most samples. There were significant positive relationships between biomarker levels and exposure of children in the home. Levels were highest in homes with no smoking restrictions. African American children had significantly higher levels than other children. iso-NNAL was not detected in any urine sample.
Conclusions: There was nearly universal exposure of children to the lung carcinogen NNK, due mainly to exposure to SHS from adult smokers in their homes.
Impact: Homes with adult smokers should adopt restrictions to protect their children from exposure to a potent lung carcinogen. Cancer Epidemiol Biomarkers Prev; 20(6); 1213–21. ©2011 AACR.
Crohn's Disease and Small Bowel Adenocarcinoma: A Population-Based Case–Control Study
Authors: Shaukat Aasma , Virnig Daniel J. , Howard David , Sitaraman Shanthi V. , Liff Jonathan M. , Lederle Frank A. 
Published: June 2011

Abstract
Background: Although Crohn's disease (CD) is thought to predispose to adenocarcinomas of the small bowel, the association has not been well studied in an older population.
Aims: The objective of our study was to evaluate the association of CD with small bowel cancer in a population-based case–control study.
Methods: All cases of small bowel cancer in persons 67 and older in the Surveillance, Epidemiology and End Results catchment area and in the Medicare claims data base were compared with cancer-free controls residing in the same geographic area. We used multivariable logistic regression models adjusted for demographic and other factors.
Results: We identified 923 cases of small bowel cancer and 142,273 controls. Although we found a strong association between CD and small bowel cancer (OR = 12.07; 95% CI: 6.07–20.80; P &lt; 0.001), the prevalence of CD in patients with small bowel cancer was low (1.6%).
Conclusions: Although CD is a significant risk factor for small bowel cancers among individuals older than 67, the absolute risk is small.
Impact: Older individuals with CD can be reassured that although there is an association between CD and small bowel cancer, the absolute risk remains small. Cancer Epidemiol Biomarkers Prev; 20(6); 1120–3. ©2011 AACR.
Lymphoid Malignancies in U.S. Asians: Incidence Rate Differences by Birthplace and Acculturation
Authors: Clarke Christina A. , Glaser Sally L. , Gomez Scarlett L. , Wang Sophia S. , Keegan Theresa H. , Yang Juan , Chang Ellen T. 
Published: June 2011

AbstractBackground: Malignancies of the lymphoid cells, including non-Hodgkin lymphomas (NHL), HL, and multiple myeloma, occur at much lower rates in Asians than other racial/ethnic groups in the United States. It remains unclear whether these deficits are explained by genetic or environmental factors. To better understand environmental contributions, we examined incidence patterns of lymphoid malignancies among populations characterized by ethnicity, birthplace, and residential neighborhood socioeconomic status (SES) and ethnic enclave status.Methods: We obtained data about all Asian patients diagnosed with lymphoid malignancies between 1988 and 2004 from the California Cancer Registry and neighborhood characteristics from U.S. Census data.Results: Although incidence rates of most lymphoid malignancies were lower among Asian than white populations, only follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and nodular sclerosis (NS) HL rates were statistically significantly lower among foreign-born than U.S.-born Asians with incidence rate ratios ranging from 0.34 to 0.87. Rates of CLL/SLL and NS HL were also lower among Asian women living in ethnic enclaves or lower SES neighborhoods than those living elsewhere.Conclusions: These observations support strong roles of environmental factors in the causation of FL, CLL/SLL, and NS HL.Impact: Studying specific lymphoid malignancies in U.S. Asians may provide valuable insight toward understanding their environmental causes. Cancer Epidemiol Biomarkers Prev; 20(6); 1064–77. ©2011 AACR.
CYP2D6 Gene Variants and Their Association with Breast Cancer Susceptibility
Authors: Abraham Jean E. , Maranian Mel J. , Driver Kristy E. , Platte Radka , Kalmyrzaev Bolot , Baynes Caroline , Luccarini Craig , Earl Helena M. , Dunning Alison M. , Pharoah Paul D.P. , Caldas Carlos 
Published: June 2011

Abstract
Background: The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility.
Methods: DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) ≥ 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF &gt; 0.05) in CYP2D6.
Results: One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (Ptrend = 0.02; OR = 1.32; 95% CI = 1.04–1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility.
Conclusions: Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation.
Impact: This large case–control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study. Cancer Epidemiol Biomarkers Prev; 20(6); 1255–8. ©2011 AACR.
Late Outcomes of a Single-Center Experience of 400 Consecutive Thoracic Endovascular Aortic Repairs
Authors: Lee W. Anthony , Daniels Michael J. , Beaver Thomas M. , Klodell Charles T. , Raghinaru Dan E. , Hess Philip J. 
Published: June 2011

Background—
In this study, we report the late outcomes of a large, decade-long single-center thoracic endovascular aortic repair experience.

Methods and Results—
A prospectively maintained registry and the electronic medical records of 400 consecutive thoracic endovascular aortic repair performed at a tertiary care center were reviewed. The distribution of pathologies treated included aneurysms (198, 49%), dissections (100, 25%), penetrating ulcers (54, 14%), traumatic transections (25, 6%), and other pathologies (23, 6%). Spinal drains were placed prophylactically in 127 cases (32%) of planned extended aortic coverage. There were no acute surgical conversions. Adjunctive surgical procedures were performed on 94 patients (24%). Subclavian revascularizations were performed selectively in only 15% of zone 0 to 2 deployments. The median length of stay was 5 days (limits, 1 and 79 days). Overall 30-day mortality was 6.5% (elective, 2.6%; urgent, 9.5%; and emergent, 20%). Permanent spinal cord ischemia occurred in 4.5% and stroke in 3%. Kaplan-Meier estimates of survival were 82%, 76%, 68%, and 60% and freedom from secondary intervention was 90%, 86%, 81%, and 78% at 6, 12, 24, and 36 months, respectively. Risk factors for mortality included stroke, urgent/emergent repair, age ≥80 years, general anesthesia, and dissection pathology.

Conclusions—
Thoracic endovascular aortic repair may be used to treat a variety of thoracic aortic pathologies with a very low risk of intraoperative conversion. Overall rates of mortality and neurological complications were relatively low but significantly increased in emergent repairs. There appeared to be a substantial number of late deaths, which may represent a combination of poor patient selection and treatment failures.
Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation
Authors: Alonso Alvaro , Lopez Faye L. , Matsushita Kunihiro , Loehr Laura R. , Agarwal Sunil K. , Chen Lin Y. , Soliman Elsayed Z. , Astor Brad C. , Coresh Josef 
Published: June 2011

Background—
Chronic kidney disease is associated with the incidence of cardiovascular disease. Chronic kidney disease may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results.

Methods and Results—

We estimated cystatin C–based glomerular filtration rate (eGFR
cys
) and measured urinary albumin-to-creatinine ratio (ACR) in 10 328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996 to 1998. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared with individuals with eGFR
cys
≥90 mL · min
−1
· 1.73 m
−2
, multivariable hazard ratios and 95% confidence intervals (CIs) of AF were 1.3 (95% CI, 1.1 to 1.6), 1.6 (95% CI, 1.3 to 2.1), and 3.2 (95% CI, 2.0 to 5.0;
P
for trend <0.0001) in those with eGFR
cys
of 60 to 89, 30 to 59, and 15 to 29 mL · min
−1
· 1.73 m
−2
, respectively. Similarly, the presence of macroalbuminuria (ACR ≥300 mg/g; hazard ratio, 3.2; 95% CI, 2.3 to 4.5) and microalbuminuria (ACR, 30 to 299 mg/g; hazard ratio, 2.0; 95% CI, 1.6 to 2.4) was associated with higher AF risk compared with those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFR
cys
and macroalbuminuria (hazard ratio, 13.1; 95% CI, 6.0 to 28.6, comparing individuals with ACR ≥300 mg/g and eGFR
cys
of 15 to 29 mL · min
−1
· 1.73 m
−2
and those with ACR <30 mg/g and eGFR
cys
≥90 mL · min
−1
· 1.73 m
−2
).

Conclusion—
In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.
How close are we to customizing chemotherapy in early non-small cell lung cancer?
Authors: Ioannidis Georgios , Georgoulias Vassilis , Souglakos John 
Published: June 2011

Although surgery is the only potentially curative treatment for early-stage non-small cell lung cancer (NSCLC), 5-year survival rates range from 77% for stage IA tumors to 23% in stage IIIA disease. Adjuvant chemotherapy has recently been established as a standard of care for resected stage II-III NSCLC, on the basis of large-scale clinical trials employing third-generation platinum-based regimens. As the overall absolute 5-year survival benefit from this approach does not exceed 5% and potential long-term complications are an issue of concern, the aim of customized adjuvant systemic treatment is to optimize the toxicity/benefit ratio, so that low-risk individuals are spared from unnecessary intervention, while avoiding undertreatment of high-risk patients, including those with stage I disease. Therefore, the application of reliable prognostic and predictive biomarkers would enable to identify appropriate patients for the most effective treatment. This is an overview of the data available on the most promising clinicopathological and molecular biomarkers that could affect adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine practice. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information warranting further validation. On the other hand, real-time quantitative polymerase-chain reaction strategy involving relatively small number of genes offers a practical alternative, with high cross-platform performance. Although data extrapolation from the metastatic setting should be cautious, the concept of personalized, pharmacogenomics-guided chemotherapy for early NSCLC seems feasible, and is currently being evaluated in randomized phase 2 and 3 trials. The mRNA and/or protein expression levels of excision repair cross-complementation group 1, ribonucleotide reductase M1 and breast cancer susceptibility gene 1 are among the most potential biomarkers for early disease, with stage-independent prognostic and predictive values, the clinical utility of which is being validated prospectively. Inter-assay discordance in determining the biomarker status and association with clinical outcomes is noteworthing.