bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Intertumoral Heterogeneity on Predicting Chemotherapy Response of BRCA1-Deficient Mammary Tumors
Authors: Rottenberg Sven , Vollebergh Marieke A. , de Hoon Bas , de Ronde Jorma , Schouten Philip C. , Kersbergen Ariena , Zander Serge A.L. , Pajic Marina , Jaspers Janneke E. , Jonkers Martijn , Lodén Martin , Sol Wendy , van der Burg Eline , Wesseling Jelle , Gillet Jean-Pierre , Gottesman Michael M. , Gribnau Joost , Wessels Lodewyk , Linn Sabine C. , Jonkers Jos , Borst Piet
Published: March 2012

The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy. Cancer Res; 72(9); 2350–61. ©2012 AACR.
CD73-Deficient Mice Are Resistant to Carcinogenesis
Authors: Stagg John , Beavis Paul A. , Divisekera Upulie , Liu Mira C.P. , Möller Andreas , Darcy Phillip K. , Smyth Mark J.
Published: March 2012

CD73 is a cell surface 5′-nucleotidase that converts AMP to adenosine, an immune suppressive molecule. CD73 may promote immune escape in cancer by contributing to the degradation of extracellular ATP released by dying cancer cells in hypoxic tumors or following chemotherapy. However, whether CD73 exerts a critical oncogenic function during tumorigenesis is unknown. In this study, we used genetically deficient mice to investigate its contribution to autochthonous tumor formation. CD73 deficiency suppressed the development of 3-methylcholanthrene (MCA)-induced fibrosarcomas through a mechanism relying upon IFN-γ, natural killer (NK) cells, and CD8+ T cells. Similarly, CD73 deficiency also suppressed prostate tumorigenesis in TRAMP transgenic mice. Importantly, treatment with an anti-CD73 monoclonal antibody effectively suppressed growth of established MCA-induced tumors or TRAMP-C1 prostate tumors and inhibited the development of TRAMP-C1 lung metastases. The therapeutic activity of anti-CD73 monoclonal antibody against primary tumors was dependent on CD8+ T cells, whereas its antimetastatic activity was dependent on host CD73 expression independent of T cells or NK cells. Taken together, our findings indicate that CD73 is a critical factor in tumorigenesis and that anti-CD73 antibodies may offer a novel generalized strategy to blunt immune escape and treat cancer. Cancer Res; 72(9); 2190–6. ©2012 AACR.
Urinary Bladder Cancer Risk Factors in Egypt: A Multicenter Case–Control Study
Authors: Zheng Yun-Ling , Amr Sania , Saleh Doa'a A. , Dash Chiranjeev , Ezzat Sameera , Mikhail Nabiel N. , Gouda Iman , Loay Iman , Hifnawy Tamer , Abdel-Hamid Mohamed , Khaled Hussein , Wolpert Beverly , Abdel-Aziz Mohamed A. , Loffredo Christopher A.
Published: March 2012

Background: We investigated associations between tobacco exposure, history of schistosomiasis, and bladder cancer risk in Egypt.

Methods: We analyzed data from a case–control study (1,886 newly diagnosed and histologically confirmed cases and 2,716 age-, gender-, and residence-matched, population-based controls). Using logistic regression, we estimated the covariate-adjusted ORs and 95% confidence interval (CI) of the associations.

Results: Among men, cigarette smoking was associated with an increased risk of urothelial carcinoma (OR = 1.8; 95% CI, 1.4–2.2) but not squamous cell carcinoma (SCC); smoking both water pipes and cigarettes was associated with an even greater risk for urothelial carcinoma (OR = 2.9; 95% CI, 2.1–3.9) and a statistically significant risk for SCC (OR = 1.8; 95% CI, 1.2–2.6). Among nonsmoking men and women, environmental tobacco smoke exposure was associated with an increased risk of urothelial carcinoma. History of schistosomiasis was associated with increased risk of both urothelial carcinoma (OR = 1.9; 95% CI, 1.2–2.9) and SCC (OR = 1.9; 95% CI, 1.2–3.0) in women and to a lesser extent (OR = 1.4; 95% CI, 1.2–1.7 and OR = 1.4; 95% CI, 1.1–1.7, for urothelial carcinoma and SCC, respectively) in men.

Conclusions: The results suggest that schistosomiasis and tobacco smoking increase the risk of both SCC and urothelial carcinoma.

Impact: This study provides new evidence for associations between bladder cancer subtypes and schistosomiasis and suggests that smoking both cigarettes and water pipes increases the risk for SCC and urothelial carcinoma in Egyptian men. Cancer Epidemiol Biomarkers Prev; 21(3); 537–46. ©2011 AACR.
Gene Set Analysis of Survival Following Ovarian Cancer Implicates Macrolide Binding and Intracellular Signaling Genes
Authors: Fridley Brooke L. , Jenkins Gregory D. , Tsai Ya-Yu , Song Honglin , Bolton Kelly L. , Fenstermacher David , Tyrer Jonathan , Ramus Susan J. , Cunningham Julie M. , Vierkant Robert A. , Chen Zhihua , Chen Y. Ann , Iversen Ed , Menon Usha , Gentry-Maharaj Aleksandra , Schildkraut Joellen , Sutphen Rebecca , Gayther Simon A. , Hartmann Lynn C. , Pharoah Paul D.P. , Sellers Thomas A. , Goode Ellen L.
Published: March 2012

Background: Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single-nucleotide polymorphism (SNP) individually may not be well suited to detect small effects of multiple SNPs, such as those operating within the same biologic pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes.

Methods: To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWAS (N cases = 2,813, N deaths = 1,116), with a novel Principal Component-Gamma GSA method. Analysis was completed for all cases and then separately for high-grade serous histologic subtype.

Results: Analysis of the high-grade serous subjects resulted in 43 gene sets with P < 0.005 (1.7%); of these, 21 gene sets had P < 0.10 in both GWAS, including intracellular signaling pathway (P = 7.3 × 10−5) and macrolide binding (P = 6.2 × 10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (P = 6.3 × 10−4) and macrolide binding (P = 1.0 × 10−3). Of 18 gene sets with P < 0.005 (0.7%), eight had P < 0.10 in both GWAS.

Conclusion: This research detected novel gene sets associated with EOC survival.

Impact: Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies. Cancer Epidemiol Biomarkers Prev; 21(3); 529–36. ©2012 AACR.
Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake
Authors: Han Summer S. , Sue Laura Y. , Berndt Sonja I. , Selhub Jacob , Burdette Laurie A. , Rosenberg Philip S. , Ziegler Regina G.
Published: March 2012

Background: Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer.

Methods: We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels.

Results: Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10−5]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10−5).

Conclusions and Impact: Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev; 21(3); 417–27. ©2012 AACR.
Vitamin D and Calcium Supplementation and One-Year Change in Mammographic Density in the Women's Health Initiative Calcium and Vitamin D Trial
Authors: Bertone-Johnson Elizabeth R. , McTiernan Anne , Thomson Cynthia A. , Wactawski-Wende Jean , Aragaki Aaron K. , Rohan Thomas E. , Vitolins Mara Z. , Tamimi Rulla M. , Johnson Karen C. , Lane Dorothy , Rexrode Kathryn M. , Peck Jennifer D. , Chlebowski Rowan T. , Sarto Gloria , Manson JoAnn E.
Published: March 2012

Background: Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density.

Methods: We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women's Health Initiative hormone therapy (HT) and calcium and vitamin D (CaD) trials. Women were randomized to receive 1,000 mg/d of elemental calcium carbonate plus 400 IU/d of vitamin D3 or placebo.

Results: After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% CI = 0.81–1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95% CI = 0.61–1.11) vs. 1.16 (95% CI = 0.92–1.45) in women randomized to active HT. In sensitivity analyses limited to women taking ≥80% of study supplements, ratios were 0.67 (95% CI = 0.41–1.07) in women not assigned to HT and 1.07 (95% CI = 0.79–1.47) women assigned to HT.

Conclusions: We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year.

Impact: Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study. Cancer Epidemiol Biomarkers Prev; 21(3); 462–73. ©2012 AACR.
The Role of Polymorphisms in DNA Repair Genes and HPV 18 Integration Status in Cervical Dysplasia
Authors: ES Amirian , D Marquez-Do , K Adler-Storthz , M Follen , ME Scheurer
Published: March 2012

Despite the fact that cervical cancer is one of the leading causes of death in women worldwide, research has yet to elucidate why some HPV-infected women develop cancerous lesions while others are able to clear the infection. Previous studies have shown that HPV integration status may be associated with cervical cancer development, and yet, host genetic factors that may be involved in the viral integration process have not yet been identified. The purpose of this study was to examine the association between both HPV 18 viral integration status and single nucleotide polymorphisms (SNPs) in non-homologous end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Specifically, we sought to compare women with no dysplasia to those with low-grade or high-grade squamous intraepithelial lesions.

Methods: A total of 765 women were selected from two large trials designed to evaluate optical technologies for cervical cancer. Genotyping was performed using the Illumina Golden Gate platform. HPV 18 integration status was determined using a previously established protocol. Chi-square tests were conducted to determine which SNPs were associated with normal cytology, low-grade, or high-grade lesions. Among participants with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each polymorphism on viral integration status. An additive genetic model was used for all tests. P-values were adjusted using the false discovery rate method.

Results: Women with high-grade lesions were significantly younger than women with low-grade or no lesions. Tag-SNPs in 13 DNA repair genes, including MRE11A, ATM, and XRCC4, were significantly associated with cervical dysplasia. Most participants had a mix of both episomal and integrated HPV 18. Tag-SNPs in the XRCC4, PRKCH, and MRE11A genes were found to be significantly associated with HPV 18 integration status.

Conclusion: Our study indicates that host genetic variation in NHEJ DNA repair pathway genes, including MRE11A and XRCC4, are significantly associated with HPV 18 integration, and that these genes may play a key role in determining cervical cancer development and progression. This is the first study to examine host genetic variation in association with the viral integration event.
Ruminant Fatty Acids and Prostate Cancer Risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
Authors: M Wright , D Albanes , A Moser , K Snyder , J Virtamo , P Gann
Published: March 2012

Consumption of high fat animal products is a characteristic feature of Western diets, which have been consistently linked with elevated risks of prostate cancer. In order to elucidate which specific fatty acids may contribute to this association, we measured circulating concentrations of myristic (C14:0), pentadecanoic (C15:0), palmitic (C16:0), heptadecanoic (C17:0), vaccenic (C18:1n-7), and alpha-linolenic (C18:3n-3) acids - all of which are present in ruminant meat and/or dairy products - in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Prediagnostic blood samples from 300 prostate cancer cases and 300 controls matched on age and date of serum blood draw were analyzed for the aforementioned fatty acids by gas chromatography-mass spectrometry. There was a positive association between serum alpha-linolenic acid and overall prostate cancer risk, with a notable threshold effect (for increasing quartiles, odds ratios and 95% confidence intervals = 1.0 (referent), 1.65 (1.02–2.67), 1.96 (1.22–3.14), and 1.57 (0.97–2.54); p trend = 0.15). This association was stronger among men with low baseline levels of beta-carotene and vitamin E. The other fatty acids were unrelated to prostate cancer risk. Our findings indicate that higher blood levels of alpha-linolenic acid - the predominant omega-3 fatty acid in Western diets - is associated with elevated risks of prostate cancer, particularly within subgroups of men with low antioxidant levels.
Prospective Cohort Studies of Vitamin B6 Intake and Colorectal Cancer Incidence: Modification by Time?
Authors: X Zhang , JE Lee , J Ma , Y Je , K Wu , WC Willett , CS Fuchs , EL Giovannucci
Published: March 2012

Background: Vitamin B6 may influence colorectal carcinogenesis through its role in one-carbon metabolism related DNA synthesis and methylation. However, observational studies have been inconclusive and no studies have investigated when in the natural history vitamin B6 intake may prevent colorectal cancer.

Method: We followed 86,440 women in the Nurses' Health Study and 44,410 men in the Health Professionals Follow-up Study for up to 28 years. We assessed vitamin B6 intake every 4 years using validated food frequency questionnaires. We evaluated whether higher vitamin B6 intake in the remote past is strongly associated with a lower risk of colorectal cancer than intake in the recent past. Cox proportional hazards regression models were used to estimate multivariable relative risks (MV RRs, 95%CIs).

Results: Comparing top with bottom quintiles of total vitamin B6 intake, the mean plasma pyridoxal 5–phosphate (PLP, the active form of vitamin B6) levels were 98.3 pmol/mL and 38.9 pmol/mL in women and were 183.2 pmol/mL and 66.0 pmol/mL in men. Total vitamin B6 intake was significantly associated with an approximately 20–30% lower risk of colorectal cancer in age-adjusted results but these significant associations became attenuated and non-significant after adjustment for other colorectal cancer risk factors. Compared extreme quintiles of cumulative intake of total vitamin B6, the MV RRs (95%CIs) for colorectal cancer were 0.98 (0.80, 1.22; P trend = 0.79) in women and 0.98 (0.76, 1.26; P trend = 0.60) in men. For the same comparison, the MV RRs were 0.92 (0.73, 1.16) for total vitamin B6 intake 0–4 year before diagnosis, 0.99 (0.78, 1.26) for intake 4–8 year before diagnosis, 0.93 (0.71, 1.21) for intake 8–12 year before diagnosis, and 0.93 (0.69, 1.26) for intake 12–16 years before diagnosis. The corresponding MV RRs for men were 0.85 (0.63, 1.16), 0.98 (0.70, 1.37), 0.90 (0.63, 1.28), and 1.19 (0.78, 1.83), respectively. Additionally, results did not differ by cancer sub-site, sources of vitamin B6 (food or supplement), or intake of alcohol and folate.

Conclusion: Although a small effect cannot be excluded, our results do not support a strong role of vitamin B6 intake in adulthood in colorectal carcinogenesis among middle-aged U.S. health professionals.
Phenol Xenoestrogens and Mammographic Breast Density
Authors: A Trentham-Dietz , BL Sprague , J Wang , JM Hampton , DSM Buist , E Aiello Bowles , G Sisney , E Burnside , J Hemming , C Hedman
Published: March 2012

Concerns have been raised, largely on the basis of laboratory studies, regarding exposure to phenols, particularly bisphenol-A (BPA), in relation to hormone-related cancers. BPA is present in plastic consumer products including canned food linings and #7 polycarbonate plastics. According to recent NHANES data, human exposure as measured in urine is widespread (about 93% of people aged >5) and more common in females than males (Calafat EHP 2008). Concern regarding BPA in relation to breast cancer risk is based on in vivo and in vitro studies that suggest BPA may have a role in estrogen metabolism and mammary gland development. We examined the cross-sectional association of circulating serum levels of 3 phenols with mammographic breast density - a strong marker for breast cancer risk. A total of 264 postmenopausal women ages 55–70 years with no history of postmenopausal hormone use were recruited from mammography clinics in Madison, Wisconsin. Subjects completed a questionnaire regarding known breast cancer risk factors and provided a blood sample that was analyzed for octylphenol, nonylphenol, and BPA. Percent breast density (mean 15.3%, range 0.4–71.2%) was measured from subjects' mammograms using a computer-assisted thresholding method (Cumulus software). Since phenol levels are higher in the urine than in the serum, as expected many women had undetectable levels of the phenols in their serum: 86.7% octylphenol, 58.7% nonylphenol, and 73.1% BPA. After adjusting for age and body mass index in analysis of variance models, women with detectable serum BPA levels above the median (>0.56 ng/mL; N = 35) had higher percent breast density than women with BPA levels below the median (0.01–0.56 ng/mL; N = 36) and women with no detectable BPA (N = 193) in their serum (17.8% vs. 13.3% vs 12.7%, respectively; P = 0.01). Breast density was not associated with serum levels of either octylphenol or nonylphenol (P = 0.77, P = 0.36, respectively). Given that this study suggests that higher levels of BPA were associated with a clinically-relevant 5% greater breast density, further investigation into the potential influence of BPA on breast cancer risk using human populations is warranted. Supported by DOD BC062649, Komen FAS0703857, and NIH R03 CA139548.
Non-Physician Providers, Cancer Screening and Health Behavior Counseling
Authors: D Kepka , KR Yabroff
Published: March 2012

Purpose: Patients who receive a physician's recommendation for cancer screening and behavioral modification are most likely to comply with these recommendations. However, physicians face time constraints that make it nearly impossible to provide all recommended preventive services. The 2010 Affordable Care Act will expand health insurance coverage to 42 million Americans by 2014. Non-physician providers may help meet this new demand for primary care and ensure compliance with preventive services recommendations.

Methods: Data from the 2005 National Health Interview Survey were analyzed using multivariate logistic regression to assess the association between provider type seen in the past 12 months and compliance with U.S. Preventive Services Task Force cancer screening recommendations and receipt of behavior counseling among age-eligible adults (n = 23,201). Models were adjusted for age, level of education, and insurance status and stratified by gender.

Results: About 15% of NHIS participants (N = 4,652) saw a non-physician provider (nurse practitioner, certified nurse midwife or physician assistant) and a primary care physician. In adjusted analyses, age-eligible women were more likely to be compliant with Pap screening (OR: 5.0; 95% CI: 4.2–5.9), mammography (OR: 6.6; 95% CI: 5.2–8.4) and colorectal screening recommendations (OR: 7.8; 95% CI: 5.3–11.4) if they saw a non-physician provider and a primary care physician compared to not seeing any provider. Similarly, men were more likely to be compliant with colorectal screening recommendations (OR: 9.6; 95% CI: 6.9–13.5) if they saw a non-physician provider and a primary care physician. Women and men were more likely to report a provider asking about smoking status if they saw a non-physician provider and a primary care physician than those who saw other types of healthcare providers ((OR: 2.2; 95% CI: 2.0–2.4) and (OR: 3.0; 95% CI: 2.4–3.7), respectively).

Conclusions: Seeing a non-physician provider and a primary care physician is related to an increased likelihood of compliance with cancer screening recommendations and receipt of health behavior counseling. Opportunities exist for non-physician providers during this era of healthcare reform.
Risk of Non-Hodgkin Lymphoma in Relation to Tricyclic Antidepressant Use
Authors: S Lowry , J Chubak , B McKnight , O Press , N Weiss
Published: March 2012

Purpose: We investigated the relationship between prior use of tricyclic antidepressants (TCA) and risk of non-Hodgkin lymphomas (NHL), both overall and for common subtypes of NHL; previous studies provided some evidence of an association with NHL, but did not assess the risk of specific subtypes of NHL, which have been shown to be etiologically diverse.

Methods: We conducted a population-based matched case-control study among members of Group Health (GH), an integrated healthcare delivery system. Cases included GH members diagnosed with NHL between 1980–2011 at age ≥25 with no record of a prior cancer or of certain autoimmune conditions, who had been enrolled for ≥2 years at the reference date (date of diagnosis). Eight controls were matched to each case on age, sex, enrollment on the reference date, and length of prior enrollment at GH. Information on prior TCA use, including dose, duration, recency, and type, was ascertained from automated pharmacy data. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for NHL (and common subtypes) in relation to various patterns of TCA exposure using conditional logistic regression adjusted for confounders.

Results: We identified 2,768 cases and 22,127 matched controls. We did not observe an appreciably increased risk of NHL among persons who had filled ≥2 TCA prescriptions prior to the reference date compared to those who had filled none (OR: 1.1; 95% CI: 1.0–1.2). Overall risk of NHL was associated to at most a small degree with longer-term use (OR: 1.2; 95% CI: 1.0–1.4 for ≥10 prescriptions), high-dose use (OR: 1.1; 95% CI: 0.8–1.5 for ≥50 mg or equivalent), or use that began more than 5 years prior to reference date (OR: 1.0; 95% CI: 0.9–1.2). TCA use was generally not associated with most major NHL subtypes, though longer-term TCA use was associated with increased risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (OR: 1.5; 95% CI: 1.1–2.0).

Conclusions: We found little evidence that TCA use increases risk of NHL, overall or for specific common subtypes of NHL.
Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase I NCI Organ Dysfunction Working Group Study NCI-6432
Authors: LoRusso Patricia M. , Venkatakrishnan Karthik , Ramanathan Ramesh K. , Sarantopoulos John , Mulkerin Daniel , Shibata Stephen I. , Hamilton Anne , Dowlati Afshin , Mani Sridhar , Rudek Michelle A. , Takimoto Chris H. , Neuwirth Rachel , Esseltine Dixie-Lee , Ivy Percy
Published: March 2012

Purpose: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations.

Experimental Design: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements.

Results: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment.

Conclusions: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. Clin Cancer Res; 18(10); 2954–63. ©2012 AACR.
Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors
Authors: Doshi Sameer , Sutjandra Liviawati , Zheng Jenny , Sohn Winnie , Peterson Mark , Jang Graham , Chow Andrew T. , Pérez-Ruixo Juan Jose
Published: March 2012

Purpose: To quantitatively characterize the longitudinal dose exposure–response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors.

Experimental Design: Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid IMax model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression.

Results: The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4- and 12-week doses evaluated.

Conclusions: Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors. Clin Cancer Res; 18(9); 2648–57. ©2012 AACR.
Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer’s Disease
Authors: Kramberger Milica Gregoric , Jelic Vesna , Kåreholt Ingemar , Enache Daniela , Eriksdotter Jönhagen Maria , Winblad Bengt , Aarsland Dag
Published: March 2012

Background: The aim of this study was to explore the relationship between cerebrospinal fluid Alzheimer’s disease (AD) markers and depression in elderly people. Method: We included subjects with AD as well as persons with subjective cognitive impairment and normal cognition. Depression was assessed with the Cornell Scale for Depression in Dementia, and a cut-off score of >6 was used to define depression. Cerebrospinal fluid was analyzed using commercially available assays for β-amyloid 1–42, total tau, and phosphorylated tau 181. Results: A total of 183 participants (66.7% female) were included (92 with AD and 91 with subjective cognitive impairment), with a mean age (±SD) of 67.6 ± 7.4 years, a Mini-Mental State Examination score of 26.0 ± 4.0, and a median Cornell Scale for Depression in Dementia score of 5 (range 0–19). Depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced β-amyloid 1–42 in AD or non-demented subjects. Conclusions: These results suggest that AD pathology does not contribute to depression, indicating that other factors may be more important. Further studies of the aetiology of depression in elderly people with and without AD are warranted.
Co-Occurrence of Addictive Behaviours: Personality Factors Related to Substance Use, Gambling and Computer Gaming
Authors: Walther Birte , Morgenstern Matthis , Hanewinkel Reiner
Published: March 2012

Aim: To investigate co-occurrence and shared personality characteristics of problematic computer gaming, problematic gambling and substance use. Methods: Cross-sectional survey data were collected from 2,553 German students aged 12–25 years. Self-report measures of substance use (alcohol, tobacco and cannabis), problematic gambling (South Oaks Gambling Screen – Revised for Adolescents, SOGS-RA), problematic computer gaming (Video Game Dependency Scale, KFN-CSAS-II), and of twelve different personality characteristics were obtained. Results: Analyses revealed positive correlations between tobacco, alcohol and cannabis use and a smaller positive correlation between problematic gambling and problematic computer gaming. Problematic computer gaming co-occurred only with cannabis use, whereas problematic gambling was associated with all three types of substance use. Multivariate multilevel analyses showed differential patterns of personality characteristics. High impulsivity was the only personality characteristic associated with all five addictive behaviours. Depression and extraversion were specific to substance users. Four personality characteristics were specifically associated with problematic computer gaming: irritability/aggression, social anxiety, ADHD, and low self-esteem. Conclusions: Problematic gamblers seem to be more similar to substance users than problematic computer gamers. From a personality perspective, results correspond to the inclusion of gambling in the same DSM-V category as substance use and question a one-to-one proceeding for computer gaming.
Cold Urticaria Patients Exhibit Normal Skin Levels of Functional Mast Cells and Histamine after Tolerance Induction
Authors: Kring Tannert Line , Stahl Skov Per , Bjerremann Jensen Louise , Maurer Marcus , Bindslev-Jensen Carsten
Published: March 2012

Cold urticaria is a skin condition characterized by rapid appearance of itchy wheals and occasionally angioedema in response to cold stimulation. Antihistamines do not sufficiently protect all patients from symptoms, even when used in higher than standard doses. In these patients, desensitization to cold can be beneficial. The aim was to investigate whether desensitization can lower temperature thresholds and reduce release of histamine in the skin. Cold urticaria patients were subjected to desensitization and assessed for skin responses to cold stimulation and codeine before and after. Histamine levels mediated by cold and codeine were determined by cutaneous microdialysis before and after desensitization in patients and healthy controls. Desensitization to cold resulted in protection from cold-induced symptoms and lower temperature thresholds in six out of nine patients. Desensitization also prevented histamine release after skin exposure to cold. Surprisingly, skin histamine levels and release after codeine injection were found to be normal in desensitized patients.
Perceived Eye Region and the Processing of Fearful Expressions in Mild Cognitive Impairment Patients
Authors: Richard-Mornas Aurélie , Borg Céline , Klein-Koerkamp Yanica , Paignon Adeline , Hot Pascal , Thomas-Antérion Catherine
Published: March 2012

Background: The aim of the present study was to assess the possibility of compensating early facial expression recognition impairments in amnestic Mild Cognitive Impairment (a-MCI) patients. Methods: Twelve patients with a-MCI and 17 healthy participants matched according to age and education participated in the study. The originality of the present study was to cue the recognition of facial expressions (happiness, anger, fear, and neutral) by comparing eye region expressions and entire facial expressions. Results: A deficit in the recognition of fearful expressions was observed in a-MCI patients relative to the control group, whereas recognition of all the other emotional expressions was spared. Nevertheless, when eye expressions cued the recognition of fearful facial expressions, the performance of normal controls and a-MCI patients was comparable. Conclusion: The present paper indicates a selective impairment in fear recognition in the prodromal state of Alzheimer’s disease, and the possibility of compensating this deficit by orienting selective attention on specific facial features.
Phenotypic and Molecular Characterization of Partial Trisomy 2q Resulting from Insertion-Duplication in Chromosome 18q: A Case Report and Review of Literature
Authors: Ponnala R. , Ranganath P. , Dutta U.R. , Pidugu V.K. , Dalal A.B.
Published: March 2012

Trisomy 2q is a well-documented chromosomal anomaly with considerable variation in the phenotype depending upon the breakpoints and the co-existing chromosomal aberrations. The case of a dysmorphic male infant found to have trisomy of the 2q31.1–q37.3 segment, resulting from insertion-duplication of this segment in chromosome 18q23 is reported here. The rearrangement was resolved in detail by cytogenetic microarray and whole chromosome paint-based fluorescence in situ hybridization studies. There is some overlap of the phenotypic features in the reported patient with those described in previously reported cases with partial trisomy 2q. A detailed review of the available literature on 2q trisomy has also been presented and delineation of the phenotypic characteristics common to all patients with 2q trisomy has been attempted.
De novo Deletion of 1q31.1–q32.1 in a Patient with Developmental Delay and Behavioral Disorders
Authors: Milani D. , Bedeschi M.F. , Iascone M. , Chiarelli G. , Cerutti M. , Menni F.
Published: March 2012

We describe the case of a 6-year-old boy with a de novo deletion of the long arm of chromosome 1 encompassing band 1q31.1–q32.1, minor facial anomalies, mild developmental delay, and behavioral disorders. His postnatal karyotype was normal. Using array-comparative genomic hybridization, we identified and characterized a de novo 1q interstitial deletion of about 15.6 Mb, which partially overlaps those of other reported cases. We considered the gene content of the deleted region in an attempt to compare the clinical features of our patient with these other cases, even though they were not characterized molecularly in detail. The most remarkable difference was the absence of microcephaly. To the best of our knowledge, this is the first report of a de novo 1q31.1–q32.1 deletion. Moreover, it illustrates how molecular delineation associated with fine clinical characterization can improve the genotype-phenotype correlations of classical cytogenetic abnormalities.
Platelet Function Measurement–Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery
Authors: Mahla Elisabeth , Suarez Thomas A. , Bliden Kevin P. , Rehak Peter , Metzler Helfried , Sequeira Alejandro J. , Cho Peter , Sell Jeffery , Fan John , Antonino Mark J. , Tantry Udaya S. , Gurbel Paul A.
Published: March 2012

Background—

Aspirin and clopidogrel therapy is associated with a variable bleeding risk in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the role of platelet function testing in clopidogrel-treated patients undergoing CABG.

Methods and Results—

One hundred eighty patients on background aspirin with/without clopidogrel therapy undergoing elective first time isolated on-pump CABG were enrolled in a prospective single-center, nonrandomized, unblinded investigation (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG [TARGET-CABG] study) between September 2008 and January 2011. Clopidogrel responsiveness (ADP-induced platelet-fibrin clot strength [MA
ADP
]) was determined by thrombelastography; CABG was done within 1 day, 3–5 days, and >5 days in patients with an MA
ADP
>50 mm, 35–50 mm, and <35 mm, respectively. The primary end point was 24-hour chest tube drainage and key secondary end point was total number of transfused red blood cells. Equivalence was defined as ≤25% difference between groups. ANCOVA was used to adjust for confounders. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% confidence interval, 81–107%) of the amount observed in clopidogrel-naive patients, and the total amount of red blood cells transfused did not differ between groups (1.80 U versus 2.08 U, respectively,
P
=0.540). The total waiting period in clopidogrel-treated patients was 233 days (mean, 2.7 days per patient).

Conclusions—

A strategy based on preoperative platelet function testing to determine the timing of CABG in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and ≈50% shorter waiting time than recommended in the current guidelines.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00857155.
A Cell-Based Phenotypic Assay to Identify Cardioprotective Agents
Authors: Guo Stephanie , Olm-Shipman Adam , Walters Andrew , Urciuoli William R. , Devito Stefanie , Nadtochiy Sergiy M. , Wojtovich Andrew P. , Brookes Paul S.
Published: March 2012

Rationale:

Tissue ischemia/reperfusion (IR) injury underlies several leading causes of death such as heart-attack and stroke. The lack of clinical therapies for IR injury may be partly due to the difficulty of adapting IR injury models to high-throughput screening (HTS).

Objective:

To develop a model of IR injury that is both physiologically relevant and amenable to HTS.

Methods and Results:

A microplate-based respirometry apparatus was used. Controlling gas flow in the plate head space, coupled with the instrument's mechanical systems, yielded a 24-well model of IR injury in which H9c2 cardiomyocytes were transiently trapped in a small volume, rendering them ischemic. After initial validation with known protective molecules, the model was used to screen a 2000-molecule library, with post-IR cell death as an end point. P
o
2
and pH monitoring in each well also afforded metabolic data. Ten protective, detrimental, and inert molecules from the screen were subsequently tested in a Langendorff-perfused heart model of IR injury, revealing strong correlations between the screening end point and both recovery of cardiac function (negative,
r
2
=0.66) and infarct size (positive,
r
2
=0.62). Relationships between the effects of added molecules on cellular bioenergetics and protection against IR injury were also studied.

Conclusions:

This novel cell-based assay can predict either protective or detrimental effects on IR injury in the intact heart. Its application may help identify therapeutic or harmful molecules.
Lack of Neutrophil-Derived CRAMP Reduces Atherosclerosis in Mice
Authors: Döring Yvonne , Drechsler Maik , Wantha Sarawuth , Kemmerich Klaus , Lievens Dirk , Vijayan Santosh , Gallo Richard L. , Weber Christian , Soehnlein Oliver
Published: March 2012

Rationale:

Neutrophils have been reported to contribute to early atherosclerotic lesion formation. Mechanisms of neutrophil-driven atherosclerosis remain unclear so far.

Objective:

Investigation of the role of the neutrophil granule protein cathelicidin (CRAMP in mouse, LL37 in human) in atherosclerosis.

Methods and Results:

Compared to

Apoe
−/−

mice,

Cramp
−/−
Apoe
−/−

mice exhibit reduced lesion sizes with lower macrophage numbers. In atherosclerotic aortas, we could detect CRAMP specifically in neutrophils, but not in monocytes or macrophages. By use of intravital microscopy, CRAMP was found to be deposited by activated neutrophils on inflamed endothelium of large arteries. In this location cathelicidins promote adhesion of classical monocytes and neutrophils, but not nonclassical monocytes in a formyl-peptide receptor-dependent manner.

Conclusions:

Cathelicidins promote atherosclerosis by enhancement of the recruitment of inflammatory monocytes.
Spatial Heterogeneity of Air–Sea Energy Fluxes over a Coral Reef—Heron Reef, Australia
Authors: MacKellar Mellissa C. , McGowan Hamish A. , Phinn Stuart R.
Published: March 2012

The thermal environment of a coral reef is moderated by complex interactions of air–sea heat and moisture fluxes, local to synoptic-scale weather and reef hydrodynamics. Measurements of air–sea energy fluxes over coral reefs are essential to understanding the reef–atmosphere processes that underpin coral reef environmental conditions such as water temperature, cloud, precipitation, and local winds (such as during coral bleaching events). Such measurements over coral reefs have been rare, however, and the spatial heterogeneity of surface–atmosphere energy exchanges due to the different geomorphic and biological zones on coral reefs has not been captured. Accordingly, the heterogeneity of coral reefs with regard to substrate, benthic communities, and hydrodynamic processes has not been considered in the characterization of the surface radiation budget and energy balance of coral reefs. Here, the first concurrent in situ eddy covariance measurements of the surface energy balance and radiation transfers over different geomorphic zones of a coral reef are presented. Results showed differences in radiation transfers and sensible and latent heat fluxes over the reef, with higher Bowen ratios over the shallow reef flat zone. The energy flux divergence between sites increased with wind speed and during unstable, southeasterly trade winds with the net flux of heat being positive and negative over different geomorphic zones. The surface drag coefficient at measurement height ranged from 1 × 10−3 to 2.5 × 10−3, with no significant difference between sites. Results confirm that spatial variation in radiation and air–reef–water surface heat and moisture fluxes occurs across a lagoonal platform reef in response to local meteorological conditions, hydrodynamics, and benthic–substrate cover.
Spatiotemporal Characteristics of Drought Occurrences over Japan
Authors: Lee Sang-Min , Byun Hi-Ryong , Tanaka Hiroshi L.
Published: March 2012

The drought climate of Japan from 1902 to 2009 was analyzed using an effective drought index (EDI). Drought regions were identified by hierarchical cluster analysis using drought characteristics (duration, severity, and onset and end dates) obtained from 50 observation stations. The results indicated that droughts could be divided into four groups (G1–G4) that reflected the local climate. The four groups were related to precipitation as follows. The summer rainy season affected groups G2–G4, in which droughts occurred mainly during spring and summer and were relieved before and after the rainy season. The G1 group was not affected by the summer rainy season and droughts were spread evenly throughout the year; it even had cases of droughts relieved by winter snow. All groups included dry conditions over the 108-yr period, and the driest conditions occurred in the late twentieth century. The statistical analysis of drought data showed that a total of 23 country-wide droughts occurred and that the most extreme droughts occurred in 1939–41 and 1984–85, with an EDI of −1.55. In addition, four dry seasons (1939–45, 1997–98, 1994–97, and 2005–09) were found using regime shift analysis. Regional droughts occurred 54, 54, 49, and 59 times in groups G1–G4, respectively. On average, short-term droughts with a duration shorter than 6 months occurred 3.5 times per decade, whereas long-term droughts extending over 1 yr occurred 0.3 times per decade. The drought duration and intensity were used to calculate the statistical return period of country-wide droughts. The 1939–41 drought had the longest return period, at 104.7 yr. The 1987–88 and 1995–97 droughts had return periods of 65.9 and 65.5 yr, respectively.