Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Wage losses in the year after breast cancer: Extent and determinants among Canadian women

This article is available open access through the publisher’s website at the link below. © The Author 2008.Background - Wage losses after breast cancer may result in considerable financial burden. Their assessment is made more urgent because more women now participate in the workforce and because breast cancer is managed using multiple treatment modalities that could lead to long work absences. We evaluated wage losses, their determinants, and the associations between wage losses and changes for the worse in the family's financial situation among Canadian women over the first 12 months after diagnosis of early breast cancer. Methods - We conducted a prospective cohort study among women with breast cancer from eight hospitals throughout the province of Quebec. Information that permitted the calculation of wage losses and information on potential determinants of wage losses were collected by three pretested telephone interviews conducted over the year following the start of treatment. Information on medical characteristics was obtained from medical records. The main outcome was the proportion of annual wages lost because of breast cancer. Multivariable analysis of variance using the general linear model was used to identify personal, medical, and employment characteristics associated with the proportion of wages lost. All statistical tests were two-sided. Results - Among 962 eligible breast cancer patients, 800 completed all three interviews. Of these, 459 had a paying job during the month before diagnosis. On average, these working women lost 27% of their projected usual annual wages (median = 19%) after compensation received had been taken into account. Multivariable analysis showed that a higher percentage of lost wages was statistically significantly associated with a lower level of education (Ptrend = .0018), living 50 km or more from the hospital where surgery was performed (P = .070), lower social support (P = .012), having invasive disease (P = .086), receipt of chemotherapy (P < .001), self-employment (P < .001), shorter tenure in the job (Ptrend < .001), and part-time work (P < .001). Conclusion - Wage losses and their effects on financial situation constitute an important adverse consequence of breast cancer in Canada.The Canadian Breast Cancer Research Alliance, Canadian Institutes of Health Research, and Fondation de l’Université Laval

Distinct neuropeptide-receptor modules regulate a sex-specific behavioral response to a pheromone

Dioecious species are a hallmark of the animal kingdom, with opposing sexes responding differently to identical sensory cues. Here, we study the response of C. elegans to the small-molecule pheromone, ascr#8, which elicits opposing behavioral valences in each sex. We identify a novel neuropeptide-neuropeptide receptor (NP/NPR) module that is active in males, but not in hermaphrodites. Using a novel paradigm of neuropeptide rescue that we established, we leverage bacterial expression of individual peptides to rescue the sex-specific response to ascr#8. Concurrent biochemical studies confirmed individual FLP-3 peptides differentially activate two divergent receptors, NPR-10 and FRPR-16. Interestingly, the two of the peptides that rescued behavior in our feeding paradigm are related through a conserved threonine, suggesting that a specific NP/NPR combination sets a male state, driving the correct behavioral valence of the ascr#8 response. Receptor expression within pre-motor neurons reveals novel coordination of male-specific and core locomotory circuitries

Constructing the digitalized sporting body: black and white masculinity in NBA/NHL internet memes

In this article, I examine the ways sport fans construct and circulate discourses of race and masculinity in cyberspace. I do this through an examination of a set of Internet memes that juxtapose the bodies of National Hockey League players with National Basketball Association players in one single image. I argue these memes celebrate White masculinity, while at the same time constructing African American athletes as individualistic, selfish, and unwilling to sacrifice their bodies for the greater good of the team. More so, I argue that these memes construct a form of racial ideology that is representative of White backlash politics

He Scores Through a Screen: Mediating Masculinities Through Hockey Video Games

Hockey video games highlight the ways in which the video game medium shapes and conditions the experience of producing and/or performing the sport “in real life.” Indeed, the accumulation of advanced statistics in and through the constant evaluation, measurement, and surveillance which are inherent to video games—and increasingly seen as foundational for sport—reveals important contradictions not only in the way the embodied sport is played and understood, but also in terms of the proofs of masculinity upon which the sport is built. It then becomes clear that the building of masculinity and the empowerment of the character become one and the same. The ludic function reinforces the cultural imperative and vice versa. Thus, our chapter prizes apart the conflation of masculinity with hockey while showing the ways that video game studies can contribute to existing disciplines

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease

Aims: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe−/− mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. Results: Both aged (16 months) Apoe−/− and Apoe−/−/p47phox−/− mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox−/− mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe−/− mice treated with MitoTEMPO and 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function. Innovation and Conclusion: These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD. Antioxid. Redox Signal. 23, 1389–1409

Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women

Abstract Background PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. Methods We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. Results We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. Conclusion We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population

Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25

Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 × 10-9]

Melt Inclusion Vapour Bubbles: The Hidden Reservoir for Major and Volatile Elements

Olivine-hosted melt inclusions (MIs) provide samples of magmatic liquids and their dissolved volatiles from deep within the plumbing system. Inevitable post-entrapment modifications can lead to significant compositional changes in the glass and/or any contained bubbles. Re-heating is a common technique to reverse MI crystallisation; however, its effect on volatile contents has been assumed to be minor. We test this assumption using crystallised and glassy basaltic MIs, combined with Raman spectroscopy and 3D imaging, to investigate the changes in fluid and solid phases in the bubbles before and after re-heating. Before re-heating, the bubble contains CO2&nbsp;gas and anhydrite (CaSO4) crystallites. The rapid diffusion of major and volatile elements from the melt during re-heating creates new phases within the bubble: SO2, gypsum, Fe-sulphides. Vapour bubbles hosted in naturally glassy MIs similarly contain a plethora of solid phases (carbonates, sulphates, and sulphides) that account for up to 84% of the total MI sulphur, 80% of CO2, and 14% of FeO. In both re-heated and naturally glassy MIs, bubbles sequester major and volatile elements that are components of the total magmatic budget and represent a “loss” from the glass. Analyses of the glass alone significantly underestimates the original magma composition and storage parameters