Association of sperm-associated antigen 5 and treatment response in patients With estrogen receptor–positive breast cancer

Importance: There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor–positive breast cancer. Objective: To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor–positive breast cancer. Design, Settings, and Participants: This retrospective cohort study included patients with estrogen receptor–positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse–free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019. Main Outcomes and Measures: The primary outcomes were breast cancer–specific survival, distal relapse–free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models. Results: This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor–positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor–positive breast cancer was associated with prolonged 5-year distal relapse–free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001). Conclusions and Relevance: These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor–positive breast cancer. Retrospective and prospective clinical trials are warranted

Validity of a self-reported measure of familial history of obesity

<p>Abstract</p> <p>Background</p> <p>Familial history information could be useful in clinical practice. However, little is known about the accuracy of self-reported familial history, particularly self-reported familial history of obesity (FHO).</p> <p>Methods</p> <p>Two cross-sectional studies were conducted. The aims of study 1 was to compare self-reported and objectively measured weight and height whereas the aims of study 2 were to examine the relationship between the weight and height estimations reported by the study participants and the values provided by their family members as well as the validity of a self-reported measure of FHO. Study 1 was conducted between 2004 and 2006 among 617 subjects and study 2 was conducted in 2006 among 78 participants.</p> <p>Results</p> <p>In both studies, weight and height reported by the participants were significantly correlated with their measured values (study 1: r = 0.98 and 0.98; study 2: r = 0.99 and 0.97 respectively; p < 0.0001). Estimates of weight and height for family members provided by the study participants were strongly correlated with values reported by each family member (r = 0.96 and 0.95, respectively; p < 0.0001). Substantial agreement between the FHO reported by the participants and the one obtained by calculating the BMI of each family members was observed (kappa = 0.72; p < 0.0001). Sensitivity (90.5%), specificity (82.6%), positive (82.6%) and negative (90.5%) predictive values of FHO were very good.</p> <p>Conclusion</p> <p>A self-reported measure of FHO is valid, suggesting that individuals are able to detect the presence or the absence of obesity in their first-degree family members.</p

Adherence to yoga and exercise interventions in a 6-month clinical trial

<p>Abstract</p> <p>Background</p> <p>To determine factors that predict adherence to a mind-body intervention in a randomized trial.</p> <p>Design</p> <p>We analyzed adherence data from a 3-arm trial involving 135 generally healthy seniors 65–85 years of age randomized to a 6-month intervention consisting of: an Iyengar yoga class with home practice, an exercise class with home practice, or a wait-list control group. Outcome measures included cognitive function, mood, fatigue, anxiety, health-related quality of life, and physical measures. Adherence to the intervention was obtained by class attendance and biweekly home practice logs.</p> <p>Results</p> <p>The drop-out rate was 13%. Among the completers of the two active interventions, average yoga class attendance was 77% and home practice occurred 64% of all days. Average exercise class attendance was 69% and home exercise occurred 54% of all days. There were no clear effects of adherence on the significant study outcomes (quality of life and physical measures). Class attendance was significantly correlated with baseline measures of depression, fatigue, and physical components of health-related quality of life. Significant differences in baseline measures were also found between study completers and drop-outs in the active interventions. Adherence was not related to age, gender, or education level.</p> <p>Conclusion</p> <p>Healthy seniors have good attendance at classes with a physically active intervention. Home practice takes place over half of the time. Decreased adherence to a potentially beneficial intervention has the potential to decrease the effect of the intervention in a clinical trial because subjects who might sustain the greatest benefit will receive a lower dose of the intervention and subjects with higher adherence rates may be functioning closer to maximum ability before the intervention. Strategies to maximize adherence among subjects at greater risk for low adherence will be important for future trials, especially complementary treatments requiring greater effort than simple pill-taking.</p

Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: A study of 522 consecutive cases

<p>Abstract</p> <p>Background</p> <p>Malignant melanoma is a rare disease in Asia, and knowledge on its characteristics and clinical outcome in Asian patients is limited. The purpose of this observational study was to determine the clinical presentation and outcome of patients with melanoma in China.</p> <p>Methods</p> <p>A database was prospectively established for the purpose of this analysis. The elements of the database included basic demographic data of patients and prognosticators previously reported in literature, as well as follow-up data including clinical outcome after treatment. Medical record of all patients with pathologically diagnosed malignant melanoma consulted in our center since 2006 were retrieved and reviewed. No patient was excluded in this study. Statistical analyses including survival and multivariate analyses of factors associated with survival were respectively performed by Kaplan-Meier method and Cox proportional hazard model.</p> <p>Results</p> <p>A total of 522 consecutive and nonselected cases were evaluated. There were 218 cases (41.8%) of acral lentiginous melanoma (ALM), 118 (22.6%) of mucosal melanoma (MCM), 103 (19.7%) of nodular melanoma (NM), 33 (6.3%) of superficial spreading melanoma (SSM), and others were Lentigo maligna melanoma or unclassifiable disease. The proportion of patients with clinical stage I, II, III, and IV diseases were 6.1%, 55.9%, 25.1%, and 12.8%, respectively. Among the 357 cases of cutaneous melanoma, 234 patients (65.5%) had ulceration.</p> <p>The 5-year overall survival rate of all 522 patients was 41.6%, and the median survival time was 3.92 years (95% CI, 3.282 to 4.558). Five-year survival rates of patients with stage I, II, III, and IV diseases were 94.1%, 44.0%, 38.4% and 4.6% respectively (P < 0.001). Multivariate analysis revealed that clinical stage and the ulceration were two significant prognosticators for OS. In addition, extent of surgery and use of adjuvant therapy were significant prognosticators for DFS in patients with non-metastatic disease after definitive treatment. Pathological subtype was not a significant prognostic factor to predict wither OS or DFS.</p> <p>Conclusions</p> <p>Prognoses of patients with malignant melanoma diagnosed in China were suboptimal, and most patients were diagnosed with locally advanced disease (i.e., stage II or above). ALM and MCM are the two most commonly diagnosed pathological subtypes. Clinical staging and presence of ulceration was significantly associated with clinical outcome in terms of OS, while treatment strategy including extent of surgery and use of adjuvant therapy were significant predictors of DFS.</p

Meaning in life in the Federal Republic of Germany: results of a representative survey with the Schedule for Meaning in Life Evaluation (SMiLE)

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Electronic Cigarette Advertising Impacts Adversely on Smoking Behaviour Within a London Student Cohort: A Cross-Sectional Structured Survey.

INTRODUCTION: In contrast to tobacco smoking, electronic cigarette ("vaping") advertisement had been approved in the United Kingdom (UK) in January 2013. Currently, there are an estimated 3.2 million UK e-cigarette users. The impact of e-cigarette advertisement on tobacco use has not been studied in detail. We hypothesised that e-cigarette advertisement impacts on conventional smoking behaviour. METHODS: A cross-sectional structured survey assessed the impact of e-cigarette advertising on the perceived social acceptability of cigarette and e-cigarette smoking and on using either cigarettes or e-cigarettes (on a scale of 1 to 5/'not at all' to 'a lot'). The survey was administered between January to March 2015 to London university students, before and after viewing 5 UK adverts including a TV commercial. RESULTS: Data were collected from 106 participants (22 ± 2 years, 66% male), comprising cigarette smokers (32%), non-smokers (54%) and ex-smokers (14%). This included vapers (16%), non-vapers (77%) and ex-vapers (7%). After viewing the adverts, smokers (2.6 ± 1.0 vs. 3.8 ± 1.1, p = 0.001) and non-smokers (3.2 ± 0.7 vs. 3.7 ± 0.8, p = 0.007) felt smoking was more socially acceptable, compared to before viewing them. Participants were more likely to try both e-cigarettes (1.90 ± 1.03 to 3.09 ± 1.11, p < 0.001) and conventional cigarettes (1.73 ± 0.83 to 2.27 ± 1.13, p < 0.001) after viewing the adverts compared to before. Vapers were less likely to smoke both an e-cigarette, and a conventional cigarette after viewing the adverts. CONCLUSION: E-cigarette advertising encourages both e-cigarette and conventional cigarette use in young smokers and non-smokers. The adverts increase the social acceptability of smoking without regarding the importance of public health campaigns that champion smoking cessation

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases

Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood.The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin.Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes

Whose Sense of Place? A Political Ecology of Amenity Development

Using a political ecology framework, this chapter examines the ways in which sense of place and amenity migration contribute to alternative residential development, which relies on uneven use of conservation subdivision features in the American West. Using case studies from Central Oregon, this chapter demonstrates how senses of place and developer decision-making are tied to wider political economic changes. It highlights the roles that amenity migrants and developers, two groups that are sometimes identical, play in landscape transformations that simultaneously draw on a particular sense of place and commodify landscapes in new ways