Differences in uveal melanomas between men and women from the British Isles.
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ABSTRACT:
SUBMITTER: Damato BE
PROVIDER: S-EPMC3272186 | biostudies-other | 2012 Feb
REPOSITORIES: biostudies-other
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Project description:Uveal melanoma (UM) is a subtype of melanoma. Although they share a melanocytic origin with cutaneous melanoma (CM), patients with UM have few treatment options. BCL2 homologous 3 mimetics are small-molecule drugs that mimic proapoptotic BCL2 family members. We compared BCL2 family member expression between UM and CM using immunoblot and The Cancer Genome Atlas transcriptomic analysis. UM has a unique signature of low BFL1 and high PUMA proteins compared with CM and 30 other cancer types, making them an attractive candidate for BCL2 homologous 3 protein mimetics. We tested the efficacy of a BCL2 inhibitor and MCL1 inhibitor (MCL1i) in UM, with viability assays, live-cell imaging, sphere assays, and mouse xenograft models. UM had a higher sensitivity to MCL1i than CM. Overexpression of BFL1 or knockdown of PUMA made the UM more resistant to MCL1i. In contrast, MAPK/extracellular signal‒regulated kinase inhibitor treatment in CM made them more sensitive to MCL1i. However, MCL1i-alone treatment was not very effective to reduce the UM initiating cells; to overcome this, we employed a combination of MCL1i with BCL2 inhibitor that synergistically inhibited UM initiating cell's capacity to expand. Overall, we identify a distinct expression profile of BCL2 family members for UM that makes them susceptible to BCL2 homologous 3 mimetics.
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Project description:There is debate about whether distinct designs of femoral components for men and women are needed based on morphologic and size differences between genders. We asked whether anthropomorphic differences exist between the distal femoral dimensions in women and men. We measured the distal femora of 100 women and 100 men intraoperatively after preparation for prosthetic implantation. The measured dimensions included the anteroposterior height from the posterior edge of the medial femoral condyle to the flush anterior cut, the mediolateral width at the transepicondylar axis, the anterior and posterior edges of the anterior chamfer, and the medial and lateral trochlear flanges. These measurements were compared between genders using independent-samples t test. The aspect ratio (a measure of the shape of the distal femur), the ratio between the anteroposterior and mediolateral dimensions, was calculated for men and women to determine whether there is a shape difference between genders. The mean aspect ratio was larger for women than for men (0.84 [range, 0.57-1.03] versus 0.81 [range, 0.066-1.34], respectively). The standard deviation and range of each measurement of size and morphology suggest variability not only between genders but also within genders. Whether the aspect ratios and variations will reflect clinically important differences in outcomes after TKA with available prostheses will require additional study.
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Project description:BackgroundThe principal aim of this study was to explore if biological differences between men and women can be explained by gendered mechanisms.MethodsWe used data from the 1958 National Child Development Study, including all the living subjects of the cohort at the outcome collection wave (44-45 years). We explored several biomarkers as outcomes: systolic blood pressure, triglycerides, LDL cholesterol, HbA1c, CRP, and cortisol. Three conceptualizations of gender have been used to define methodological strategies: (a) Gender as an individual characteristic; (b) Gender as an effect of sex on socio-behavioural characteristics; (c) Gender as an interaction between sex and the social environment, here the early-life social environment. We estimated the total effect of sex and the proportion of total effect of sex at birth eliminated by gender, measured by 3 different ways according to these 3 concepts, using g-computation.ResultsThe average level of each biomarker was significantly different according to sex at birth, higher in men for cardiometabolic biomarkers and higher in women for inflammatory and neuroendocrine biomarkers. The sizes of the differences were always smaller than one standard deviation but were larger than differences due to early-life deprivation, except for CRP. We observed gender mechanisms underlying these differences between men and women, even if the mediation effects were rarely statistically significant. These mechanisms were of three kinds: (1) mediation by socio-behavioural characteristics; (2) attenuation by gendered mechanisms; (3) interaction with early social environment. Indeed, we observed that being born into a deprived rather than non-deprived family increased metabolic and inflammatory biomarkers levels more strongly in females than in males.ConclusionsThe biological differences between men and women seem to not be purely explained by biological mechanisms. The exploration of gender mechanisms opens new perspectives, in terms of methodology, understanding and potential applications.
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Project description:Do men and women have different brains? Previous neuroimage studies sought to answer this question based on morphological difference between specific brain regions, reporting unfortunately conflicting results. In the present study, we aim to use a deep learning technique to address this challenge based on a large open-access, diffusion MRI database recorded from 1,065 young healthy subjects, including 490 men and 575 women healthy subjects. Different from commonly used 2D Convolutional Neural Network (CNN), we proposed a 3D CNN method with a newly designed structure including three hidden layers in cascade with a linear layer and a terminal Softmax layer. The proposed 3D CNN was applied to the maps of factional anisotropy (FA) in the whole-brain as well as specific brain regions. The entropy measure was applied to the lowest-level image features extracted from the first hidden layer to examine the difference of brain structure complexity between men and women. The obtained results compared with the results from using the Support Vector Machine (SVM) and Tract-Based Spatial Statistics (TBSS). The proposed 3D CNN yielded a better classification result (93.3%) than the SVM (78.2%) on the whole-brain FA images, indicating gender-related differences likely exist in the whole-brain range. Moreover, high classification accuracies are also shown in several specific brain regions including the left precuneus, the left postcentral gyrus, the left cingulate gyrus, the right orbital gyrus of frontal lobe, and the left occipital thalamus in the gray matter, and middle cerebellum peduncle, genu of corpus callosum, the right anterior corona radiata, the right superior corona radiata and the left anterior limb of internal capsule in the while matter. This study provides a new insight into the structure difference between men and women, which highlights the importance of considering sex as a biological variable in brain research.
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Project description:Help seeking (HS) is a core coping strategy that is directed towards obtaining support, advice, or assistance as means of managing stress. Women have been found to use more HS than men. Neural correlates of sex differences have also been reported in prefrontal-limbic system (PLS) regions that are linked to stress and coping, yet structural differences between men and women relating to HS in the PLS are still unknown. Thus, the association between gray matter volume (GMV) and HS was investigated using voxel-based morphometry (VBM) in a large healthy sample (126 men and 156 women). Results indicated women reported more HS than men did. VBM results showed that the relation between HS scores and GMV differed between men and women in regions of the bilateral orbitofrontal cortex extending to the subgenual anterior cingulate cortex(OFC/sgACC). Among women, higher HS scores were associated with smaller GMV in these areas while a positive correlation between GMV and HS scores was observed among men. These results remained significant after controlling for general intelligence, stress, anxiety and depression. Thus, this study suggested that structural differences between men and women are correlated to characteristic brain regions known to be involved in the PLS which is considered critical in stress regulation.
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Project description:This study explored gender differences in correct response rates and response times on a task involving left or right arrow selection and another involving the transformation of mental rotation of the hand. We recruited 15 healthy, right-handed men (age 24.5 ± 6.4) and 15 healthy, right-handed women (age 21.3 ± 4.9). For the tasks, we used pictures of left and right arrows and 32 hand pictures (left and right, palm and back) placed in cons (each at 45° from 0° to 315°). Hand and arrow pictures alternated and were shown at random. Participants decided as quickly as possible whether each picture was left or right. To compare the time taken for the transformation of mental rotation of the hand, we subtracted the average arrow response time from that for the left and right hand pictures for each participant. Correct response rates did not differ significantly between men and women or left and right for either arrow or hand pictures. Regardless of gender, the response time was longer for the left arrow picture than right arrow picture. The response time for the hand picture was longest for both men and women for pictures at rotation angles that were most difficult to align with participants' hands. While there was no difference between men's responses for left and right hand pictures, the responses of women were longer for left than right hand pictures and also than those of men. These findings suggest that both men and women mainly perform the hand mental rotation task with implicit motor imagery. On the other hand, the gender difference in performance might be explained by the difference in balance with other strategies, such as visual imagery, and by cognitive, neurophysiological, and morphological differences.
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Project description:IntroductionThis study examines whether differences exist by sex in support for specific gun policies aimed at reducing gun violence.MethodsInvestigators combined 2 waves of the National Survey of Gun Policy administered in January 2017 and January 2019. Data were analyzed in 2020. Opinions on 21 gun policies were examined. Respondents rated their support on a 5-point Likert scale ranging from strongly favor to strongly oppose. Somewhat favor and strongly favor were combined to create a dichotomous measure to indicate the proportion in favor of each policy. Respondents were categorized by their answer on the demographic profile as male or female and whether they personally owned a gun.ResultsWomen had higher levels of support than men for 20 of 21 policies, with 7 policies having a ≥10 percentage point difference in support. Differences in support between women and men who own guns were less pronounced. Only 3 of 21 policies had a ≥10 percentage point difference in support. Among women and men who do not personally own guns, 4 of 21 policies had a ≥10 percentage point difference in support.ConclusionsThis survey is the first to explore differences in public support for specific gun policies between women and men. Policy support was substantially higher among women than men and higher among gun owners who are women compared with men. These findings provide important context for understanding differences in public opinion and suggest the need to tailor messages that will resonate within demographic groups.
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Project description:Metastasis is a defining feature of malignant tumors and is the most common cause of cancer-related death, yet the genetics of metastasis are poorly understood. We used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye. Inactivating somatic mutations were identified in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin carboxyl-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. These findings implicate loss of BAP1 in uveal melanoma metastasis and suggest that the BAP1 pathway may be a valuable therapeutic target.
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Project description:Uveal melanoma (UM) represents the most frequent primary tumor of the eye. Despite the development of new drugs and screening programs, the prognosis of patients with UM remains poor and no effective prognostic biomarkers are yet able to identify high‑risk patients. Therefore, in the present study, microRNA (miRNA or miR) expression data, contained in the TCGA UM (UVM) database, were analyzed in order to identify a set of miRNAs with prognostic significance to be used as biomarkers in clinical practice. Patients were stratified into 2 groups, including tumor stage (high‑grade vs. low‑grade) and status (deceased vs. alive); differential analyses of miRNA expression among these groups were performed. A total of 20 deregulated miRNAs for each group were identified. In total 7 miRNAs were common between the groups. The majority of common miRNAs belonged to the miR‑506‑514 cluster, known to be involved in UM development. The prognostic value of the 20 selected miRNAs related to tumor stage was assessed. The deregulation of 12 miRNAs (6 upregulated and 6 downregulated) was associated with a worse prognosis of patients with UM. Subsequently, miRCancerdb and microRNA Data Integration Portal bioinformatics tools were used to identify a set of genes associated with the 20 miRNAs and to establish their interaction levels. By this approach, 53 different negatively and positively associated genes were identified. Finally, DIANA‑mirPath prediction pathway and Gene Ontology enrichment analyses were performed on the lists of genes previously generated to establish their functional involvement in biological processes and molecular pathways. All the miRNAs and genes were involved in molecular pathways usually altered in cancer, including the mitogen‑activated protein kinase (MAPK) pathway. Overall, the findings of the presents study demonstrated that the miRNAs of the miR‑506‑514 cluster, hsa‑miR‑592 and hsa‑miR‑199a‑5p were the most deregulated miRNAs in patients with high‑grade disease compared to those with low‑grade disease and were strictly related to the overall survival (OS) of the patients. However, further in vitro and translational approaches are required to validate these preliminary findings.
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