Epidemiology of ovarian cancer： a review Reid, Brett M; Permuth, Jennifer B; Sellers, Thomas A
Cancer biology & medicine,
02/2017, Letnik:
14, Številka:
1
Journal Article
Recenzirano
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Ovarian cancer （OC） is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five ...major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.
Epidemiology of Ovarian Cancer Permuth-Wey, Jennifer; Sellers, Thomas A.
Cancer Epidemiology,
2009, Letnik:
472
Book Chapter, Journal Article
Ovarian cancer represents the sixth most commonly diagnosed cancer among women in the world, and causes more deaths per year than any other cancer of the female reproductive system. Despite the high ...incidence and mortality rates, the etiology of this disease is poorly understood. Established risk factors for ovarian cancer include age and having a family history of the disease, while protective factors include increasing parity, oral contraceptive use, and oophorectomy. Lactation, incomplete pregnancies, and surgeries such as hysterectomy and tubal ligation may confer a weak protective effect against ovarian cancer. Infertility may contribute to ovarian cancer risk among nulliparous women. Other possible risk factors for ovarian cancer include postmenopausal hormone-replacement therapy and lifestyle factors such as cigarette smoking and alcohol consumption. Many of the causes of ovarian cancer are yet to be identified. Additional research is needed to better understand the etiology of this deadly disease.
Abstract
Conditional degron tags (CDTs) are a powerful tool for target validation that combines the kinetics and reversible action of pharmacological agents with the generalizability of genetic ...manipulation. However, successful design of a CDT fusion protein often requires a prolonged, ad hoc cycle of construct design, failure, and re-design. To address this limitation, we report here a system to rapidly compare the activity of five unique CDTs: AID/AID2, IKZF3d, dTAG, HaloTag, and SMASh. We demonstrate the utility of this system against 16 unique protein targets. We find that expression and degradation are highly dependent on the specific CDT, the construct design, and the target. None of the CDTs leads to efficient expression and/or degradation across all targets; however, our systematic approach enables the identification of at least one optimal CDT fusion for each target. To enable the adoption of CDT strategies more broadly, we have made these reagents, and a detailed protocol, available as a community resource.
Inferring the locomotor behaviour of the last common ancestor (LCA) of humans and African apes is still a divisive issue. An African great-ape-like ancestor using knuckle-walking is still the most ...parsimonious hypothesis for the LCA, despite diverse conflicting lines of evidence. Crucial to this hypothesis is the role of the centrale in the hominoid wrist, since the fusion of this bone with the scaphoid is among the clearest morphological synapomorphies of African apes and hominins. However, the exact functional significance of this fusion remains unclear. We address this question by carrying out finite element simulations of the hominoid wrist during knuckle-walking by virtually generating fused and unfused morphologies in a sample of hominoids. Finite element analysis was applied to test the hypothesis that a fused scaphoid-centrale better withstands the loads derived from knuckle-walking. The results show that fused morphologies display lower stress values, hence supporting a biomechanical explanation for the fusion as a functional adaptation for knuckle-walking. This functional interpretation for the fusion contrasts with the current inferred positional behaviour of the earliest hominins, thus suggesting that this morphology was probably retained from an LCA that exhibited knuckle-walking as part of its locomotor repertoire and that was probably later exapted for other functions.
We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case ...patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval CI = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.
Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It ...has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1 ᴱᴷ) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1 ⁿᵘˡˡ) mouse. In contrast to Exo1 ⁿᵘˡˡ/ⁿᵘˡˡ mice, Exo1 ᴱᴷ/ᴱᴷ mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1 -mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1 ⁿᵘˡˡ mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo.
NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic ...potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer’s disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12–20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments.
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•AD and DS mice display aberrant 12- to 20-Hz oscillations associated with epileptic spikes•GluN2A-NMDAR enhancement reduces aberrant oscillations and spikes in AD and DS mice•Chronic GluN2A-NMDAR activation improves cognitive functions in AD and DS mice•GluN2A PAMs could benefit brain disorders with hypersynchrony and cognitive deficits
Hanson et al. examine the therapeutic effects of enhancing GluN2A-subunit-containing NMDAR function in Dravet syndrome and Alzheimer’s disease mice. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in both disease models. GluN2A NMDAR enhancers may benefit brain disorders with network hypersynchrony and cognitive impairments.
Purpose: A meta-analytic approach was used to estimate the frequency of: ( a ) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and ( b ) various histologic subtypes of ...mismatch repair (MMR)-deficient epithelial ovarian cancers.
Methods: A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966,
and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample
size, MSI-H frequency, and histology of MMR-deficient ovarian tumors.
Results: The pooled proportion of MSI-H ovarian cancers was 0.12 95% confidence interval (CI), 0.08-0.17 from 18 studies with 977
cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95%
CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI,
0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies.
Conclusions: The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem
to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians
in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications
for medical management.
The talus is one of the most commonly preserved post-cranial elements in the platyrrhine fossil record. Talar morphology can provide information about postural adaptations because it is the ...anatomical structure responsible for transmitting body mass forces from the leg to the foot. The aim of this study is to test whether the locomotor behaviour of fossil Miocene platyrrhines could be inferred from their talus morphology. The extant sample was classified into three different locomotor categories and then talar strength was compared using finite-element analysis. Geometric morphometrics were used to quantify talar shape and to assess its association with biomechanical strength. Finally, several machine-learning (ML) algorithms were trained using both the biomechanical and morphometric data from the extant taxa to infer the possible locomotor behaviour of the Miocene fossil sample. The obtained results show that the different locomotor categories are distinguishable using either biomechanical or morphometric data. The ML algorithms categorized most of the fossil sample as arboreal quadrupeds. This study has shown that a combined approach can contribute to the understanding of platyrrhine talar morphology and its relationship with locomotion. This approach is likely to be beneficial for determining the locomotor habits in other fossil taxa.
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