Teaching nature of science in introductory biology: Impacts on students' acceptance of biological evolution.

The present study investigates the impact of explicit, reflective Nature of Science instruction on students' evolution acceptance, understanding of evolution as a theory, and understanding of Nature of Science in an introductory biology course. Results revealed similar improvement in evolution acceptance in both the treatment and control groups, but also that Nature of Science instruction had disproportionately large impacts on evolution acceptance for women and individuals who already had high acceptance. We also found evidence of relationships between understanding and acceptance of evolution and Nature of Science understanding, particularly the creativity aspect of Nature of Science. Together, these results suggest that targeted Nature of Science instruction can have differential impacts on students with particular characteristics, such as women and individuals with high acceptance, but also point to the need to consider additional interventions that can reach men and individuals with low acceptance.

Factors Predicting the Extent to which STEM Students Value Cross-Disciplinary Skills: A Study across Four Institutions.

Expectancy-value theory of motivation (EVT) suggests that student values influence their likelihood of putting in the effort required to learn, and these values can be shaped by student characteristics, such as their experiences, sociodemographics, and disciplinary norms. To understand the extent to which these characteristics relate to students' values, we surveyed 1162 graduating science, technology, engineering, and mathematics (STEM) students across four universities using the previously developed and validated Survey of Teaching Beliefs and Practices for Undergraduates (STEP-U). The STEP-U survey included Likert questions to capture students' values of 27 cross-disciplinary skills and the frequency with which they experienced 27 instructional methods thought to develop particular skills. Exploratory factor analyses (EFA) showed an understandable factor structure for both students' perceived value of cross-disciplinary skills and frequency of classroom experiences. Using multiple regression, we identified differences in values that were associated with classroom experiences, STEM discipline, participation in undergraduate research, and student sociodemographics. Findings were generalizable across institutions and disciplines. The theoretical framework (EVT), the broad data collection (four institutions with multiple disciplines), and the type of data analyses (e.g., EFA) used provide theoretical, methodological, and practical contributions and suggest additional directions for future research.

Vulvar sarcoma outcomes by histologic subtype: a Surveillance, Epidemiology, and End Results (SEER) database review.

OBJECTIVE: Vulvar cancers account for 5% of all gynecologic malignancies; only 1%-3% of those vulvar cancers are primary vulvar sarcomas. Given the rarity of vulvar sarcomas, outcome data specific to histopathologic subtypes are sparse. The aim of this study was to identify clinical and pathologic factors of primary vulvar sarcomas that are associated with survival and may inform treatment decisions. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched for women diagnosed with vulvar sarcoma between 1973 and 2018. We identified 315 patients and reviewed their demographic, clinicopathologic, surgical, and survival information. Statistical analyses included χ2 and t-tests, Kaplan-Meier survival, and Cox regression analyses. RESULTS: The most common histopathologies of vulvar sarcomas were dermatofibrosarcomas (85/315, 27%) and leiomyosarcomas (72/315, 22.9%). Rhabdomyosarcomas (18/315, 5.7%), liposarcomas (16/315, 5.1%), and malignant fibrous histiocytomas (16/315, 5.1%) were less frequent. The majority of patients underwent surgery (292/315, 92.7%), which included lymph node dissections in 21.6% (63/292). Survival and lymph node involvement varied significantly with histologic subtype. The 5-year disease-specific survival for dermatofibrosarcomas, liposarcomas, and fibrosarcomas was 100% and only 60.3% and 62.5% for malignant fibrous histiocytomas and rhabdomyosarcomas, respectively. None of the patients with (dermato)fibrosarcomas, liposarcomas, or leiomyosarcomas had positive lymph nodes, in contrast to rhabdomyosarcomas and malignant fibrous histiocytomas with 77.8% and 40% positive lymph nodes, respectively. The 5-year disease-specific survival for women with positive lymph nodes was 0%. CONCLUSIONS: Vulvar sarcomas are heterogeneous with survival highly dependent on the histopathologic subtype. While surgical excision is the mainstay of treatment for all vulvar sarcomas, staging lymphadenectomy should be deferred for (dermato)fibrosarcomas, liposarcomas, and leiomyosarcomas as there were no cases of lymph nodes metastases.

Safety and Efficacy of Apixaban vs Enoxaparin for Preventing Postoperative Venous Thromboembolism in Women Undergoing Surgery for Gynecologic Malignant Neoplasm: A Randomized Clinical Trial.

Importance: Current guidelines recommend a 28-day course of enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The high cost of this medication and the low adherence rates observed in prior studies provide an opportunity to benefit patients by demonstrating the safety of a more cost-effective, easier to use thromboprophylactic. Objective: To investigate the safety and efficacy of an oral treatment alternative for thromboprophylaxis in postoperative patients with gynecologic cancer. Design, Setting, and Participants: This was a patient-based, multicenter, open-label, blinded, end point, randomized clinical trial conducted May 2015 to March 2019 in outpatient and inpatient gynecologic oncology settings. Women undergoing surgery for suspected or confirmed gynecologic cancer were approached for recruitment. The trial compared rates of major bleeding and clinically relevant nonmajor bleeding events during a 90-day follow-up period in patients taking apixaban or enoxaparin for postoperative thromboprophylaxis using a modified intent-to-treat analysis. Data analysis was performed from October to December 2019. Interventions: Women were randomized to 28 days of apixaban (2.5 mg orally twice daily) or enoxaparin (40 mg subcutaneously daily). Main Outcomes and Measures: The primary outcome was major bleeding and clinically relevant nonmajor bleeding events. Secondary outcomes included incidence of venous thromboembolic events, adverse events, medication adherence, participant quality of life, and medication satisfaction. Results: Of 500 women recruited for the study, 400 were enrolled and randomized (median age, 58.0 years; range, 18.0-89.0 years); 204 received apixaban and 196 received enoxaparin. Treatment groups did not differ in terms of race/ethnicity, cancer stage, or surgery modality (open vs robotic). There were no statistically significant differences between the apixaban and enoxaparin groups in terms of rates of major bleeding events (1 patient [0.5%] vs 1 patient [0.5%]; odds ratio [OR], 1.04; 95% CI, 0.07-16.76; P > .99), clinically relevant nonmajor bleeding events (12 patients [5.4%] vs 19 patients [9.7%]; OR, 1.88; 95% CI, 0.87-4.1; P = .11), venous thromboembolic events (2 patients [1.0%] vs 3 patients [1.5%]; OR, 1.57; 95% CI, 0.26-9.50; P = .68), adverse events, medication adherence, or quality of life between the groups. Participant satisfaction was significantly greater in the apixaban group with regard to ease of taking the medication (186 patients [98.9%] vs 110 patients [58.8%]; OR, 0.06; 95% CI, 0.01-0.25; P < .001) and pain associated with taking the medication (4 patients [2.1%] vs 92 patients [49.2%]; OR, 9.20; 95% CI, 2.67-31.82; P < .001). Conclusions and Relevance: These findings suggest that oral apixaban is a potentially safe, less painful, and easier-to-take alternative to subcutaneous enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The efficacy of apixaban to prevent venous thromboembolic events is hypothesized as being equivalent. Trial Registration: ClinicalTrials.gov Identifier: NCT02366871.

Female Sexual Dysfunction: Pharmacologic and Therapeutic Interventions.

Female sexual dysfunction is associated with personal distress and includes female sexual interest and arousal disorder (including former hypoactive sexual desire disorder), female orgasmic disorder, genitopelvic pain and penetration disorder, and substance- or medication-induced sexual dysfunction. These disorders are remarkably common among women, with an estimated prevalence of 20-40%. It is our responsibility as obstetrician-gynecologists to identify risk factors and screen for female sexual dysfunction. Appropriate screening allows for further exploration into sexual function and dysfunction and, ultimately, determination of associated distress. Treatment often involves addressing the underlying issue through therapy or medical management. For female sexual interest and arousal disorder, treatment generally includes cognitive behavioral therapy, often with a mindfulness focus, and consideration of pharmaceutical management. Female orgasmic disorder is treated with education and awareness, as well as therapy. Evaluation for underlying etiology is particularly critical for genitopelvic pain and penetration disorder to allow treatment of an underlying condition. Finally, substance- or medication-induced sexual dysfunction is best managed by cessation of the implicated substance and consideration of adjunctive therapy if dysfunction is related to antidepressants. Female sexual dysfunction is often overlooked in clinical practice; however, there are effective medical and psychological options for management.

Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma.

BACKGROUND: Euchromatic histone-lysine-N-methyltransferases 1 and 2 (EHMT1/2, aka GLP/G9A) catalyze dimethylation of histone H3 lysine 9 (H3K9me2) and have roles in epigenetic silencing of gene expression. EHMT1/2 also have direct roles in DNA repair and are implicated in chemoresistance in several cancers. Resistance to chemotherapy and PARP inhibitors (PARPi) is a major cause of mortality in high-grade serous ovarian carcinoma (HGSOC), but the contribution of the epigenetic landscape is unknown. RESULTS: To identify epigenetic mechanisms of PARPi resistance in HGSOC, we utilized unbiased exploratory techniques, including RNA-Seq and mass spectrometry profiling of histone modifications. Compared to sensitive cells, PARPi-resistant HGSOC cells display a global increase of H3K9me2 accompanied by overexpression of EHMT1/2. EHMT1/2 overexpression was also observed in a PARPi-resistant in vivo patient-derived xenograft (PDX) model. Genetic or pharmacologic disruption of EHMT1/2 sensitizes HGSOC cells to PARPi. Cell death assays demonstrate that EHMT1/2 disruption does not increase PARPi-induced apoptosis. Functional DNA repair assays show that disruption of EHMT1/2 ablates homologous recombination (HR) and non-homologous end joining (NHEJ), while immunofluorescent staining of phosphorylated histone H2AX shows large increases in DNA damage. Propidium iodide staining and flow cytometry analysis of cell cycle show that PARPi treatment increases the proportion of PARPi-resistant cells in S and G2 phases, while cells treated with an EHMT1/2 inhibitor remain in G1. Co-treatment with PARPi and EHMT1/2 inhibitor produces an intermediate phenotype. Immunoblot of cell cycle regulators shows that combined EHMT1/2 and PARP inhibition reduces expression of specific cyclins and phosphorylation of mitotic markers. These data suggest DNA damage and altered cell cycle regulation as mechanisms of sensitization. RNA-Seq of PARPi-resistant cells treated with EHMT1/2 inhibitor showed significant gene expression changes enriched in pro-survival pathways that remain unexplored in the context of PARPi resistance, including PI3K, AKT, and mTOR. CONCLUSIONS: This study demonstrates that disrupting EHMT1/2 sensitizes HGSOC cells to PARPi, and suggests a potential mechanism through DNA damage and cell cycle dysregulation. RNA-Seq identifies several unexplored pathways that may alter PARPi resistance. Further study of EHMT1/2 and regulated genes will facilitate development of novel therapeutic strategies to successfully treat HGSOC.

Intrauterine Device Use and Ovarian Cancer Risk: A Systematic Review and Meta-analysis.

OBJECTIVE: To explore the relationship between intrauterine device (IUD) use and risk of ovarian cancer through systematic review of the literature and meta-analysis. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, Web of Science Core Collection from inception to June 2018. For the MEDLINE search, we included the MeSH terms "intrauterine devices" AND "ovarian neoplasms," however also searching "intrauter*," "ovar*" and "fallopian tube," as well as "cancer" and "carcinoma" as keywords to include all possible variations. Similar search terms were used in the other databases. We also searched ClinicalTrials.gov. METHODS OF STUDY SELECTION: Case-control and cohort studies that collected individual level data on IUD use and ovarian cancer diagnosis were critically reviewed and data extracted. Review of abstracts from 399 articles through systematic database review and an additional 200 articles through Google Scholar identified a total of 15 studies with individual level data regarding IUD use and incident ovarian cancer. On critical review, 11 of these studies were used for meta-analysis. All case reports and reviews were excluded. TABULATION, INTEGRATION, AND RESULTS: The data were harmonized and weighted and summary odds ratios (ORs) were calculated. Covariates were identified evaluated separately. A random-effects meta-analysis was performed to confirm minimal bias. Harmonization and weighting of the data revealed an OR association between ever use of an IUD and incident ovarian cancer to be 0.68 (95% CI 0.62-0.75). There were no significant differences found between covariates. Heterogeneity among all studies was found to be I=68%. CONCLUSION: Intrauterine device use is associated with a reduced incidence of ovarian cancer based on a review of existing retrospective data. Unfortunately, prospective investigation into the role of IUDs in ovarian cancer prevention is limited.

Pre-operative opioid use in gynecologic oncology: a common comorbidity relevant to the peri-operative period.

OBJECTIVES: Pre-operative opioid use is common and should be considered a comorbidity among surgical candidates. Our objective was to describe the rate of pre-operative opioid use and patterns of post-operative outpatient opioid prescribing in a cohort of gynecologic oncology patients. METHODS: A retrospective cohort study was conducted with 448 gynecologic oncology surgical patients undergoing surgery for a suspected or known cancer diagnosis from January 2016 to December 2016. Pre-operative opioid users (n=97) were identified. Patient and surgical characteristics were abstracted, as was post-operative opioid prescription (type of opioid, oral morphine equivalents amount) and length of stay. For pre-operative opioid users, the type of opioid prescribed post-operatively was compared with the type of pre-operative opioid. Pre-operative opioid users were compared with non-users, stratified by surgery type. Descriptive statistics were analyzed using χ2 statistic, and medians were compared using a Mann-Whitney U statistic. RESULTS: Pre-operative opioid prescriptions were noted in 21% of patients, and 24% of these had two or more opioid prescriptions before surgery. The majority of pre-operative opioid users (51%) were maintained on the same agent post-operatively at the time of discharge, but 36% were switched to a different opioid and 7% were prescribed an additional opioid. Overall and in laparotomies, pre-operative opioid users received higher volume post-operative prescriptions than non-users. There was no difference in post-operative prescription volume for minimally invasive surgeries or in length of stay between pre-operative users and non-users. CONCLUSIONS: Pre-operative opioid use is common in gynecologic oncology patients and should be considered during pre-operative planning. Pre-operative opioid use was associated with a higher volume and wider range of post-operative prescription. Over 40% of opioid users were discharged with either an additional opioid or a new opioid, highlighting a potential missed opportunity to optimize opioid safety. Further research is needed to characterize the relationship between pre-operative opioid use and peri-operative outcomes and to develop strategies to manage pain effectively in this population without compromising opioid safety.

Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination.

High-grade serous ovarian cancers (HGSOCs) arise from exfoliation of transformed cells from the fallopian tube, indicating that survival in suspension, and potentially escape from anoikis, is required for dissemination. We report here the results of a multi-omic study to identify drivers of anoikis escape, including transcriptomic analysis, global non-targeted metabolomics, and a genome-wide CRISPR/Cas9 knockout (GeCKO) screen of HGSOC cells cultured in adherent and suspension settings. Our combined approach identified known pathways, including NOTCH signaling, as well as novel regulators of anoikis escape. Newly identified genes include effectors of fatty acid metabolism, ACADVL and ECHDC2, and an autophagy regulator, ULK1. Knockdown of these genes significantly inhibited suspension growth of HGSOC cells, and the metabolic profile confirmed the role of fatty acid metabolism in survival in suspension. Integration of our datasets identified an anoikis-escape gene signature that predicts overall survival in many carcinomas.

Clinical presentation of brain metastases from endometrial carcinoma: A case series.

Brain metastases from endometrial carcinoma are rare, however they do occur, and they are associated with an especially poor prognosis. There is evidence demonstrating improved outcomes with early diagnosis and subsequent multimodal treatment. This study therefore aims to review cases of brain metastases from endometrial carcinoma with specific focus on clinical presentation and disease history. This retrospective case series evaluated all cases of brain metastases from endometrial carcinoma at a single institution over a seven-year period. A medical records search was performed using ICD codes for endometrial cancer, brain lesions and brain imaging. Analysis of patient and disease characteristics was performed with descriptive statistics. Twelve cases were identified. The majority of cases had intermediate or high-grade histology (97.7%), advanced stage disease (58.3%), and at least one prior disease recurrence (66.7%). Eleven of 12 cases (91.7%) had lung metastases diagnosed prior to brain metastases. All 12 cases had neurologic signs and symptoms present at time of brain metastases diagnosis; 14 different types of neurologic deficits were noted. Headache was the most common neurologic symptom (5/12, 41.7%), followed by focal weakness (3/12, 25.0%) and aphasia (3/12, 25.0%). In conclusion, clinical presentation at time of diagnosis of brain metastases consistently includes neurologic signs and symptoms with persistent headache being the most common. Endometrial cancer patients that present with new neurologic complaints or exam findings should be evaluated for brain metastases.

CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer.

High grade serous ovarian carcinoma (HGSOC) is often diagnosed at an advanced stage. Chromobox 2 (CBX2), a polycomb repressor complex subunit, plays an oncogenic role in other cancers, but little is known about its role in HGSOC. We hypothesize that CBX2 upregulation promotes HGSOC via induction of a stem-like transcriptional profile and inhibition of anoikis. Examination of Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) established that increased CBX2 expression conveyed chemoresistance and worse disease-free and overall survival. In primary HGSOC tumors, we observed CBX2 expression was significantly elevated compared to benign counterparts. In HGSOC cell lines, forced suspension promoted CBX2 expression. Subsequently, CBX2 knockdown inhibited anchorage-independent proliferation and potentiated anoikis-dependent apoptosis. Furthermore, CBX2 knockdown re-sensitized cells to platinum-based chemotherapy. Forced suspension promoted increased ALDH activity and ALDH3A1 expression and CBX2 knockdown led to a decrease in both ALDH activity and ALDH3A1 expression. Investigation of CBX2 expression on a HGSOC tissue microarray revealed CBX2 expression was apparent in both primary and metastatic tissues. CBX2 is an important regulator of stem-ness, anoikis escape, HGSOC dissemination, and chemoresistance and potentially serves as a novel therapeutic target.

PARP inhibitors: Clinical utility and possibilities of overcoming resistance.

PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.

Adenocarcinoma With Breast/Adnexal and Upper Gastrointestinal Differentiation Arising in an Ovarian Mature Cystic Teratoma: A Case Report and Review of the Literature.

Mature cystic teratomas are the most common type of ovarian germ cell tumors. In about 1% of cases, usually among postmenopausal women, a mature cystic teratoma can undergo malignant transformation. Among malignant transformations, squamous cell carcinoma is the most common histology, comprising approximately 80% of cases. In this report, we present the unique case of a 55-yr-old woman with a pelvic mass found to be a mature cystic teratoma with malignant transformation to adenocarcinoma with breast/adnexal, upper gastrointestinal, and neuroendocrine differentiation. The predominant malignant component was the adenocarcinoma exhibiting breast/skin adnexal differentiation, which was found to involve the omentum and a right para-aortic node. We provide an in-depth review of the pathologic findings, as well as a review of the current literature on malignant transformation to adenocarcinoma. This report aims to open a conversation regarding the management of these patients, with a specific focus on the role of molecular analysis and targeted therapies.