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Persistent organic pollutants (POPs) are highly lipophilic compounds that accumulate at increased concentrations in high tropic level organisms like marine mammals. Marine mammals' reliance on blubber makes them susceptible to accumulating POPs at potentially toxic concentrations. In this study, we analyzed POP concentrations, (polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and methoxylated-BDE (MeOBDE), in the blubber of 16 subsistence harvested sub-adult, male northern fur seals as well as assessed changes in mRNA gene expression of nine relevant biomarkers including the aryl hydrocarbon receptor, thyroid receptor-α, and adiponectin. PBDE and MeOBDE concentrations were significantly lower than PCB and OCP concentrations. A negative relationship was observed between percent lipid in the blubber and contaminant concentrations, both individual and sum. Expression changes in eight biomarkers were correlated with individual and sum contaminant concentrations. This study shows that contaminant concentrations measured are correlated to changes in expression of genes from different physiological systems, metabolism and endocrine, that are important for the regulation of blubber metabolism. Northern fur seals are reliant on blubber as an energy source during times of low food intake. Potential contaminant induced changes in blubber metabolism pathways could have significant impacts on the health of individuals during critical periods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Episodes of Quaternary environmental change shaped the genomes of extant species, influencing their response to contemporary environments, which are changing rapidly. Island endemics are among the most vulnerable to such change, accounting for a disproportionate number of recent extinctions. To prevent extinctions and conserve island biodiversity it is vital to combine knowledge of species' ecologies with their complex evolutionary histories. The Bering Sea has a history of cyclical island isolation and reconnection, coupled with modern rates of climate change that exceed global averages. The endangered Pribilof Island shrew (Sorex pribilofensis) is endemic to St. Paul Island, Alaska, which was isolated from mainland Beringia ~14,000 years ago by rising sea levels. Using ~11,000 single nucleotide polymorphisms, 17 microsatellites and mitochondrial sequence data, we test predictions about the evolutionary processes driving shrew speciation across Beringia. Our data show considerable differentiation of S. pribilofensis from mainland sibling species, relative to levels of divergence between mainland shrews. We also find a genome-wide loss of diversity and extremely low N e for S. pribilofensis. We then show that intraspecific genetic diversity is significantly related to interspecific divergence, and that differentiation between S. pribilofensis and other Beringian shrews is highest across loci that are fixed in S. pribilofensis, indicating that strong drift has driven differentiation of this island species. Our findings show that drift as a consequence of Arctic climate cycling can rapidly reshape insular biodiversity. Arctic island species that lack genomic diversity and have evolved in response to past climate may have limited ability to respond to modern environmental changes., (© 2022 John Wiley & Sons Ltd.)

Between 2014 and 2017, widespread seabird mortality events were documented annually in the Bering and Chukchi seas, concurrent with dramatic reductions of sea ice, warmer than average ocean temperatures, and rapid shifts in marine ecosystems. Among other changes in the marine environment, harmful algal blooms (HABs) that produce the neurotoxins saxitoxin (STX) and domoic acid (DA) have been identified as a growing concern in this region. Although STX and DA have been documented in Alaska (US) for decades, current projections suggest that the incidence of HABs is likely to increase with climate warming and may pose a threat to marine birds and other wildlife. In 2017, a multispecies die-off consisting of primarily Northern Fulmars (Fulmarus glacialis) and Short-tailed Shearwaters (Ardenna tenuirostris) occurred in the Bering and Chukchi seas. To evaluate whether algal toxins may have contributed to bird mortality, we tested carcasses collected from multiple locations in western and northern Alaska for STX and DA. We did not detect DA in any samples, but STX was present in 60% of all individuals tested and in 88% of Northern Fulmars. Toxin concentrations in Northern Fulmars were within the range of those reported from other STX-induced bird die-offs, suggesting that STX may have contributed to mortalities. However, direct neurotoxic action by STX could not be confirmed and starvation appeared to be the proximate cause of death among birds examined in this study., (© Wildlife Disease Association 2021.)

The state of Alaska is experiencing increased coastal erosion due to climatic changes that threaten shoreline, infrastructure, and Alaska Native ways of life. While several Alaska Native villages have been impacted by severe erosion, additional communities face burgeoning erosion concerns. St. Paul, a remote island located in the Bering Sea, Alaska, and home to ~450 Unangan, or Aleut, residents, is experiencing relatively new erosion and associated flooding issues. This study aimed to inform St. Paul's erosion monitoring and climate adaptation strategies by documenting community perceptions of coastal erosion as an ecological and social threat within a broader context of multiple established climate stressors. We interviewed 21 residents to answer: (1) what are the community's perceptions of erosion on St. Paul in the context of the island's other environmental concerns?; (2) do current perceptions of erosion affect how local governing and management entities address erosion impacts?; and (3) how does erosion relate to and impact Unangan cultural traditions and heritage? Residents identified six locations of primary concern, owing to how erosion of those areas impact their culture, subsistence practices, and sense of place. We suggest methods in which local entities can better support proactive climate adaptation and mitigation measures and utilize resources for community-driven adaption planning. By documenting perspectives in Indigenous communities on emergent climate impacts, as well as perceptions of adaptation planning and implementation, it can establish the foundation for more collaborative, culturally relevant, and successful community-driven climate adaptation planning.

Mass mortality events are increasing in frequency and magnitude, potentially linked with ongoing climate change. In October 2016 through January 2017, St. Paul Island, Bering Sea, Alaska, experienced a mortality event of alcids (family: Alcidae), with over 350 carcasses recovered. Almost three-quarters of the carcasses were unscavenged, a rate much higher than in baseline surveys (17%), suggesting ongoing deposition and elevated mortality around St Paul over a 2-3 month period. Based on the observation that carcasses were not observed on the neighboring island of St. George, we bounded the at-sea distribution of moribund birds, and estimated all species mortality at 3,150 to 8,800 birds. The event was particularly anomalous given the late fall/winter timing when low numbers of beached birds are typical. In addition, the predominance of Tufted puffins (Fratercula cirrhata, 79% of carcass finds) and Crested auklets (Aethia cristatella, 11% of carcass finds) was unusual, as these species are nearly absent from long-term baseline surveys. Collected specimens were severely emaciated, suggesting starvation as the ultimate cause of mortality. The majority (95%, N = 245) of Tufted puffins were adults regrowing flight feathers, indicating a potential contribution of molt stress. Immediately prior to this event, shifts in zooplankton community composition and in forage fish distribution and energy density were documented in the eastern Bering Sea following a period of elevated sea surface temperatures, evidence cumulatively suggestive of a bottom-up shift in seabird prey availability. We posit that shifts in prey composition and/or distribution, combined with the onset of molt, resulted in this mortality event., Competing Interests: The authors have declared that no competing interests exist.

The mesenchymal gene program has been shown to promote the metastatic progression of ovarian cancer; however, specific proteins induced by this program that lead to these metastatic behaviors have not been identified. Using patient derived tumor cells and established human ovarian tumor cell lines, we find that the Epithelial-to-Mesenchymal Transition inducing factor TWIST1 drives expression of discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase (RTK) that recognizes fibrillar collagen as ligand. The expression and action of DDR2 was critical for mesothelial cell clearance, invasion and migration in ovarian tumor cells. It does so, in part, by upregulating expression and activity of matrix remodeling enzymes that lead to increased cleavage of fibronectin and spreading of tumor cells. Additionally, DDR2 stabilizes SNAIL1, allowing for sustained mesenchymal phenotype. In patient derived ovarian cancer specimens, DDR2 expression correlated with enhanced invasiveness. DDR2 expression was associated with advanced stage ovarian tumors and metastases. In vivo studies demonstrated that the presence of DDR2 is critical for ovarian cancer metastasis. These findings indicate that the collagen receptor DDR2 is critical for multiple steps of ovarian cancer progression to metastasis, and thus, identifies DDR2 as a potential new target for the treatment of metastatic ovarian cancer.

Objectives: To evaluate the effect of palliative care (PC) consultation on hospice enrollment and end-of-life care in gynecologic oncology patients., Methods: A retrospective chart review of gynecologic oncology patients who died 1year before and after 2014 implementation of a PC initiative for patients at a single NCI-designated comprehensive cancer center. Patient demographics, admission and procedural history, anti-cancer therapy, and end-of- life care were collected retrospectively. Data was analyzed using Student's t-test, Mann-Whitney U test, Chi-Square test, or Fisher's exact test., Results: We identified 308 patients. Median age at death was 63years (range 17 to 91). Most patients were white (78.2%), married (47.4%), and had ovarian (35.7%) or uterine cancers (35.4%). Introduction of the PC initiative was associated with increased PC consultations (40%, 53%, p=0.02), increased hospice enrollment (57%, 61%, p=0.29), and fewer procedures in the last 30days of life (44%, 31%, p=0.01). The rate of enrollment to inpatient hospice doubled from 12.5% to 25.7% (p=0.02) while time from inpatient hospice enrollment to death increased from 1.9 to 6.0days (p=0.02). Time from outpatient hospice enrollment to death increased from 26.2 to 35.4days (p=0.18). PC consultation was associated with a doubling of outpatient (40%) and inpatient (80%) hospice enrollment., Conclusions: The PC quality improvement initiative was associated with more palliative care consults, increased rates of inpatient and outpatient hospice utilization, increased time on hospice, and fewer procedures in the last 30days of life, although most women were not enrolled until the last days of life., (Copyright © 2017. Published by Elsevier Inc.)

Objective: The optimal strategy for adjuvant therapy in stage IIIC endometrial cancer has not been determined. Our aim was to evaluate survival benefit of different treatments and to investigate if benefit varied by histologic grade., Methods: We identified 199 patients with stage IIIC endometrial cancer from 2000 to 2012 through the Siteman Cancer Center registry. All patients underwent surgical staging followed by no adjuvant therapy (NAT), radiation (RT), chemotherapy (CT) or chemoradiation (CRT). The association between adjuvant treatment and overall survival was explored using Kaplan-Meier plots and multivariable Cox regression analysis. Multivariable analysis was stratified by low- or high-grade to explore the interaction between grade and treatment., Results: Most patients received CRT (50.3%) followed by CT (23.1%), RT (16.1%) and NAT (10.5%). Survival after CRT was superior to NAT (p<0.001), RT (p=0.010) and CT (p<0.001). After adjusting for covariates, treatment with RT, CT and CRT led to a 57% (p=0.024), 62% (p=0.003) and 83% (p<0.001) reduction in risk of death compared to NAT, respectively. With CRT as the reference, the adjusted hazard of death was higher with NAT (5.94, p<0.001), RT (2.56, p=0.009) and CT (2.24, p=0.004). Stratifying by grade, RT and CRT led to a 67% (p=0.039) and 85% (p<0.001) reduction in death, compared to NAT in low-grade patients. CT and CRT led to a 72% (p=0.003) and 83% (p<0.001) reduction in death, compared to NAT in high-grade patients., Conclusions: Our findings suggest that CRT should be the preferred adjuvant treatment strategy for patients with stage IIIC endometrial cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.

Objective: No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment., Methods: This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations)., Results: On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival., Conclusions: Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases., Competing Interests: Dr. Hagemann reports that research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. All other authors have nothing to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine the costs and outcomes of inguinal-femoral lymph node dissection (IF-LND) versus sentinel lymph node biopsy (SLNB) for the management of early-stage vulvar cancer., Methods: A cost-effectiveness model compared 2 different strategies for the management of early-stage vulvar cancer: (1) vulvectomy and SLNB and (2) vulvectomy and IF-LND. Probabilities of inguinal-femoral node metastases and recurrence rates associated with each strategy were estimated from published data. Actual payer costs of surgery and radiation therapy were obtained using 2012 CPT codes and Medicare payment information. Rates and costs of postoperative complications including lymphedema, lymphocyst formation, and infection were estimated and included in a separate model. Cost-effectiveness ratios were determined for each strategy. Sensitivity analyses were performed to evaluate pertinent uncertainties in the models., Results: For the estimated 3000 women diagnosed annually with early-stage vulvar cancer in the United States, the annual cost of the SLNB strategy is $65.2 million compared with $76.8 million for the IF-LND strategy. Three-year inguinal-femoral recurrence-free survival was similar between groups (96.9% vs 97.3%). This translates into a lower cost-effectiveness ratio for the SLNB strategy ($22,416), compared with the IF-LND strategy ($26,344). When adding complication costs to the model, cost-effectiveness ratios further favor the SLNB strategy ($23,711 vs $31,198). Sensitivity analysis revealed that the SLNB strategy remained cost-effective until the recurrence rate after a negative sentinel lymph node approaches 9%., Conclusions: Sentinel lymph node biopsy is the most cost-effective strategy for the management of patients with early-stage vulvar cancer due to lower treatment costs and lower costs due to complications.

Human pappilomavirus (HPV) has been recognized as the most common sexually transmitted disease in the world and over 100 different HPV types have been identified. Persistent HPV infection has been closely linked to the development of invasive cervical cancer. Although surgical and ablative therapies have been the mainstay of treatment, vaccination against the main oncogenic type of HPV is a reasonable preventive strategy for HPV-induced cervical cancer.