Modeling Malignant Mesothelioma in Genetically Engineered Mice.

Mesothelioma is a lethal cancer of the serosal lining of the body cavities. Risk factors include environmental and genetic factors. Asbestos exposure is considered the principal environmental risk factor, but other carcinogenic mineral fibers, such as erionite, also have a causal role.

Tumor infiltrating T-cells and loss of expression of SWI/SNF genes in varying stages of clear cell renal cell carcinoma.

Background: Patients with clear cell renal cell carcinoma (ccRCC) metastases face poor prognoses, even with adjuvant therapies. Tumor-infiltrating T-cells and macrophages are critical in targeting tumor cells within the renal microenvironment. Beyond VHL mutations, loss-of-function mutations in SWI/SNF complex genes, including PBRM1, BAP1, ARID1A, SETD2, SMARCA4 (BRG1), and SMARCA2 (BRM), have been implicated in ccRCC progression.

Climate resilience and profitability thresholds in Chesapeake Bay oyster aquaculture.

Shellfish aquaculture producers in coastal systems are facing uncertain future growing conditions as climate change alters weather patterns and raises sea level. We examined expected mid-century (2059-2068) changes in aquaculture profitability from recent conditions by integrating models of climate change, estuarine hydrodynamics and biogeochemistry, oyster growth, oyster mortality, and economics, using the Chesapeake Bay, USA as a case study. We developed an economic stochastic dynamic programming (SDP) approach that generates optimal grower behavior to maximize profits under uncertainty by dynamically choosing planting density, replanting and mitigation use, in response to changing oyster stock status and water quality conditions.

Continuity of Care and Lifestyle Intervention Programs for Spanish-Speaking Immigrants Without Health Insurance at a Free Clinic in Rhode Island.

Introduction: We conducted a retrospective cohort study to evaluate changes in metabolic biomarkers among participants in Bridging the [Health Equity] Gap (BTG), a free program run by Clínica Esperanza/Hope Clinic (CEHC) for Spanish-speaking immigrants without health insurance in Rhode Island.

Methods: From July 2019 through June 2021, 471 people volunteered to participate in the BTG program. Participants enrolled in lifestyle change classes and visited quarterly with health care providers.

AKT and the Hallmarks of Cancer.

Nearly a quarter century ago, Hanahan and Weinberg conceived six unifying principles explaining how normal cells transform into malignant tumors. Their provisional set of biological capabilities acquired during tumor development-cancer hallmarks-would evolve to 14 tenets as knowledge of cancer genomes, molecular mechanisms, and the tumor microenvironment expanded, most recently adding four emerging enabling characteristics: phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes, and senescent cells. AKT kinases are critical signaling molecules that regulate cellular physiology upon receptor tyrosine kinases and PI3K activation.

First report of V1016I, F1534C and V410L kdr mutations associated with pyrethroid resistance in Aedes aegypti populations from Niamey, Niger.

Background: Ae. aegypti is the vector of important μ arboviruses, including dengue, Zika, chikungunya and yellow fever. Despite not being specifically targeted by insecticide-based control programs in West Africa, resistance to insecticides in Ae.

Targeting inflammatory factors for chemoprevention and cancer interception to tackle malignant mesothelioma.

Mesothelioma is an incurable cancer of the mesothelial lining often caused by exposure to asbestos. Asbestos-induced inflammation is a significant contributing factor in the development of mesothelioma, and genetic factors also play a role in the susceptibility to this rapidly progressive and treatment-resistant malignancy. Consequently, novel approaches are urgently needed to treat mesothelioma and prevent or reduce the overall incidence of this fatal disease.

Chesapeake DolphinWatch sightings data (2017-2022): Citizen science reports of bottlenose dolphins observed in the Chesapeake Bay, USA.

Atlantic bottlenose dolphins are extensively studied, though little has been published regarding their occurrence patterns in the large and highly urbanized estuary of the Chesapeake Bay, USA. To address this knowledge gap, the Chesapeake DolphinWatch project was initiated in the summer of 2017. Utilizing a citizen science (also known as volunteer science) methodology, members of the public were encouraged to report dolphin sightings through a specialized mobile (iOS and Android) and web-based (https://chesapeakedolphinwatch.

Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment.

Unlabelled: Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice.

Multiple Genomic Alterations, Including a Novel Fusion Gene, in a Treatment-Refractory Blastic Plasmacytoid Dendritic-Cell Neoplasm: A Case Report and Literature Review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. The genetic abnormalities in BPDCN are heterogeneous; therefore, its molecular pathogenesis and the prognostic importance of genomic alterations associated with the disease are not well defined. Here we report a case of BPDCN with a novel AFF4::IRF1 fusion predicted to lead to a loss-of-function of the IRF1 tumor suppressor, somatic mutations of ASXL1, TET2, and MYD88, as well as multiple intrachromosomal deletions.

Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities.

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality.

Isochromosome 7p, i(7)(p10): A rare AML, myelodysplasia-related entity.

We describe genomic findings in an AML case with isochromosome 7p, i(7)(p10), in which SNP array analysis uncovered an additional 7.07-Mb 20q deletion not detected by karyotyping. Several AML cases with i(7)(p10) as an isolated cytogenetic finding have been previously reported.

Interannual variability of air-water CO flux in a large eutrophic estuary.

Air-water CO fluxes in estuarine environments are characterized by high interannual variability, in part due to hydrological variability that alters estuarine carbonate chemistry through multiple physical and biogeochemical processes. To understand the relative contributions of these varied controls on interannual air-water CO fluxes in the mainstem Chesapeake Bay, we implemented both hindcast and scenario simulations using a coupled physical-biogeochemical model. Significant spatiotemporal variability in bay-wide fluxes was found over a 10-year period (1996-2005), where the mainstem Bay was primarily a net CO sink, except in drought periods.

"Stapling" scFv for multispecific biotherapeutics of superior properties.

Single-chain fragment variable (scFv) domains play an important role in antibody-based therapeutic modalities, such as bispecifics, multispecifics and chimeric antigen receptor T cells or natural killer cells. However, scFv domains exhibit lower stability and increased risk of aggregation due to transient dissociation ("breathing") and inter-molecular reassociation of the two domains (VL and VH). We designed a novel strategy, referred to as stapling, that introduces two disulfide bonds between the scFv linker and the two variable domains to minimize scFv breathing.

The Circle Method: A Novel Approach to Clinical Ethics Consultation.

AbstractDifferent methods are available in clinical ethics consultation. In our experience as ethics consultants, certain individual methods have proven insufficient, and so we use a combination of methods. Based on these considerations, we first critically analyze the pros and cons of two well-known methods in the working field of clinical ethics, namely Beauchamp and Childress's four-principle approach and Jonsen, Siegler, and Winslade's four-box method.

Decoupling of Estuarine Hypoxia and Acidification as Revealed by Historical Water Quality Data.

Hypoxia and acidification are commonly coupled in eutrophic aquatic environments because aerobic respiration is usually dominant in bottom waters and can lower dissolved oxygen (DO) and pH simultaneously. However, the degree of coupling, which can be weakened by non-aerobic respiration and CaCO cycling, has not been adequately assessed. In this study, we applied a box model to 20 years of water quality monitoring data to explore the relationship between hypoxia and acidification along the mainstem of Chesapeake Bay.

A hydrodynamic model-based approach to assess sampling approaches for dissolved oxygen criteria in the Chesapeake Bay.

Technological advances in water quality measurement systems have provided the potential to expand high-frequency observations into coastal monitoring programs. However, with limited resources for monitoring budgets in natural waters that exhibit high temporal and spatial variability in water quality, there is a need to identify the locations and time periods where these new technologies can be deployed for maximum efficacy. To advance the capacity to make quantitative and objective decisions on the selection of monitoring locations and sampling frequency, we combined high-resolution numerical model simulations and multi-frequency water quality measurements to conduct a power analysis comparing alternative sampling designs in the assessment of water quality in the Chesapeake Bay.

Isolated Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response.

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) , , and are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown.

Data supporting the roles of BAP1, STING, and IFN-β in ISGF3 activation in ccRCC.

The data presented in this article are companion materials to our manuscript titled "BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma" (Langbein et al., 2022), where we investigated the downstream effects of BAP1 (BRCA1-associated protein 1) expression in clear cell renal cell carcinoma (ccRCC) cell lines and mouse xenograft models. In the manuscript, we showed that BAP1 upregulates STING (stimulator of interferon genes) expression and activity in ccRCC cells, leading to IFN-β transcription and activation of interferon stimulated gene factor 3 (ISGF3), the transcription factor that mediates the effects of type I interferons (IFNs).