Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.

Presumed Pathogenic Germ Line and Somatic Variants in African American Thyroid Cancer.

Background: African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA), which has been attributed to both health care disparities and possible genetic differences. We investigated the impact of both germ line and somatic variants on clinical outcome in a cohort of AA nonmedullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers. Methods: Whole-exome sequencing was performed on DNA from available blood/normal tissues (N = 37) and paired tumor samples (N = 32) collected from 37 and 29 AA NMTC patients, respectively. Variants with Combined Annotation Depletion Dependent (CADD) score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germ line or somatic variants (PPGVs/PPSVs). PPGVs/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGVs/PPSVs associated with African (AFR) ancestry were identified. Results: Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most the prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGVs/PPSVs among three patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease. Conclusion: In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that health care disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate the acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events, which could be exacerbated by therapy-induced cardiotoxicity, needs to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

A distinct P-body-like granule is induced in response to the disruption of microtubule integrity in Saccharomyces cerevisiae.

The Processing-body is a conserved membraneless organelle that has been implicated in the storage and/or decay of mRNAs. Although Processing-bodies have been shown to be induced by a variety of conditions, the mechanisms controlling their assembly and their precise physiological roles in eukaryotic cells are still being worked out. In this study, we find that a distinct subtype of Processing-body is induced in response to conditions that disrupt microtubule integrity in the budding yeast, Saccharomyces cerevisiae. For example, treatment with the microtubule-destabilizing agent, benomyl, led to the induction of these novel ribonucleoprotein granules. A link to microtubules had been noted previously and the observations here extend our understanding by demonstrating that the induced foci differ from traditional P-bodies in a number of significant ways. These include differences in overall granule morphology, protein composition, and the manner in which their induction is regulated. Of particular note, several key Processing-body constituents are absent from these benomyl-induced granules, including the Pat1 protein that is normally required for efficient Processing-body assembly. However, these novel ribonucleoprotein structures still contain many known Processing-body proteins and exhibit similar hallmarks of a liquid-like compartment. In all, the data suggest that the disruption of microtubule integrity leads to the formation of a novel type of Processing-body granule that may have distinct biological activities in the cell. Future work will aim to identify the biological activities of these benomyl-induced granules and to determine, in turn, whether these Processing-body-like granules have any role in the regulation of microtubule dynamics.

Risk Haplotypes Uniquely Associated with Radioiodine-Refractory Thyroid Cancer Patients of High African Ancestry.

BACKGROUND: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. METHODS: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R in AA patients whose primary tumor samples were available (28/55). RESULTS: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, and HRASQ61R. CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.

Active Surveillance for Papillary Thyroid Microcarcinoma: Challenges and Prospects.

Active surveillance (AS) can be considered as an alternative to immediate surgery in low-risk papillary thyroid microcarcinoma (PTMC) without clinically apparent lymph nodes, gross extrathyroidal extension (ETE), and/or distant metastasis according to American Thyroid Association. However, in the past AS has been controversial, as evidence supporting AS in the management of PTMC was scarce. The most prominent of these controversies included, the limited accuracy and utility of ultrasound (US) in the detection of ETE, malignant lymph node involvement or the advent of novel lymph node malignancy during AS, and disease progression. We summarized publications and indicated: (1) US, performer-dependent, could not accurately diagnose gross ETE or malignant lymph node involvement in PTMC. However, the combination of computed tomography and US provided more accurate diagnostic performance, especially in terms of selection sensitivity. (2) Compared to immediate surgery patients, low-risk PTMC patients had a slightly higher rate of lymph node metastases (LNM), although the overall rate for both groups remained low. (3) Recent advances in the sensitivity and specificity of imaging and incorporation of diagnostic biomarkers have significantly improved confidence in the ability to differentiate indolent vs. aggressive PTMCs. Our paper reviewed current imagings and biomarkers with initial promise to help select AS candidates more safely and effectively. These challenges and prospects are important areas for future research to promote AS in PTMC.

Dynamic edge effects in small mammal communities across a conservation-agricultural interface in Swaziland.

Across the planet, high-intensity farming has transformed native vegetation into monocultures, decreasing biodiversity on a landscape scale. Yet landscape-scale changes to biodiversity and community structure often emerge from processes operating at local scales. One common process that can explain changes in biodiversity and community structure is the creation of abrupt habitat edges, which, in turn, generate edge effects. Such effects, while incredibly common, can be highly variable across space and time; however, we currently lack a general analytical framework that can adequately capture such spatio-temporal variability. We extend previous approaches for estimating edge effects to a non-linear mixed modeling framework that captures such spatio-temporal heterogeneity and apply it to understand how agricultural land-uses alter wildlife communities. We trapped small mammals along a conservation-agriculture land-use interface extending 375 m into sugarcane plantations and conservation land-uses at three sites during dry and wet seasons in Swaziland, Africa. Sugarcane plantations had significant reductions in species richness and heterogeneity, and showed an increase in community similarity, suggesting a more homogenized small mammal community. Furthermore, our modeling framework identified strong variation in edge effects on communities across sites and seasons. Using small mammals as an indicator, intensive agricultural practices appear to create high-density communities of generalist species while isolating interior species in less than 225 m. These results illustrate how agricultural land-use can reduce diversity across the landscape and that effects can be masked or magnified, depending on local conditions. Taken together, our results emphasize the need to create or retain natural habitat features in agricultural mosaics.