Citations

The microbe-stuffed gut, rather than the genome, represents the most dynamic gene reservoir within complex, multicellular metazoa (animals). Microbes are known to confer increased metabolic efficiency, increased nutrient recovery, and tolerance of ocean acidity to basal taxa such as sponges, arguably the extant taxa most comparable to the first metazoan. We hypothesize that metazoan origins may be rooted in the capability to compartmentalize, metabolize, and exchange genetic material with a modulated microbiome. We present evidence that the most parsimonious adaptive response of clonal eukaryotic colonies experiencing oligotrophic (nutrient-limited) conditions that accompanied Neoproterozoic glaciation events, which were broadly contemporaneous with metazoan origins, is to evolve a morphological volume to harbor a densified microbiome. Dense microbial communities housed within a cavity would increase instances of horizontal gene transfer between microorganisms and host, accelerating evolutionary innovation at the genetic and epigenetic levels for the holobiont. The accelerated tempo of genetic exchange would continue until the host’s metabolic and reproductive cells became spatially and temporally segregated from one another, at which point the process is effectively suppressed with the emergence of specialized gut and reproductive tissues. This framework may lead to new, testable hypotheses regarding metazoan evolution on Earth and a more tractable means of estimating the pervasiveness of complex, multicellular animal-like life with convergent morphologies on other planets.

BackgroundQuality improvement (QI) in the management of chronic rhinosinusitis (CRS) is garnering increasing attention. Defining frameworks and metrics to assess the quality of key components in CRS management could assist in reducing unwarranted practice variation and increase high‐quality care.MethodsA panel of the American Rhinologic Society (ARS) QI committee reviewed the literature to determine important presurgical components of CRS care that warrant QI. The evidence was organized into 4 categories: (1) diagnosis, (2) medical management, (3) appropriate patient selection for surgery, and (4) patient‐centered discussion. The combination of these categories was used to develop a framework termed the CRS Appropriate Presurgical Algorithm (CAPA).ResultsPrior to offering surgery for CRS, the best available evidence support the following quality metrics: (1) a guideline‐based diagnosis should be confirmed; (2) appropriate medical management, including a minimum of topical corticosteroid therapy and saline irrigations, should have been attempted (assuming patient tolerance); (3) a computed tomography (CT) scan should be obtained (to confirm the presence of sinus inflammation and for surgical planning); and (4) a patient‐centered discussion regarding treatment options for refractory CRS (ie, alternative medical therapies vs surgery vs observation) while focusing on risks and benefits, the need for long‐term medical compliance, and understanding of patient preferences and expectations.ConclusionDefining metrics that assess key components to CRS care prior to offering surgery has the potential to further improve upon an already successful treatment paradigm, reduce unwarranted practice variation, and to ensure that patients are receiving a similar level of high‐quality care.

Abstract To assess cellular mechanisms that could contribute to muscle weakness in the context of cancer cachexia, we evaluated the effect of conditioned medium (CM) from highly tumorigenic Lewis lung carcinoma (LLC1) cells, CM from less tumorigenic MLE12 cells and non-CM on human skeletal muscle mitochondrial morphology and function. We assessed mitochondrial oxygen consumption, morphology, enzyme activity and gene expression in human skeletal muscle cells in the presence of tumor conditioned medium or control medium. We examined the secretome of LLC1 cells for mediators of skeletal muscle changes. We demonstrate that LLC1 CM inhibits cellular O2 consumption rate (OCR) and increases the proton production rate in human skeletal muscle cells. Mitochondrial fragmentation and the expression of the fission mediator, FIS1, are increased, whereas the expression of fusion mediators, OPA1 and MFN2 are reduced by LLC1 CM. LLC1 CM reduces pyruvate dehydrogenase (PDH) activity thereby limiting the production of acetyl CoA. Reduced PDH activity is associated with reduced PDHA1 sub-unit expression. The amount inactive phospho-PDH is increased in association with reduced PDP2 expression and increased PDK4 and SIRT4 expression in human skeletal muscle cells treated with LLC1 CM. The expression of several signaling pathways is altered by LLC1 CM in human skeletal muscle cells. When compared to MLE12 cells, LLC1 cells show increased expression of mRNAs encoding several potential mediators of altered muscle function such as Gdf15, TGFβ-induced protein, IL11, Il27, Il33, Il34, and PTH-like protein. We show that the active vitamin D metabolite, 1α,25(OH)2D3, that we previously demonstrated increases myoblast mitochondrial oxygen consumption and PDH activity, mitigates LLC1 CM effects on hSkMC OCR, mitochondrial fragmentation and mediators thereof. Mitochondrial oxygen consumption, morphology and enzyme activity in human skeletal muscle cells are inhibited or altered by tumor cell conditioned medium, and are reversed by 1α,25(OH)2D3, the active metabolite of vitamin D. Citation Format: Zachary C. Ryan, Theodore A. Craig, Xuewei Wang, Philippe Delmotte, Jeffrey L. Salisbury, Ian R. Lanza, Gary C. Sieck, Rajiv Kumar. 1,25-Dihydroxyvitamin D3 mitigates lung cancer cell mediated mitochondrial dysfunction in human skeletal muscle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5232.

Abstract In the United States, over 80% of prostate cancer patients die with bone metastases. Second-line hormonal therapies, such as enzalutamide, only improve overall patient survival by a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance in order to provide better treatments for prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor. Our study showed that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted subcutaneously, it had no effect on the growth of C4-2B tumors in the bone or on the development of bone lesions. These data suggested a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. To dissect the role of enzalutamide on the bone microenvironment, we treated bone cells, both osteoblasts and osteoclasts, with enzalutamide. We found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer bone metastatic tissue microarray, in which we performed immunohistochemistry and found a significant decrease of TGFBR2 expression specifically in cancer-associated osteoblasts from patients who had undergone treatment with second-line hormonal therapies, either enzalutamide or abiraterone. Statistical analysis showed that the decrease of TGFBR2 in cancer-associated osteoblasts was a causative effect from the hormonal therapies. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that loss of TGFBR2 in osteoblasts significantly promoted prostate cancer bone metastasis. Together, our data showed for the first time that reduction of TGFBR2 in osteoblasts by enzalutamide causes resistance to the drug in prostate cancer bone metastasis. Citation Format: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li. Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4898.

Objectives To investigate the impact of implementing magnetic resonance imaging (MRI) and ultrasonography fusion technology on biopsy and prostate cancer (PCa) detection rates in men presenting with clinical suspicion for PCa in the clinical practice setting. Patients and Methods We performed a review of 1 808 consecutive men referred for elevated prostate‐specific antigen (PSA) level between 2011 and 2014. The study population was divided into two groups based on whether MRI was used as a risk stratification tool. Univariable and multivariable analyses of biopsy rates and overall and clinically significant PCa detection rates between groups were performed. Results The MRI and PSA‐only groups consisted of 1 020 and 788 patients, respectively. A total of 465 patients (45.6%) in the MRI group and 442 (56.1%) in the PSA‐only group underwent biopsy, corresponding to an 18.7% decrease in the proportion of patients receiving biopsy in the MRI group ( P < 0.001). Overall PCa (56.8% vs 40.7%; P < 0.001) and clinically significant PCa detection (47.3% vs 31.0%; P < 0.001) was significantly higher in the MRI vs the PSA‐only group. In logistic regression analyses, the odds of overall PCa detection (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.29–2.35; P < 0.001) and clinically significant PCa detection (OR 2.04, 95% CI 1.48–2.80; P < 0.001) were higher in the MRI than in the PSA‐only group after adjusting for clinically relevant PCa variables. Conclusion Among men presenting with clinical suspicion for PCa, addition of MRI increases detection of clinically significant cancers while reducing prostate biopsy rates when implemented in a clinical practice setting.

OBJECTIVES: We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE). METHODS: There were 775 children with a new diagnosis of epilepsy (&lt;3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012–2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities. RESULTS: Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed. CONCLUSIONS: Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group.