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Abstract Clinically, the body mass index remains the most frequently used metric of overall obesity, although it is flawed by its inability to account for different adipose (i.e., visceral, subcutaneous, and inter/intramuscular) compartments, as well as muscle mass. Numerous prior studies have demonstrated linkages between specific adipose or muscle compartments to outcomes of multiple diseases. Although there are no universally accepted standards for body composition measurement, many studies use a single slice at the L3 vertebral level. In this study, we use computed tomography (CT) studies from patients in The Cancer Genome Atlas (TCGA) to compare current L3-based techniques with volumetric techniques, demonstrating potential limitations with level-based approaches for assessing outcomes. In addition, we identify gene expression signatures in normal kidney that correlate with fat and muscle body composition traits that can be used to predict sex-specific outcomes in renal cell carcinoma.

Purpose: Proton therapy (PT) for partial breast irradiation (PBI) in early-stage breast cancer can decrease morbidity versus photon PBI with superior organs-at-risk sparing. We report 3-year outcomes of the first prospective, multicenter, phase II trial of proton PBI. Methods and Materials: This Proton Collaborative Group phase II trial (PCG BRE007-12) recruited women ≥ 50 years with node-negative, estrogen receptor (ER)-positive, ≤3cm, invasive ductal carcinoma (IDC) or ductal carcinoma in situ undergoing breast conserving surgery followed by proton PBI (40 Gy(RBE), 10 daily fractions). Primary endpoint was freedom from ipsilateral breast cancer recurrence. Adverse events were prospectively graded using CTCAEv4.0. Breast Cancer Treatment Outcome Scale (BCTOS) assessed patient-reported quality of life (PRQOL). Results: Thirty-eight evaluable patients enrolled between 2/2013–11/2016. Median age was 67 years (range 50–79); 55 % had left-sided disease, and median tumor size was 0.9 cm. Treatment was delivered in ≥ 2 fields predominantly with uniform scanning PT (n = 37). At 35-month median follow-up (12–62), all patients were alive, and none had local, regional or distant disease progression. One patient developed an ER-negative contralateral IDC. Seven grade 2 adverse events occurred; no radiotherapy-related grade ≥ 3 toxicities occurred. Changes in BCTOS subdomain mean scores were maximum 0.36, indicating no meaningful change in PRQOL. Median heart volume receiving 5 Gy (V5Gy), lung V20Gy, and lung V10Gy were 0 %, 0 % and 0.19 %, respectively. Conclusion: At 3 years, proton PBI provided 100 % cancer control for early-stage, ER-positive breast cancer. Toxicities are minimal, and PRQOL remains acceptable with continued follow-up. These findings support PT as a safe and effective PBI delivery option.

Sessile marine invertebrate (biofouling) communities have served as an important model in ecology for evaluating fundamental patterns and processes, including invasion dynamics, which vary at broad spatial and temporal scales. Here, we tested for differences in biofouling community development among three biogeographically distinct bays in North America (Chesapeake Bay, Tampa Bay, and San Francisco Bay), exploring possible explanations for differential non-native species success. In particular, we aimed to examine if San Francisco Bay (a global hotspot for non-native species richness) differed in composition and space occupation, especially since open space can facilitate colonization. Additionally, we explored how biogeography, assembly and succession dynamics over the short and long term, and space availability affect marine communities across broad spatial scales. Patterns of community assembly differed among bays, with more bare space and less secondary cover (species settling on species) in San Francisco Bay. San Francisco Bay was also distinguished by a higher percent cover of Tunicata (almost all of which are non-native and historically absent) over multiple time scales. Cirripedia recruited on bare panels in all three Bays but cover increased only in Tampa Bay, as soak time increased. Tube-dwelling Polychaeta distinguished Chesapeake Bay from Tampa Bay and San Francisco Bay. Low-salinity events temporarily restructured the communities in all three bays. Whether differences among bays reflect coastal versus bay-specific patterns remains to be tested.

The pathogenic yeast Cryptococcus neoformansC. neoformans

Long-term measurements are imperative to detect, understand, and predict changes in coastal biological communities, but can be both costly and difficult to implement. Here, we compare measurement methods used to document community structure and assess changes in marine systems, and explore potential applications in citizen science. The use of photographs for species identifications and monitoring has become a popular and useful data collection tool, but its use requires evaluation of its effectiveness in comparison to data collected from live examinations. We used settlement panels in San Francisco Bay, a well-studied and vital coastal ecosystem, to compare standardized measures of the invertebrate fouling community through examination of live organisms in the field and via photographs. Overall, our study found that live measurements were more accurate and better represented these marine communities, having higher richness, and diversity measurements than photographic measurements. However, photographic analyses accurately captured the relative abundances of some species and functional groups. We suggest that highly recognizable target taxa or broad scale comparisons of functional group composition are easily tracked through photographs and offer the best potential for research conducted by citizen scientists.

ABSTRACT Cryptococcus neoformans kills 200,000 people worldwide each year. After inhalation, this environmental yeast proliferates either extracellularly or within host macrophages. Under conditions of immunocompromise, cryptococci disseminate from the lungs to the brain, causing a deadly meningoencephalitis that is difficult and expensive to treat. Cryptococcal adaptation to the harsh lung environment is a critical first step in its pathogenesis, and consequently a compelling topic of study. This adaptation is mediated by a complex transcriptional program that integrates cellular responses to environmental stimuli. Although several key regulators in this process have been examined, one that remains understudied in C. neoformans is the Mediator complex. In other organisms, this complex promotes transcription of specific genes by increasing assembly of the RNA polymerase II preinitiation complex. We focused on the Kinase Module of Mediator, which consists of cyclin C (Ssn801), cyclin-dependent kinase 8 (Cdk8), Med12, and Med13. This module provides important inhibitory control of Mediator complex assembly and activity. Using transcriptomics, we discovered that Cdk8 and Ssn801 together regulate cryptococcal functions such as the ability to grow on acetate and the response to oxidative stress, both of which were experimentally validated. Deletion of CDK8 yielded altered mitochondrial morphology and the dysregulation of genes involved in oxidation-reduction processes. This strain exhibited increased susceptibility to oxidative stress, resulting in an inability of mutant cells to proliferate within phagocytes, decreased lung burdens, and attenuated virulence in vivo. These findings increase our understanding of cryptococcal adaptation to the host environment and its regulation of oxidative stress resistance and virulence. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that primarily affects severely immunocompromised patients, resulting in 200,000 deaths every year. This yeast occurs in the environment and can establish disease upon inhalation into the lungs of a mammalian host. In this harsh environment it must survive engulfment by host phagocytes, including the oxidative stresses it experiences inside them. To adapt to these challenging conditions, C. neoformans deploys a variety of regulatory proteins to alter gene expression levels and enhance its ability to survive. We have elucidated the role of a protein complex that regulates the cryptococcal response to oxidative stress, survival within phagocytes, and ability to cause disease. These findings are important because they advance our understanding of cryptococcal disease, which we hope will help in the efforts to control this devastating infection.

ABSTRACT Mitochondria are essential organelles that act in pathways including ATP production, β-oxidation, and clearance of reactive oxygen species. They occur as a complex reticular network that constantly undergoes fusion and fission, mediated by dynamin-related proteins (DRPs). DRPs include Fzo1, which mediates fusion, and Dnm1, Mdv1, and Fis1, which mediate fission. Mitochondrial morphology has been implicated in virulence in multiple fungi, as with the association between virulence and increased mitochondrial fusion in Cryptococcus gattii. This relationship, however, has not been studied in Cryptococcus neoformans, a related opportunistic pathogen. C. neoformans is an environmental yeast that can adapt to the human host environment, overcome the innate immune system, and eventually disseminate and cause lethal meningoencephalitis. We used gene deletion of key DRPs to study their role in mitochondrial morphology and pathogenesis of this yeast. Interestingly, increasing mitochondrial fusion did not increase resistance to oxidative stress, unlike in model yeast. Blocking mitochondrial fusion, however, yielded increased susceptibility to oxidative and nitrosative stresses as well as complete avirulence. This lack of virulence was not mediated by any effects of altered mitochondrial function on two major virulence factors, capsule and melanin. Instead, it was due to decreased survival within macrophages, which in turn was a consequence of increased susceptibility to oxidative and nitrosative stress. Supporting this conclusion, reactive oxygen species (ROS) scavengers rescued the ability of fusion mutants to survive intracellularly. These findings increase our understanding of cryptococcal biology and virulence and shed light on an important group of proteins and cellular processes in this pathogen. IMPORTANCE C. neoformans is a yeast that causes fatal brain infection in close to 200,000 people worldwide every year, mainly afflicting individuals with AIDS or others who are severely immunocompromised. One feature of this microbe that helps it cause disease is that it is able to withstand toxic molecules it encounters when host cells engulf it in their efforts to control the infection. Mitochondria are important organelles responsible for energy production and other key cellular processes. They typically exist in a complex network that changes morphology by fusing and dividing; these alterations also influence mitochondrial function. Using genetic approaches, we found that changes in mitochondrial morphology dramatically influence cryptococcal virulence. We showed that this occurs because the altered mitochondria are less able to eliminate the harmful molecules that host cells produce to kill invading microbes. These findings are important because they elucidate fundamental biology and virulence and may suggest avenues for therapy.

Background/objectivesThe Pediatric Proton Consortium Registry (PPCR) was established to expedite proton outcomes research in the pediatric population requiring radiotherapy. Here, we introduce the PPCR as a resource to the oncology community and provide an overview of the data available for further study and collaboration.Design/methodsA multi-institutional registry of integrated clinical, dosimetric, radiographic, and patient-reported data for patients undergoing proton radiation therapy was conceived in May 2010. Massachusetts General Hospital began enrollment in July of 2012. Subsequently, 12 other institutions joined the PPCR and activated patient accrual, with the latest joining in 2017. An optional patient-reported quality of life (QoL) survey is currently implemented at six institutions. Baseline health status, symptoms, medications, neurocognitive status, audiogram findings, and neuroendocrine testing are collected. Treatment details of surgery, chemotherapy, and radiation therapy are documented and radiation plans are archived. Follow-up is collected annually. Data were analyzed 25 September, 2017.ResultsA total of 1,854 patients have consented and enrolled in the PPCR from October 2012 until September 2017. The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents. Central nervous system (CNS) tumors comprise 61% of the cohort. The most common CNS histologies are as follows: medulloblastoma (n = 276), ependymoma (n = 214), glioma/astrocytoma (n = 195), craniopharyngioma (n = 153), and germ cell tumors (n = 108). The most common non-CNS tumors diagnoses are as follows: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and neuroblastoma (n = 55). The median follow-up is 1.5 years with a range of 0.14 to 4.6 years.ConclusionA large prospective population of children irradiated with proton therapy has reached a critical milestone to facilitate long-awaited clinical outcomes research in the modern era. This is an important resource for investigators both in the consortium and for those who wish to access the data for academic research pursuits.

In order to explore biotic attraction to structure, we examined how the amount and arrangement of artificial biotic stalks affected responses of a shrimp, Palaemon macrodactylus, absent other proximate factors such as predation or interspecific competition. In aquaria, we tested the effect of differing densities of both un-branched and branched stalks, where the amount of material in the branched stalk equaled four-times that of the un-branched. The results clearly showed that it was the amount of material, not how it was arranged, that elicited responses from shrimp. Also, although stalks were not purposefully designed to mimic structural elements found in nature, they did resemble biogenic structure such as hydroids, algae, or plants. In order to test shrimp attraction to a different, perhaps more unfamiliar habitat type, we examined responses to plastic “army men.” These structural elements elicited similar attraction of shrimp, and, in general, shrimp response correlated well with the fractal dimension of both stalks and army men. Overall, these results indicate that attraction to physical structure, regardless of its nature, may be an important driver of high abundances often associated with complex habitats.

The early stages of biological invasions are rarely observed, but can provide significant insight into the invasion process as well as the influence vectors have on invasion success or failure.We characterized three newly discovered populations of an introduced gastropod, Littorina littorea (Linné, 1758), in California, USA, comparing them to potential source populations in native Europe and the North American East Coast, where the snail is also introduced. Demographic surveys were used to assess spatial distribution and sizes of the snail in San Francisco and Anaheim Bays, California. Mitochondrial DNA was sequenced and compared among these nascent populations, and various populations from the North American East Coast and Europe, to characterize the California populations and ascertain their likely source. Demographic and genetic data were considered together to deduce likely vectors for the California populations. We found that the three large California L. littorea populations contained only adult snails and had unexpectedly high genetic diversity rather than showing an extreme bottleneck as typically expected in recent introductions. Haplotype diversity in Californian populations was significantly reduced compared to European populations, but not compared to East Coast populations. Genetic analyses clearly suggested the East Coast as the source region for the California introductions.The California L. littorea populations were at an early, non-established phase of invasion with no evidence of recruitment. The live seafood trade is the most likely invasion vector for these populations, as it preferentially transports large numbers of adult L. littorea, matching the demographic structure of the introduced California L. littorea populations. Our results highlight continued operation of live seafood trade vectors and the influence of vectors on the demographic and genetic structure of the resulting populations, especially early stages of the invasion process.