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The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.

Neuroblastoma: a genetic link to ALK Neuroblastoma is the most common childhood cancer. There is a strong familial association and it was predicted over 30 years ago that there was a genetic element to the disease. Four groups now report the identification of mutations in the tyrosine kinase receptor ALK (anaplastic lymphoma kinase) in neuroblastoma patients. ALK acts as a neuroblastoma predisposition gene, and somatic point mutations occur in sporadic neuroblastoma cases. These mutations promote ALK's kinase activity and can transform cells and display tumorigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferation, so have potential as anticancer drugs. This is one of four papers in this issue that identifies mutations in the tyrosine kinase receptor ALK in neuroblastoma, the most frequent childhood cancer. ALK is found to be a neuroblastoma predisposition gene and somatic points mutations were found in sporadic cases of neuroblastoma. These mutations lead the ALK kinase activation and are able to transform cells and display tumourigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferating and are potential anti-cancer drugs for the treatment of neuroblastoma. Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer 1 . High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal 2 , 3 . Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK , of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4 ). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.

According to the National Hospital Ambulatory Medical Care Survey (NHAMCS), ED visits increased from 123.8 million annually in 2008 to 138.9 million in 2017 [1,9]. Access to primary care was higher among patients with increasing age, ambulance arrival, Triage level 2, access to transportation, college or postgraduate education, private medical insurance, and annual income greater than $60,000.Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Poster presentation Hanna M, Marco CA, Seitz N, Repas S, Harrington M, House DL, Le TN, & Sorensen D. Boonshoft School of Medicine Medical Student Research Symposium, Dayton, OH. Factor Odds Ratio Triage acuity level 2 5.6 College of postgraduate education 4.2 Access to transportation 2.1 Private medical insurance 1.9 Increasing age 1.05 Walk-ins 0.5 Annual income <45,000 0.1 Self-pay 0.1 Table 2 Factors associated with having a primary care physician.

It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer.

Habitat‐based approaches to animal conservation are bolstered by an understanding of resource selection, that is, use of resources (i.e., habitat features) relative to their availability in the environment. Quantifying resource selection is especially valuable when data characterizing animal space use are limited, as is often the case with mobile and/or cryptic species. Documenting associations with habitat features can better inform management in space in time, while also revealing key insight into movement ecology and behavior. Here, we evaluate resource selection by a megaomnivore whose highly mobile nature within marine habitats has resulted in an incomplete understanding of drivers of space use. We used satellite telemetry to track 29 green turtles (Chelonia mydas) from an eastern Pacific foraging aggregation in San Diego Bay, California, USA during 2013–2023. Tracking produced 5023 Fastloc‐GPS points which we used to model selection for local environmental resources relative to their availability. We employed logistic models to evaluate associations with seagrass, bathymetry, and water temperatures, implementing a framework that additionally allowed us to explore the roles of season, diel period, and turtle body size. Our methods demonstrate an approach for down‐weighting observations according to assumed telemetry error and autocorrelation. Results from fine‐scale resource selection models provide evidence that green turtles in San Diego Bay select for eelgrass meadows (Zostera marina), particularly during the warmest months of the year, but the strength of this selection changes from day to night. We additionally found day–night shifts in depth and temperature selection that changed with turtle body size and season. We discuss these findings in the context of diel patterns in resting and foraging behavior in addition to seasonal changes in thermally sensitive metabolic rates. Our study documents resource associations and provides quantitative information for the management of sea turtle foraging populations and their habitats. We offer key insight into habitat use by green turtles in the eastern Pacific at a pivotal time when multiple indicators point to population growth and expansion within the region. We used satellite telemetry data for 29 green turtles (Chelonia mydas) in San Diego Bay, California, USA to analyze selection for seagrass, bathymetry, and water temperatures relative to their local availability. We found that green turtles in San Diego Bay select for eelgrass meadows (Zostera marina) and certain depths and water temperatures, but patterns were contingent on diel period, turtle body size, and season. We present quantitative resource associations representing actionable information for management at a pivotal time when multiple indicators point to green turtle population growth and expansion within the eastern North Pacific region.

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

Background Bisulfite sequencing allows base-pair resolution profiling of DNA methylation and has recently been adapted for use in single-cells. Analyzing these data, including making comparisons with existing data, remains challenging due to the scale of the data and differences in preprocessing methods between published datasets. Results We present a set of preprocessing pipelines for bisulfite sequencing DNA methylation data that include a new R/Bioconductor package, scmeth , for a series of efficient QC analyses of large datasets. The pipelines go from raw data to CpG-level methylation estimates and can be run, with identical results, either on a single computer, in an HPC cluster or on Google Cloud Compute resources. These pipelines are designed to allow users to 1) ensure reproducibility of analyses, 2) achieve scalability to large whole genome datasets with 100 GB+ of raw data per sample and to single-cell datasets with thousands of cells, 3) enable integration and comparison between user-provided data and publicly available data, as all samples can be processed through the same pipeline, and 4) access to best-practice analysis pipelines. Pipelines are provided for whole genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS) and hybrid selection (capture) bisulfite sequencing (HSBS). Conclusions The workflows produce data quality metrics, visualization tracks, and aggregated output for further downstream analysis. Optional use of cloud computing resources facilitates analysis of large datasets, and integration with existing methylome profiles. The workflow design principles are applicable to other genomic data types.

East Pacific (EP) green turtles ( Chelonia mydas ) have undergone substantial population recovery over the last two decades owing to holistic protection at nesting beaches and foraging areas. At the northern end of their range in southern California United States, green turtles have been seen in more areas and in greater numbers since 2014 than before as a result. A resident population of green turtles has established near La Jolla Shores (LJS), a protected site with daily marine tourism (e.g., kayakers, snorkelers, divers). To study this local aggregation, innovative and non-invasive methods were required because the traditional capture-recapture methods were infeasible due to public relations sensitivities. Green turtle habituation to humans at this site has created a unique opportunity for citizen-based science using underwater photography to document turtles and their surroundings. We obtained 309 usable photographs of local green turtles from members of the dive/snorkel community in LJS. Photos were taken from April 2016 to June 2019. Images were processed in Hotspotter—a patterned species instance recognition software—to identify seven individuals, five of which were consistently photographed throughout that period. These images helped infer minimum residency duration (MRD), seasonal differences in algal coverage on the carapace, habitat association, behavioral patterns, and diet. Mean MRD was 424 days ( SE = 131 days, calculated from entire population, n = 7), during which turtles were active in 82.8% of the photographs; the remainder of the photographs depicted foraging (14.9%) or resting behavior (2.3%). Green turtles were seen foraging in water temperatures as low as 15.8°C, the lowest recorded temperature for foraging green turtles documented in literature. Additional opportunistic observational platforms were used to look at trends of increasing green turtle abundance in southern California since 2015 that supported the arrival of a new aggregation of green turtles in LJS. Our use of citizen-sourced photographs confirms the presence of a resident aggregation of green turtles in LJS. Existence of green turtles and other protected species in highly populated areas provide excellent opportunities to educate beachgoers and seafarers about conservation of these species. This study also highlights the value of citizen-based science in areas where traditional research techniques are ill-suited.

Lyme disease is a progressive infectious disease caused by the species that affects multiple organ systems, including the brain, heart, skin, and musculoskeletal systems. The cardiac manifestations of Lyme disease typically present with atrioventricular nodal conduction abnormalities and, more rarely, myocarditis. We report a case of an immunocompromised 57-year-old woman who presented with acute onset shortness of breath, hypervolemia, injective conjunctiva, and global vision loss of the left eye in the setting of a recent tick bite. Serologic testing confirmed borreliosis, and cardiac testing demonstrated acute isolated systolic heart failure without any cardiac conduction system abnormalities on the electrocardiogram. The diagnosis of Lyme carditis was made, and the patient was started on doxycycline with complete recovery of cardiac systolic function. This case demonstrates atypical cardiac manifestations of Lyme disease and highlights the difficulty in workup and understanding of Lyme carditis particularly in immunocompromised patients.

A variety of gram-positive infections can be treated with daptomycin. Daptomycin-induced acute eosinophilic pneumonia (DEP) is a rare adverse drug reaction with nonspecific clinical findings of dyspnea, dry cough, and fever. Although diagnostic criteria exist, prompt recognition is important to prevent rapid progression and respiratory failure. In this case, a 69-year-old female was initially admitted due to a prosthetic joint infection; however, her case was complicated by DEP.