Next-generation sequencing of prostate cancer: genomic and pathway alterations, potential actionability patterns, and relative rate of use of clinical-grade testing.

Despite being one of the most common cancers, treatment options for prostate cancer are limited. Novel approaches for advanced disease are needed. We evaluated the relative rate of use of clinical-grade next generation sequencing (NGS) in prostate cancer, as well as genomic alterations identified and their potential actionability. Of 4864 patients from multiple institutions for whom NGS was ordered by physicians, only 67 (1.4%) had prostate cancer, representing 1/10 the ordering rate for lung cancer. Prostate cancers harbored 148 unique alterations affecting 63 distinct genes. No two patients had an identical molecular portfolio. The median number of characterized genomic alterations per patient was 3 (range, 1 to 9). Fifty-six of 67 patients (84%) had ≥ 1 potentially actionable alteration. TMPRSS2 fusions affected 28.4% of patients. Genomic aberrations were most frequently detected in TP53 (55.2% of patients), PTEN (29.9%), MYC (17.9%), PIK3CA (13.4%), APC (9.0%), BRCA2 (9.0%), CCND1 (9.0%), and RB1 genes (9.0%). The PI3K (52.2% of patients), WNT (13.5%), DNA repair (17.9%), cell cycle (19.4%), and MAPK (14.9%) machinery were commonly impacted. A minority of patients harbored BRAF, NTRK, ERBB2, or mismatch repair gene abnormalities, which are highly druggable in some cancers. Only ~ 10% of prostate cancer trials (clinicaltrials.gov, year 2017) applied a (non-hormone) biomarker before intervention. In conclusion, though use of clinical-grade NGS is relatively low and only a minority of trials deploy DNA-based biomarkers, many prostate cancer-associated molecular alterations may be pharmacologically tractable with genomcially targeted therapy or, in the case of mismatch repair anomalies, with checkpoint inhibitor immunotherapy

Genomic landscape of salivary gland tumors.

Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients). The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies

Differences in radionuclide and heavy metal concentrations found in the kidneys of barren-ground caribou from the western Northwest Territories 1994/95 to 2000/01

Aluminum, nickel, cadmium, mercury, and lead concentrations were measured in the kidney tissue of known aged barren-ground caribou wintering in the western Northwest Territories harvested during winter 1994/1995 and during winters 2000/2001 and 2001/2002. 40K, 137Cs, and 210Pb concentrations were measured in the kidney tissue of known aged barren-ground caribou during winter 2000/2001 and compared to concentrations in winter 1993/1994 reported in Macdonald et al. (1996). Renal concentrations of aluminum were higher (P<0.001)in winter 2000/2001 than winter 1994/1995. Contrastingly renal concentrations of mercury were lower (P<0.001) in winter 2000/2001 than 1994/1995. 137Cs (P<0.02), 40K (P=0.01), 210Pb (P<0.01) had lower renal concentrations in winter 2000/2001 than 1993/1994. Renal concentrations of cadmium (P<0.001) and 137Cs (P<0.04) had a positive relationship with caribou age. We also document renal concentrations of arsenic, copper, selenium, zinc, 232Th, 226Ra, and 235U in the kidneys of caribou harvested in winters 2000/2001 and 2001/2002. Renal zinc concentrations were positively correlated with the age of caribou

Examining the Risk of Disease Transmission between Wild Dall’s Sheep and Mountain Goats, and Introduced Domestic Sheep, Goats, and Llamas in the Northwest Territories

This risk assessment has been carried out following the guidelines for Health Risk Analysis entitled “Wild Animal Translocations” prepared by the Canadian Cooperative Wildlife Health Centre (http://wildlife1.usask.ca). It includes 9 comprehensive appendices of bacterial, viral, parasitic and fungal organisms reported from domestic sheep, goats, llamas and wild sheep and mountain goats. The report is a breakdown of those appendices into discussions of organisms of major concern, organisms of unknown concern, organisms of minimal concern, and those that cause no apparent disease, are not transmissible between the species of interest, or do not occur in Canada. Where possible, organisms were assigned a risk designation according to the probability of transmission as well as the effects on susceptible species

Serum Biochemistry and Serum Cortisol Levels of Immobilized and Hunted Muskoxen (Ovibos moschatus) from Northern Canada

Muskoxen (Ovibos moschatus) are Arctic-adapted ruminants native to the Arctic regions of Canada, Alaska, and Greenland. Little is known about the serum biochemistry and serum cortisol of this species, or the effects of chemical immobilization on serum biochemical parameters. This study aimed to describe blood chemistry parameters and cortisol levels in hunted, tame, and chemically immobilized muskoxen and to examine differences in blood chemistry parameters and levels of stress associated with different capture techniques. Serum was collected from 91 adult female muskoxen in northern Canada. For analysis, these muskoxen were classified into six groups, five of free-ranging muskoxen (10 animals shot from snowmobiles near Kugluktuk, Nunavut; 18 chemically immobilized from a helicopter near Kugluktuk; 8 chemically immobilized from a helicopter near Norman Wells, Northwest Territories; 17 shot from snowmobiles near Cambridge Bay, Nunavut; 33 chemically immobilized from a snowmobile near Kugluktuk) and one of tame muskoxen (five tame animals maintained on pasture near Saskatoon, Saskatchewan). All samples were analyzed for cortisol, and 26 serum biochemistry parameters were measured in serum collected from three of the six groups (n = 36). Comparison of four groups showed that serum cortisol levels of muskoxen chemically immobilized from a helicopter near Kugluktuk were significantly higher(p < 0.05) than those of muskoxen chemically immobilized from snowmobiles or shot. A comparison of serum biochemistry from the groups of muskoxen shot and immobilized near Kugluktuk found that serum sodium, creatinine, phosphorus, magnesium, and creatine kinase were significantly higher (p < 0.05) in hunted muskoxen than in chemically immobilized animals, while urea, glucose and gamma glutamyl transferase were significantly higher (p < 0.05) in immobilized muskoxen. Most serum biochemical parameters, however, were similar to those of captive muskoxen. This evidence of differences between hunted and immobilized muskoxen in several serum biochemistry parameters will contribute to further research on the effects of immobilization and other health assessments in this species.Le boeuf musqué (Ovibos moschatus) est un ruminant adapté à l’Arctique qui est natif des régions arctiques du Canada, de l’Alaska et du Groenland. On en sait peu à propos de la biochimie du sérum et du cortisol du sérum de cette espèce ou encore, à propos des effets de l’immobilisation chimique sur les paramètres biochimiques du sérum. Cette étude visait à décrire les paramètres de la chimie du sang et les taux de cortisol chez les boeufs musqués chassés, apprivoisés et chimiquement immobilisés, de même qu’à examiner les différences sur le plan des paramètres de la chimie du sang et des degrés de stress en fonction de diverses méthodes de capture. Du sérum a été prélevé auprès de 91 femelles adultes du nord du Canada. Aux fins de l’analyse, ces boeufs musqués ont été classés en six groupes, dont cinq des groupes étaient composés de boeufs musqués en liberté (10 des boeufs avaient été tirés depuis des motoneiges près de Kugluktuk, au Nunavut; 18 avaient été chimiquement immobilisés à partir d’un hélicoptère près de Kugluktuk; 8 avaient été chimiquement immobilisés à partir d’un hélicoptère près de Norman Wells, dans les Territoires du Nord-Ouest; 17 avaient été tirés depuis des motoneiges près de Cambridge Bay, au Nunavut; 33 avaient été chimiquement immobilisés depuis une motoneige près de Kugluktuk) et l’autre groupe était composé de boeufs musqués apprivoisés (5 bêtes évoluant dans des pâturages près de Saskatoon, en Saskatchewan). Dans tous les cas, le cortisol des échantillons a été analysé, puis 26 paramètres biochimiques du sérum ont été mesurés à partir du sérum recueilli chez trois des six groupes (n = 36). Les comparaisons établies pour quatre des groupes ont permis de constater que les taux de cortisol du sérum des boeufs musqués chimiquement immobilisés à partir d’un hélicoptère près de Kugluktuk étaient considérablement plus élevés (p < 0,05) que ceux des boeufs musqués qui avaient été chimiquement immobilisés depuis une motoneige ou qui avaient été tirés. La comparaison de la biochimie du sérum chez les boeufs musqués tirés et immobilisés près de Kugluktuk a permis de déceler que le sodium du sérum, la créatinine, le phosphore, le magnésium et la créatine kinase étaient considérablement plus élevés (p < 0,05) chez le boeuf musqué chassé que chez le boeuf musqué chimiquement immobilisé, tandis que l’urée, le glucose et la gamma-glutamyl-transférase étaient considérablement plus élevés (p < 0,05) chez le boeuf musqué immobilisé. Cependant, la plupart des paramètres biochimiques du sérum étaient semblables à ceux des boeufs musqués en captivité. Ces différences évidentes sur le plan de nombreux paramètres biochimiques du sérum entre le boeuf musqué chassé et le boeuf musqué immobilisé permettront d’approfondir les recherches sur les effets de l’immobilisation et d’autres évaluations de santé de cette espèce

Standardized monitoring of Rangifer health during International Polar Year

Monitoring of individual animal health indices in wildlife populations can be a powerful tool for evaluation of population health, detecting changes, and informing management decisions. Standardized monitoring allows robust comparisons within and across populations, and over time and vast geographic regions. As an International Polar Year Initiative, the CircumArctic Rangifer Monitoring and Assessment network established field protocols for standardized monitoring of caribou and reindeer (Rangifer tarandus) health, which included body condition, contaminants, and pathogen exposure and abundance. To facilitate use of the protocols, training sessions were held, additional resources were developed, and language was translated where needed. From March 2007 to September 2010, at least 1206 animals from 16 circumpolar herds were sampled in the field using the protocols. Four main levels of sampling were done and ranged from basic to comprehensive sampling. Possible sources of sampling error were noted by network members early in the process and protocols were modified or supplemented with additional visual resources to improve clarity when needed. This is the first time that such broad and comprehensive circumpolar sampling of migratory caribou and wild reindeer, using standardized protocols covering both body condition and parasite disease status, has been done

Giardia assemblage A: human genotype in muskoxen in the Canadian Arctic

As part of an ongoing program assessing the biodiversity and impacts of parasites in Arctic ungulates we examined 72 fecal samples from muskoxen on Banks Island, Northwest Territories, Canada for Giardia and Cryptosporidium. Cryptosporidium spp. were not detected, but 21% of the samples were positive for Giardia. Sequencing of four isolates of Giardia demonstrated G. duodenalis, Assemblage A, a zoonotic genotype

The global distribution of Bacillus anthracis and associated anthrax risk to humans, livestock and wildlife.

Bacillus anthracis is a spore-forming, Gram-positive bacterium responsible for anthrax, an acute infection that most significantly affects grazing livestock and wild ungulates, but also poses a threat to human health. The geographic extent of B. anthracis is poorly understood, despite multi-decade research on anthrax epizootic and epidemic dynamics; many countries have limited or inadequate surveillance systems, even within known endemic regions. Here, we compile a global occurrence dataset of human, livestock and wildlife anthrax outbreaks. With these records, we use boosted regression trees to produce a map of the global distribution of B. anthracis as a proxy for anthrax risk. We estimate that 1.83 billion people (95% credible interval (CI): 0.59-4.16 billion) live within regions of anthrax risk, but most of that population faces little occupational exposure. More informatively, a global total of 63.8 million poor livestock keepers (95% CI: 17.5-168.6 million) and 1.1 billion livestock (95% CI: 0.4-2.3 billion) live within vulnerable regions. Human and livestock vulnerability are both concentrated in rural rainfed systems throughout arid and temperate land across Eurasia, Africa and North America. We conclude by mapping where anthrax risk could disrupt sensitive conservation efforts for wild ungulates that coincide with anthrax-prone landscapes

Trichinella pseudospiralis in a wolverine (Gulo gulo) from the Canadian North

Species of Trichinella are a globally distributed assemblage of nematodes, often with distinct host ranges, which include people, domestic, and wild animals. Trichinella spp. are important in northern Canada, where dietary habits of people and methods of meat preparation (drying, smoking, fermenting as well as raw) increase the risk posed by these foodborne zoonotic parasites. Outbreaks in the arctic and subarctic regions of Canada and the United States are generally attributed to T. nativa (T2) or the T6 genotype, when genetic characterization is performed. We report the discovery of Trichinella pseudospiralis (T4), a non-encapsulated species, in a wolverine (Gulo gulo) from the Northwest Territories of Canada. This parasite has been previously reported elsewhere from both mammals and carnivorous birds, but our findings represent new host and geographic records for T. pseu- dospiralis. Multiplex PCR and sequencing of fragments of Cytochrome Oxidase Subunit I (COI) and D3 rDNA confirmed the identification. Phylogenetically, Canadian isolates linked with each other and others derived from Palearctic or Neotropical regions, but not elsewhere in the Nearctic (continental USA). We suggest that mi- gratory birds might have played a role in the dispersal of this pathogen 1000\u27s of km to northwestern Canada. Wolverines are not typically consumed by humans, and thus should not pose a direct food safety risk for tri- chinellosis. However, the current finding suggests that they may serve as an indicator of a broader distribution for T. pseudospiralis. Along with infection risk already recognized for T. nativa and Trichinella T6, our observa- tions emphasize the need for further studies using molecular diagnostics and alternative methods to clarify if this is a solitary case, or if T. pseudospiralis and other freeze susceptible species of Trichinella (such as T. spiralis) circulate more broadly in wildlife in Canada, and elsewhere

Dogs as Sources and Sentinels of Parasites in Humans and Wildlife, Northern Canada

A minimum of 11 genera of parasites, including 7 known or suspected to cause zoonoses, were detected in dogs in 2 northern Canadian communities. Dogs in remote settlements receive minimal veterinary care and may serve as sources and sentinels for parasites in persons and wildlife, and as parasite bridges between wildlife and humans