Academic literature on the topic 'Selby (Vic )'

In bacteria, selenocysteine (Sec) is incorporated into proteins via the recoding of a particular codon, the UGA stop codon in most cases. Sec-tRNASec is delivered to the ribosome by the Sec-dedicated elongation factor SelB that also recognizes a Sec-insertion sequence element following the codon on the mRNA. Since the excess of SelB may lead to sequestration of Sec-tRNASec under selenium deficiency or oxidative stress, the expression levels of SelB and tRNASec should be regulated. In this bioinformatic study, I analyzed the Rhizobiales SelB species because they were annotated to have a non-canonical C-terminal extension. I found that the open reading frame (ORF) of diverse Alphaproteobacteria selB genes includes an entire tRNASec sequence (selC) and overlaps with the start codon of the downstream ORF. A remnant tRNASec sequence was found in the Sinorhizobium melilotiselB genes whose products have a shorter C-terminal extension. Similar overlapping traits were found in Gammaproteobacteria and Nitrospirae. I hypothesized that once the tRNASec moiety is folded and processed, the expression of the full-length SelB may be repressed. This is the first report on a nested tRNA gene inside a protein ORF in bacteria.

BackgroundCheckpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors.MethodsThis is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies.ResultsN/AConclusionsN/AAcknowledgements• The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.).Trial RegistrationNCT04362748Ethics ApprovalThe study was approved by all institutional ethics boards.ReferencesKluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039.Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873.Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

Abstract Abstract 4192 Introduction: There are no prospective, long-term studies describing the process and quality of care, resource utilization (RU), and quality of life (QoL) associated with being on oral anticoagulant therapy for non-valvular atrial fibrillation (NVAF) patients managed through routine medical care (RMC) in Canada. Methods: Resource utilization associated with Oral Anticoagulant Management (ROAM) is a prospective cohort study being conducted across 9 Canadian provinces whose objective is to describe the process and quality of care, RU, clinical events and health utility scores associated with long-term oral anticoagulant (warfarin) therapy in patients with new onset or chronic NVAF. Eligible, consenting patients are followed for 48 weeks and complete a weekly study diary providing data on international normalized ratio (INR) test dates and values, RU associated with warfarin monitoring, and all physician visits, procedures and hospitalizations. Health utility scores, representing the patient's health state, measured using the EuroQol-5D (EQ-5D) standardized QoL instrument are collected every 4 weeks. INR test values and dates and source documentation around patient reported clinical events are also collected from the participating physicians. Results: 497 out of a planned enrolment of 600 patients have been recruited. 180 patients with completed 48 week follow-up and physician-provided INR values are included in this analysis, 98% from primary care physicians and specialists (RMC) and 2% from anticoagulant clinics. Median age [range] was 75 [39, 90] years with 67% males. Common co-morbidities were hypertension (60%) and ischemic heart disease (27%). Estimated median [range] time since NVAF diagnosis was 4 [0, 32] years. Physicians reported a total of 2484 INR tests over the study duration (a mean of 13.8 tests per patient) while patients recorded 2711 tests being completed in their diaries over the same time period (a mean of 15.06 tests per patient). Of the 2711 patient reported tests only 1914 INR results (71%) were communicated back to patients via telephone (70%) or in person (15%). Median [quartile] time between the INR test and the patient acquiring the results was 1.4 [1.0, 2.5] days. The INR test dates provided by physicians matched the dates recorded by patients in the diary 67% of the time. 51 (28%) of patients recorded no INR values. Of the 129 patients with at least one recorded INR value, physician and patient INR values matched completely for only 8 (4%) patients and matched on average 62% of the time (range 30% to 98%) for the rest. Mean [95% CI] time in therapeutic range (TTR) by the Rosendaal method was 67% [64%, 71%] using physician reported values and 67% [62%, 72%] based on patient reported values. Mean INR testing frequency was 30 days following an INR in the therapeutic range, 25 days following an INR of less than 2 and 22 days following an INR greater than 3. Three strokes and 3 bleeds were self-reported in 5 patients (9%) that are being adjudicated. The initial mean [95% CI] health utility score was 0.85 [0.83, 0.88]. A decrease in health utility score was observed in 133 (74%) of the patients based on a random effects regression model. Fixed effect estimate of the mean [95% CI] change in health utility scores per 6 months was −0.01 [0, −0.02]. Covariates (age, gender and time since diagnosis) were investigated but had limited effect on the health utility score. Conclusions: This is the first prospective cohort study of NVAF patients on long-term warfarin therapy being monitored primarily through RMC in Canada. The majority of patients are monitored via telephone with frequent miscommunication between health care providers and patients about INR results and delays in getting results to patients. TTR is higher than previously reported for RMC, which may suggest a self-selection bias for better quality physician-patient combinations. Although frequency of testing was appropriate for in-range INRs, the times to testing after out-of-range results appear delayed. Analysis of health utility scores showed a small decrease in health status over time in this cohort of patients with generally high health utility scores. Relationship between TTR and clinical events will be presented. Disclosures: Selby: Boehringer Ingelheim: Honoraria, Research Funding. Mittmann:Boehringer Ingelheim: Research Funding. Isogai:Boehringer Ingelheim: Research Funding. Kaus:Boehringer Ingelheim: Research Funding. Koo:Boehringer Ingelheim: Research Funding. Sealey:Boehringer Ingelheim: Research Funding.

ABSTRACT While investigating the virulence traits of Staphylococcus aureus adhering to the skin of atopic-dermatitis (AD) patients, we identified a novel open reading frame (ORF) with structural similarity to a superantigen from genome sequence data of an isolate from AD skin. Concurrently, the same ORF was identified in a bovine isolate of S. aureus and designated SElY (H. K. Ono, Y. Sato’o, K. Narita, I. Naito, et al., Appl Environ Microbiol 81:7034–7040, 2015, https://doi.org/10.1128/AEM.01873-15). Recombinant SElYbov had superantigen activity in human peripheral blood mononuclear cells. It further demonstrated emetic activity in a primate animal model, and it was proposed that SElY be renamed SEY (H. K. Ono, S. Hirose, K. Narita, M. Sugiyama, et al., PLoS Pathog 15:e1007803, 2019, https://doi.org/10.1371/journal.ppat.1007803). Here, we investigated the prevalence of the sey gene in 270 human clinical isolates of various origins in Japan. Forty-two strains were positive for the sey gene, and the positive isolates were from patients with the skin diseases atopic dermatitis and impetigo/staphylococcal scalded skin syndrome (SSSS), with a detection rate of ∼17 to 22%. There were three variants of SEY (SEY1, SEY2, and SEY3), and isolates producing SEY variants formed three distinct clusters corresponding to clonal complexes (CCs) 121, 59, and 20, respectively. Most sey+ isolates produced SEY in broth culture. Unlike SEYbov, the three recombinant SEY variants exhibited stability against heat treatment. SEY predominantly activated human T cells with a particular T-cell receptor (TCR) Vα profile, a unique observation since most staphylococcal enterotoxins exert their superantigenic activities through activating T cells with specific TCR Vβ profiles. SEY may act to induce localized inflammation via skin-resident T-cell activation, facilitating the pathogenesis of S. aureus infection in disrupted epithelial barriers.

The Norwegian Food Safety Authority (NFSA) and Norwegian Environmental Authority (NEA) asked the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for an opinion on factors associated with the introduction of Chronic Wasting Disease (CWD) to Norway. VKM appointed a working group consisting of two members of the Panel on Biological Hazards, one member of Panel on Animal Health and Welfare, and two external experts to prepare the answer to the questions. The Panel on Biological Hazards has reviewed and revised the draft prepared by the working group and approved the opinion. CWD was diagnosed in March 2016 in a wild reindeer (Rangifer tarandus) from the Nordfjella mountain area in Norway and in May and June in two mooses (Alces alces) in Selbu in South Trøndelag County, approximately 300 km north from the first case. There is currently no information to determine the origin(s) of CWD agents in Norway. However, the sporadic or genetic (somatic mutation) occurrence of prion disease in cervids cannot be excluded, nor can introduction from North America or other countries. Furthermore, there is no evidence that it has not been circulating at low levels in the Norwegian cervid populations for years, but has not previously been identified. In this scientific opinion, information on prion diseases in general, and CWD in particular, is presented in the light of experiences with this disease in North America. Prions are among the most resilient pathogens known and dissemination of prions into ecosystems is likely to result in long-term problems. Prions bind strongly to soil and remain infectious. In CWD, prions are present in most peripheral organs and also shed into the environment via saliva, faeces, and urine, as well as with the placenta. CWD transmits easily among cervids, either through direct contact, or indirectly via the environment. Migration of animals is relevant for the spread between areas. Strain diversification might occur in CWD and may influence transmission properties of the agents. Clinical signs of CWD are non-specific and do not alone enable confirmation of the diagnosis. Analysis of tissue from the brainstem at the level of the obex by approved methods is necessary for diagnosis of CWD. Prion infectivity is assessed by bioassays, often involving transgenic mice. In vitro conversion assays, like protein misfolding cyclic amplification (PMCA), provide sensitive quantification of converting activity, which is a good approximation of infectivity. Genetic variation (polymorphisms) in the gene that encodes PrP (PRNP) can modulate sensitivity towards CWD. The level of such genetic variation in Norwegian wild and semi-domesticated cervids is currently unknown. Cattle and sheep are at very low risk of developing CWD and it is highly unlikely that prion diseases in sheep or cattle are the origin of CWD. Although transmission of CWD to humans has never been known to occur, and animals other than cervids have not been found to be infected, indicating a species barrier, this possibility cannot be excluded. Thus, measures for reduction of human exposure are recommended. Taking into account uncertainties regarding the plasticity of the CWD agents and the lack of transmission data from the Norwegian isolates, this scientific opinion considers the zoonotic risk of CWD to be very low.

The Norwegian Food Safety Authority (Mattilsynet, NFSA) and the Norwegian Environment Agency (Miljødirektoratet, NEA) requested the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for a scientific opinion on Chronic wasting disease (CWD) in cervids. The project was divided into two phases, and VKM published the scientific opinion from phase I “CWD in Norway” in June 2016. The current report is the result of phase II. VKM was asked to provide updated information on food safety, aspects important for transmission of CWD within and between populations and species, and the potential origin of the disease in Norway. Moreover, VKM was asked to highlight important risk factors with regard to disease transmission, and how these risk factors might affect choice of management strategy. Finally, VKM was asked to highlight relevant management strategies from North America or elsewhere. VKM appointed a working group consisting of one member of the Panel on Microbial Ecology, one member of the Panel on Biological Hazards, and five external experts, as well as VKM`s secretariat to answer the questions from NEA and NFSA. One member of the Panel on Alien Organisms and Trade in Endangered Species (CITES), one member of the Panel on Animal Health and Welfare, as well as one member of the Panel on Biological Hazards commented on the draft report. The Panel on Biological Hazards assessed and approved the final report. Background: Chronic wasting disease (CWD) is a prion disease that affects deer, moose, reindeer, and related species (cervids). Prion diseases are chronic neurodegenerative diseases that occur naturally in humans and ruminants, and are invariably fatal. Some prion diseases, such as classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids, are contagious, spreading directly between animals or via environmental contamination. In contrast, prion diseases known to affect humans are not known to be contagious. Prions are extraordinary agents consisting of misfolded protein aggregates that are remarkably stable and can remain infectious for years in the environment. Prion proteins are present in most animals, but the misfolding makes them very hard to break down. Consequently, misfolded prion proteins accumulate in the brain and eventually in other tissues, causing damage to those tissues. Until recently, CWD was only known from North America and South Korea. During a routine marking event in April 2016, a female reindeer (Rangifer tarandus) of the Nordfjella wild reindeer herd in Norway exhibited unusual behaviour, and died shortly afterwards. This unusual death was routinely investigated, and the animal was diagnosed with CWD. This was the first time CWD had been diagnosed outside North America and South Korea and the first case of natural CWD in reindeer. In addition, two moose (Alces alces) in Selbu, Norway were diagnosed with CWD in May 2016. Selbu is located approximately 300 km northeast of the Nordfjella mountain range. Currently there is considerable uncertainty regarding the nature of the CWD diagnosed in the two moose. Some of the characteristics of these cases indicate consistency with atypical prion disease, as described in domestic animals, but a final conclusion depends on the results from ongoing investigations. Following the diagnosis in reindeer, Norwegian authorities initiated a screening programme in which hunters were requested to collect tissue and the heads of dead cervids during the 2016 hunting season. Animals that had died from causes other than hunting were also tested for CWD. Since March 2016, 4629 samples of moose, 2550 samples of red deer, 627 samples of roe deer, 860 samples of reindeer, 2494 semi-domesticated reindeer, 163 farmed deer and 104 samples of unidentified species were tested for CWD. Two additional cases of CWD were diagnosed in wild reindeer in the Nordfjella population. Together with a clinical, pathological and epidemiological picture consistent with contagious CWD, as described from North America, this indicated that there is an ongoing outbreak of CWD in the wild reindeer population of the northern part of Nordfjella wild reindeer range. Results: An increase in the distribution and prevalence of CWD will increase exposure of other species, including domestic animals and humans, to this infectious agent. There is currently no evidence indicating transmission of CWD to domestic animals or humans, either by direct contact with cervids, cervid meat, or other products from cervids, or through the environment. VKM continues to support the conclusion from phase I concerning food safety of meat from cervids, that the zoonotic risk of CWD (transmission to humans) is very low. Preliminary results from characterisation of the moose cases and the agent involved indicate that important features deviate significantly from those found in the reindeer and in North American cervids, raising uncertainty with regards to the zoonotic potential. Therefore, based on the data currently available, VKM is not able to reach an evidence-based conclusion regarding the food safety of meat from moose and other cervids infected with this potentially new variant of CWD. Whereas direct transmission (animal-to-animal) seems most important in the early phases of a CWD epizootic, the role of indirect transmission (from the environment) increases as the prevalence increases. Once contagious CWD is established, it is very likely that the disease will increase in prevalence within the affected population and spread to contact populations. The rate of increase in prevalence, the resulting impact in a given population, and the efficacy of spread will depend on a range of environmental factors, and the characteristics of the species and population in question. For example, in affected populations of a gregarious species like reindeer, CWD is likely to lead to population decline in the long-term. Experiences from North America indicate that prions aggregate in the environment, making eradication of the disease extremely difficult once it has been allowed to develop and become endemic. It is therefore important that efficient measures are implemented at the VKM Report 2017:9 9 earliest opportunity in order to have a realistic chance of eradicating local occurrence of CWD and preventing further spread. Contagious CWD found in a confinable population, such as many wild reindeer herds, should be managed by eradication of the host population, fallowing of the area (> 5 years), and restocking from a healthy population. The report explains that culling of the Nordfjella reindeer herd is a necessary, immediate response to the current situation. However, as part of an adaptive management strategy, this measure should be under active review and may be revised in the event that new cases of CWD are discovered. In contrast, in continuous populations, such as most red deer, moose, and roe deer populations, spatially targeted culling within a defined containment zone should be used to control a CWD outbreak. Confinement of CWD-infected populations should be increased where possible and contact with other populations of cervids restricted, for example by fencing, herding, enhancing natural or man-made obstacles, or decreasing the densities of the relevant cervid populations. Potential “hotspots” for disease transmission (supplementary salt-licks, supplementary feeding sites etc.) should be eliminated in areas with CWD as well as the surrounding areas, and should further be considered for other parts of the country. Precautionary measures should be implemented to prevent anthropogenic spread of the disease. Finally, increasing the national surveillance of CWD in cervids is essential to ensure that there is a comprehensive basis for future evidence-based management. This is required to ensure that cases and spread of disease are identified as soon as possible, as late discovery will limit the chances for successful eradication of CWD in Norway.

Histoplasma was initially described from a lesion in a horse by Rivolta in 1873, who named the organism Cryptococcus farciminosum. In 1905, Samuel Darling noted the presence of intracellular organisms in many tissues, including the lungs, of a patient suspected of succumbing to miliary tuberculosis (Darling 1906). Darling named the organism Histoplasma capsulatum , because it appeared to be an encapsulated protozoan-like organism. In 1912, mycologist Henrique da Rocha-Lima reviewed Darling’s slides and noted the cytological similarities between Darling’s Histoplasma organism and Cryptococcus farciminosum. Cryptococcus farciminosum was reclassified as Histoplasma farciminosum in 1934, and in 1985 it was again reclassified as a variant of Histoplasma capsulatum (var. farciminosum ) (Weeks et al. 1985).William De Monbreun cultured the organism from the blood of a child suffering from an unexplained febrile disease in 1934, and demonstrated it to be a dimorphic fungus (De Monbreun 1934). De Monbreun and others reported naturally occurring histoplasmosis in a dog in 1939, and subsequently demonstrated experimentally that clinically inapparent histoplasmosis occurred in dogs (De Monbreun 1939). De Monbreun and others speculated that animals might serve as the source of histoplasmosis in human beings. However, C.W. Emmons demonstrated in 1949 that Histoplasma capsulatum is a soil saprophyte, and that inhalation of aerosolized microconidia and mycelial fragments served as the source of infection (Emmons 1949).The prevalence of histoplasmosis in endemic regions was estimated to be more than 50% based on positive skin tests for histoplasmin (Edwards et al. 1969). Active histoplasmosis has been identifi ed in up to 50% of dogs in endemic regions based on culture at necropsy of healthy animals (Turner et al. 1972a). The case prevalence of disseminated histoplasmosis at a veterinary teaching hospital in an endemic region of the mid-western USA of 43 cases in cats and 12 cases in dogs per 100,000 hospital records per year has been estimated (Clinkenbeard et al. 1988; Kaplan 1973). Dogs and cats with outdoor exposure are reportedly at greater risk for histoplasmosis than those with minimal time outdoors. However, some completely indoor cats become ill with histoplasmosis (Davies and Troy 1996; Johnson et al. 2004). Young to middle-aged dogs of hunting and sporting breeds have historically been reported at greatest risk for acquiring histoplasmosis (Selby et al. 1981). Risk factors for cats have not been systematically studied.Infection by Histoplasma capsulatum var. capsulatum is not contagious except in unusual situations. Rare cases of horizontal transmission have been reported. Horizontal transmission is associated with conjugal contraction of individuals with cutaneous lesions of the genitalia (Sills et al. 1973) and by solid organ transplantation of infected organs (Limaye et al. 2000). No documented cases of transmission from animals to human beings or vice versa have been reported. In contrast to Histoplasma capsulatum var. capsulatum, equine infection by Histoplasma capsulatum var. farciminosum is contagious and is transmitted by bites of contaminated flies or ticks as well as through skin traumatized with contaminated tack (Kohn 2006).