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BackgroundWe evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic- and community-based health systems within a single Midwestern State.MethodsRetrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011–2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as “standard induction” or “other chemotherapy”/targeted therapy, and hypomethylating agents.ResultsOverall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non-therapy recipients (46% vs. 19%; p < 0.001). Most common mutations were ASXL1, NPM1, and FLT3. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years, p < 0.001), and was highest (66.2%) in patients ≥75 years.ConclusionsOur results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real-world setting, in this new era of targeted therapies.

Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1 -mutated/ FLT3 -ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).

While opioids are still one of the most common analgesics used, they elicit numerous side effects with the most important being the development of tolerance and dependence. By understanding the cellular mechanisms of tolerance, novel approaches to treating pain can be evaluated. Tolerance has been theorized to develop in response to cellular adaptations, including downregulation and desensitization. To date, the mechanisms responsible for desensitization and downregulation and their correlation with tolerance have not been fully evaluated. Phosphorylation of the carboxyl tail of the μ-opioid receptor, however, is believed to initiate these processes. From truncation, deletion, and point mutation studies, the specific amino acids, Ser 356 and Ser363, that mediate etorphine-induced down-regulation of the μ-opioid receptor have been elucidated. Interestingly, Ser 356 and Ser363 are not specifically phosphorylated, however, over-expression of GRK2 or arrestin reverses the observed attenuation. Altogether, these results suggest that phosphorylation of the μ-opioid receptor is not obligatory for etorphine-induced down-regulation. In contradiction, point mutation of the twelve serine and threonine residues to alanine within the carboxyl tail of the μ-opioid receptor has no effect on the rate of desensitization when compared to the wild-type receptor. This lack of correlation suggests that phosphorylation may not have as prominent a role in the regulation of the μ-opioid receptor as with other G-protein-coupled-receptors. In total, this investigation highlights the complexity of the regulation of the μ-opioid receptor and indicates that other constituents are involved in these processes.

There is conflicting literature regarding the ability of purposeful therapeutic activity to reduce negative physical and mental signs of aging. This researcher assessed whether Tai Chi increased geriatric perceived quality of life as measured by four scales: perceived improvements in (a) functional mobility and (b) activities of daily living; and perceived reduction in (c) mental and physical conditions and (d) need for medications. In addition, this study hypothesized a correlation between length of time spent attending Tai Chi classes, practicing Tai Chi outside of class and the scales. Questionnaires were sent to 56 geriatric Tai Chi class participants at various sites over the course of one year. Statistical tests included: Friedman, Analysis of Variance, and Paired Sign. A combination of Tai Chi class and practice yielded significant results for perceived improvements in functional mobility and perceived reduced need for certain medications.

This chapter contains sections titled: Background: The Convergence of High Content Analysis and RNAi Integrating HT‐RNAi and HCA in Drug Discovery: The Potential Combining RNAi and HCA in One Assay — The Reality HCA‐Based RNAi Studies — The Future Acknowledgments References

A series of porous crystalline materials known as metal–organic materials are prepared, and a full sorption study shows that controlled pore size (rather than large surface area) coupled with appropriate chemistry lead to materials exhibiting fast and highly selective CO 2 sorption. Pore performance good for energy storage Metal organic frameworks are porous crystalline materials widely studied as potential gas separation and storage materials for clean energy applications. A general trend in this field has been the development of materials with the largest possible surface area with the aim of maximizing uptake of gases. In this paper the authors generate a series of metal organic frameworks and carry out sorption experiments that suggest that surface area may not be as important as was thought. Rather, pore size, coupled with appropriate chemistry, are the keys to fast CO 2 uptake and strong CO 2 sorption. Materials designed on these principles attain high selectivity for CO 2 over nitrogen, oxygen, methane and hydrogen even in the presence of moisture. The energy costs associated with the separation and purification of industrial commodities, such as gases, fine chemicals and fresh water, currently represent around 15 per cent of global energy production, and the demand for such commodities is projected to triple by 2050 (ref. 1 ). The challenge of developing effective separation and purification technologies that have much smaller energy footprints is greater for carbon dioxide (CO 2 ) than for other gases; in addition to its involvement in climate change, CO 2 is an impurity in natural gas, biogas (natural gas produced from biomass), syngas (CO/H 2 , the main source of hydrogen in refineries) and many other gas streams. In the context of porous crystalline materials that can exploit both equilibrium and kinetic selectivity, size selectivity and targeted molecular recognition are attractive characteristics for CO 2 separation and capture, as exemplified by zeolites 5A and 13X (ref. 2 ), as well as metal–organic materials (MOMs) 3 , 4 , 5 , 6 , 7 , 8 , 9 . Here we report that a crystal engineering 7 or reticular chemistry 5 , 9 strategy that controls pore functionality and size in a series of MOMs with coordinately saturated metal centres and periodically arrayed hexafluorosilicate (SiF 6 2− ) anions enables a ‘sweet spot’ of kinetics and thermodynamics that offers high volumetric uptake at low CO 2 partial pressure (less than 0.15 bar). Most importantly, such MOMs offer an unprecedented CO 2 sorption selectivity over N 2 , H 2 and CH 4 , even in the presence of moisture. These MOMs are therefore relevant to CO 2 separation in the context of post-combustion (flue gas, CO 2 /N 2 ), pre-combustion (shifted synthesis gas stream, CO 2 /H 2 ) and natural gas upgrading (natural gas clean-up, CO 2 /CH 4 ).

Feeding stimulates robust increases in muscle protein synthesis (MPS); however, ageing may alter the anabolic response to protein ingestion and the subsequent aminoacidaemia. With this as background, we aimed to determine in the present study the dose–response of MPS with the ingestion of isolated whey protein, with and without prior resistance exercise, in the elderly. For the purpose of this study, thirty-seven elderly men (age 71 (sd 4) years) completed a bout of unilateral leg-based resistance exercise before ingesting 0, 10, 20 or 40 g of whey protein isolate (W0–W40, respectively). Infusion of l-[1-13C]leucine and l-[ring-13C6]phenylalanine with bilateral vastus lateralis muscle biopsies were used to ascertain whole-body leucine oxidation and 4 h post-protein consumption of MPS in the fed-state of non-exercised and exercised leg muscles. It was determined that whole-body leucine oxidation increased in a stepwise, dose-dependent manner. MPS increased above basal, fasting values by approximately 65 and 90 % for W20 and W40, respectively (P < 0·05), but not with lower doses of whey. While resistance exercise was generally effective at stimulating MPS, W20 and W40 ingestion post-exercise increased MPS above W0 and W10 exercised values (P < 0·05) and W40 was greater than W20 (P < 0·05). Based on the study, the following conclusions were drawn. At rest, the optimal whey protein dose for non-frail older adults to consume, to increase myofibrillar MPS above fasting rates, was 20 g. Resistance exercise increases MPS in the elderly at all protein doses, but to a greater extent with 40 g of whey ingestion. These data suggest that, in contrast to younger adults, in whom post-exercise rates of MPS are saturated with 20 g of protein, exercised muscles of older adults respond to higher protein doses.

BRAF -mutant melanomas are more likely than NRAS -mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS -mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single neonatal, ultraviolet-AI (UVA; 340–400 nm) or ultraviolet-B (UVB; 280–390 nm) exposure in mouse models heterozygous for mutant Braf or homozygous for mutant Nras . Tumor onset was accelerated by UVB, but not UVA, and the resulting melanomas contained recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A. Melanomas from UVB-irradiated, Braf -mutant mice averaged twice as many single-nucleotide variants and five times as many dipyrimidine variants than tumors from similarly irradiated Nras -mutant mice. A mutational signature discovered in UVB-accelerated tumors mirrored COSMIC signatures associated with human skin cancer and was more prominent in Braf - than Nras -mutant murine melanomas. These data show that a single UVB exposure yields a greater burden of mutations in murine tumors driven by oncogenic Braf.

Aeromonas hydrophila has increasingly been implicated as a virulent and antibiotic-resistant etiologic agent in various human diseases. In a previously published case report, we described a subject with a polymicrobial wound infection that included a persistent and aggressive strain of A .  hydrophila (E1), as well as a more antibiotic-resistant strain of A .  hydrophila (E2). To better understand the differences between pathogenic and environmental strains of A .  hydrophila , we conducted comparative genomic and functional analyses of virulence-associated genes of these two wound isolates (E1 and E2), the environmental type strain A .  hydrophila ATCC 7966 T , and four other isolates belonging to A .  aquariorum , A .  veronii , A .  salmonicida , and A .  caviae . Full-genome sequencing of strains E1 and E2 revealed extensive differences between the two and strain ATCC 7966 T . The more persistent wound infection strain, E1, harbored coding sequences for a cytotoxic enterotoxin (Act), a type 3 secretion system (T3SS), flagella, hemolysins, and a homolog of exotoxin A found in Pseudomonas aeruginosa . Corresponding phenotypic analyses with A .  hydrophila ATCC 7966 T and SSU as reference strains demonstrated the functionality of these virulence genes, with strain E1 displaying enhanced swimming and swarming motility, lateral flagella on electron microscopy, the presence of T3SS effector AexU, and enhanced lethality in a mouse model of Aeromonas infection. By combining sequence-based analysis and functional assays, we characterized an A .  hydrophila pathotype, exemplified by strain E1, that exhibited increased virulence in a mouse model of infection, likely because of encapsulation, enhanced motility, toxin secretion, and cellular toxicity. IMPORTANCE Aeromonas hydrophila is a common aquatic bacterium that has increasingly been implicated in serious human infections. While many determinants of virulence have been identified in Aeromonas , rapid identification of pathogenic versus nonpathogenic strains remains a challenge for this genus, as it is for other opportunistic pathogens. This paper demonstrates, by using whole-genome sequencing of clinical Aeromonas strains, followed by corresponding virulence assays, that comparative genomics can be used to identify a virulent subtype of A .  hydrophila that is aggressive during human infection and more lethal in a mouse model of infection. This aggressive pathotype contained genes for toxin production, toxin secretion, and bacterial motility that likely enabled its pathogenicity. Our results highlight the potential of whole-genome sequencing to transform microbial diagnostics; with further advances in rapid sequencing and annotation, genomic analysis will be able to provide timely information on the identities and virulence potential of clinically isolated microorganisms. Aeromonas hydrophila is a common aquatic bacterium that has increasingly been implicated in serious human infections. While many determinants of virulence have been identified in Aeromonas , rapid identification of pathogenic versus nonpathogenic strains remains a challenge for this genus, as it is for other opportunistic pathogens. This paper demonstrates, by using whole-genome sequencing of clinical Aeromonas strains, followed by corresponding virulence assays, that comparative genomics can be used to identify a virulent subtype of A .  hydrophila that is aggressive during human infection and more lethal in a mouse model of infection. This aggressive pathotype contained genes for toxin production, toxin secretion, and bacterial motility that likely enabled its pathogenicity. Our results highlight the potential of whole-genome sequencing to transform microbial diagnostics; with further advances in rapid sequencing and annotation, genomic analysis will be able to provide timely information on the identities and virulence potential of clinically isolated microorganisms.