Quadruplewild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways

A subset of GISTs lack mutations in the KIT/PDGFRA or RAS pathways and yet retain an intact succinate dehydrogensase (SDH) complex. We propose that these KIT/PDGFRA/SDH/RAS-P WT GIST tumors be designated as quadruple wild-type (WT) GIST. Further molecular and clinicophatological characterization of quadruple WT GIST will help to determine their prognosis as well as assist in the optimization of medical management, including clinical test of novel therapies

SDHC methylation in gastrointestinal stromal tumors (GIST): a case report

Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type. Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST

Factors Influencing Largemouth Bass Recruitment: Implications For The Illinois Management And Stocking Program

During the past segment, all activities outlined in the annual work plan were accomplished and within the specified budget. The goal of this study is to develop management strategies that maximize growth, recruitment, and harvest of largemouth bass Micropterus salmoides in Illinois impoundments. Largemouth bass are frequently stocked in many Illinois impoundments to compensate for variable recruitment. Even so, the long-term contribution of stocked fish to recruitment and harvest of natural bass populations is unknown and we are addressing these questions. In addition, information on the importance of rearing technique, size of stocked fish, forage base, cover, resident predators, physical-chemical conditions, and stocking stress in determining largemouth bass stocking success is needed to optimize use of hatchery produced fish. Because stocking is only one of several management options for this species, it is critical that additional information on factors limiting recruitment processes be identified.There was no new activity in Job 101.1 as final recommendations were presented in previous reports. In Job 101.2, we continued our evaluation of stocking success of largemouth bass. We conducted additional dataanalysis ina study comparing intensive and extensive rearing techniques. Intensively reared fish were raised in raceways and fed pellets, whereasextensively reared fish were raised in ponds and fed zooplankton and minnows. Extensivelyreared fish experienced better survival through the spring following stocking, but by the following fall (age-1) there was no difference in abundance between the two rearing techniques. We observed a high level of variation inthe number of fish producedinthe rearing ponds. Cost of rearing was much higher for the extensively reared fish for both hatchery ponds and lake side rearing facilities. Higher initial survival and larger size in the fall of extensively reared fish initially appears to justify the added cost. However, long term survival was low for both rearing types and very few stocked fish were recruited to the fishery. In this segment, we also continued to evaluate different stocking techniques to improve survival of stocked largemouth bass. Three lakes were stocked with largemouth bass, with half the fish stocked at the boat ramp and half dispersed throughout the lake and into woody or vegetated habitat. Very few stocked fish have been recaptured from any stockings conducted thus far regardless of method. We plan to continue additional stockings and adjust stocking time to minimize high temperatures and potential related mortality. CPUE of stocked fish in this experiment has been lower than observed in stockings conducted asprevious partsof this project and we hope to observe greater survival in the future in order to evaluate the success of these two stocking strategies.In Job 101.3, we evaluated the survival and reproductive success of stocked largemouth bass relative to resident populations. To determine the contribution of stocked fish, the MDH B2B2 allele was used as a genetic tag for fingerlings stocked into six study lakes. Once these fish were part of the reproducing population, it was possible to assess the reproductive success and recruitment of these stocked fish in five of the six lakes by comparing the pre-stocking with post stocking MDH B2 allele frequencies. We also looked at lake size and resident bass CPUE as a possible factors that may have influenced reproductive success. Stocked fish survival to adulthood was variable in the five study lakes, ranging from less than 10% to around 35%. Contribution of stocked fish to reproduction was also variable and was higher in small lakes than in larger ones. The density of resident bass as measured by CPUE had no relationship to the contribution of stocked bass reproduction in the lakes that we studied. Based on the proportion of stocked adults in the populations we could predict the change in the frequency of the MDH B2 allele to determine how reproductive success of stocked fish compared to wild fish. We found that reproductive success of stocked fish was similar to wild fish. Our results indicate that stocking is most likely to be successful in small lakes and that the genetic influence of stocked fish will persist in successive generations. In future reports, we will examine how prey availability could affect stocked largemouth bass condition and ability to secure good nesting sites differently than wild fish. In Job 101.4, we continued a multi lake experiment examining the influence of vegetation on largemouth bass recruitment. Lakes were divided into treatments by the vegetation management strategy. Two lakes (Stillwater and Airport) were treated for vegetation to reduce the vegetation present and yield more intermediate vegetation densities. The vegetation treatments were initiated in this segment and have been successful at reducing vegetation in Stillwater Lake, but not Airport Lake. Two lakes (Paradise and Dolan) experienced management to increase vegetation. Vegetation planting was initiated in 2008in Lake Paradiseand planting efforts continued in this segment. We areevaluating the success of different species of vegetation and the size of cage used. American pondweed has shown the greatest long-term survival and the large cages have been most effective in producing vegetation. In this segment, American pondweed was planted in 5 additional cages and a number of cages were expanded to promotethe spread of successful cages. We also evaluated fish and invertebrate communities associated with vegetated and non-vegetatedcages and observed higher densities of both fish and invertebrates in vegetated cages. Rehabilitation at Dolan Lake has continued to yield higher vegetation and reduced gizzard shad and carp numbers. There is some evidence of gizzard shad populations rebounding. Four lakes with experimental treatments and 7control lakes were monitored for fish populations, vegetation densities, and prey organisms and will be compared through time as the management experiment continues.CPUE of young of year largemouth bass was higher in lakes with greater vegetation densities, but differences were not significant. The density of larval gizzard shad was significantly correlated with the proportion of lake area and perimeter that was vegetated. No other lake conditions that were measured were related to vegetation density. We will continue to monitor vegetation, fish, and prey communities in the 11 research lakes to evaluate the role of vegetation management to increase largemouth bass recruitment.In this segment, we also continuedto examine patterns in abundance of young-of-year largemouth bass, other fish species, and associated biotic communities a mong vegetated, woody, and open lakeshore habitat types in two Illinois lakes. While we did not find significant differences in age-0 largemouth bass densities among the microhabitat types sampled in our enclosure surveys, we did find significant differences in the community composition and abundance of potentially important prey items (juvenile sunfishes, caddisflies, chironomids, stoneflies and cyclopoid copepods). Increases in abundance of potential invertebrate and fish prey in vegetated and wooded sites supports the idea that these habitats are important sources of littoral productivity. There is potential for dam escapement to influence largemouth bass recruitment. To assess dam escapement, we sampled downstream of the dam on two reservoirs, Ridge Lake and Forbes Lake via backpack electrofishing and seines. Some largemouth bass were observed in sampling below the dam at both Forbes and Ridge Lake following high water events however there were few fish in all sampling. The assessment of dam escapement is in the very early stages of implementation and evaluation and much more data is needed to draw conclusions about the effect of escapement on largemouth bass populations and recruitment. Additional data will be collected so that a baseline can be established in order to compare largemouth bass numbers after an increased discharge event to largemouth bass numbers during low flow periods. There is potential for angling to have a large influence on largemouth bass populations. Competitive tournament fishing for black bass has grown rapidly over the past several years. Previous work has shown high levels of mortality associated with these tournaments in other parts of the United States. However, little is known about the effects of tournaments on largemouth bass recruitment. In Job 101.5, we continued to examine effects of tournaments for largemouth bass. In this segment, we also continued monitoring largemouth bass spawning activities at Lincoln Trail Lake. Water clarity limited our ability to identify largemouth bass nests in spring 2011. We will continue to evaluate nesting activity, nest guarding behavior, vulnerability to angling, and nest predation in future segments. In this segment, we continued to conduct largemouth bass tournaments in alternating years on Ridge Lake to evaluate their effect on recruitment. A series of spring tournaments were conducted in 2007 and 2010 and largemouth bass populations were compared among tournament and non-tournament years. Initial results show no differences in recruitment between tournament and non-tournament years. In addition, no changes were observed in adult largemouth bass abundance or size structure. These results are preliminary and additional years will be needed to evaluate treatment effects. We are continuing a pond experiment examining the population effects of tournament angling during the spawning season on largemouth bass recruitment. In the current segment, we initiated the second year of the two-year study. Results from the first year indicate that tournament angling has a moderate effect on largemouth bass recruitment in terms of numbers, and a rather large effect on young-of-year largemouth bass biomass. After adjustment for summer zooplankton abundance, which was a significant covariate for largemouth bass recruitment, ponds in which tournament angling was conducted had approximately 22% less recruits and 64% less young-of-year biomass than control ponds. In the future segment, we will include data from the second year to strengthen results. In this segment we also continued to evaluate tournament activity on nine Illinois lakes as well as 5 control lakes with no tournaments. Tournament data was used to calculate total tournament angler hours per acre as well as catch rates and statistics on the sizes and types of tournaments on each lake. We evaluated the largemouth bass population in each lake by performing electrofishing transects in the spring. CPUE of young-of-year largemouth bass and largemouth bass over 14 inches was not correlated with tournament pressure (angler hours/acre). The mean number of fish weighed in at a tournament was correlated with CPUE of largemouth bass over 14 inches and was also correlated with lake size. Tournament lakes did not have reduced recruitment when compared to lakes with no tournament angling. Tournament lakes had higher CPUE of largemouth bass larger than 14 inches than control lakes, but it is difficult to separate the effects of tournaments from the size of the lake and the fact that tournaments may target lakes with more abundant adult largemouth bass. We will continue to collect tournament and largemouth bass population data in future segments to further evaluate and understand how tournaments influence largemouth bass populations. In Job 101.6, a portion of Clinton Lake that was closed to fishing was sampled to continue assessment of the effects of a refuge on largemouth bass populations. Electrofishing samples yielded a higher abundance of adult largemouth bass in the refuge than in the main lake. No increase in the number of largemouth bass has been observed throughout the lake. Sampling will continue at Clinton Lake to monitor largemouth bass populations for changes resulting from the refuge. We also continued sampling Otter Lake as an additional location to evaluate refuges. Electrofishing and seine samples were conducted in two refuge sites as well as three control sites. The refuge was closed to fishing in June 2010 and we initiated sampling for post refuge conditions. We also began assessing effects of harvest regulations on largemouth bass populations. In this segment, we expanded our database of lakes using the Fisheries Analysis System (FAS) containing electrofishing data from 2000-2007 collected by DNR biologists. We grouped lakes by regulation type into 7 groups; Bag by Size(Bag limit above and below a specified size), Catch-and Release (no harvest allowed), Standard (14” length limit, 6 fish creel), Lowered Bag (14” length limit, 14” length limit, 6 fish bag limit), Raised Length/Low Bag (>14” length limit, <6 fish bag limit), No Length (No minimum size limit), and Slot (no fish harvest slot). We compared catch rates of young-of-year and adults (greater than 14 inches), memorable (greater than 510 mm), and proportion stock density (PSD). Lakes with slot limit regulations had the highest CPUE of young-of-year, total, and memorable sized largemouth bass. No other significant differences existed among groups. In future segments, we will combine FAS, INHS sampling and creel data to further evaluate regulations and how they affect angler catch rates. These data can then be used to guide future discussions about various management experiments that might be implemented.Division of Fisheries, Illinois Department of Natural Resources Grant/Contract No: F-135-Runpublishednot peer reviewe

Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST)

BACKGROUND: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. METHODS: We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. RESULTS: We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). CONCLUSION: We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

IMPORTANCE: Immune dysregulation contributes to poorer outcomes in COVID-19. OBJECTIVE: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. INTERVENTIONS: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). MAIN OUTCOMES AND MEASURES: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. RESULTS: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. CONCLUSIONS AND RELEVANCE: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04593940

The mutable nature of particle-core excitations with spin in the one-valence-proton nucleus ¹³³Sb

The γ-ray decay of excited states of the one-valence-proton nucleus ¹³³Sb has been studied using cold-neutron induced fission of ²³⁵U and ²⁴¹Pu targets, during the EXILL campaign at the ILL reactor in Grenoble. By using a highly efficient HPGe array, coincidences between γ-rays prompt with the fission event and those delayed up to several tens of microseconds were investigated, allowing to observe, for the first time, high-spin excited states above the 16.6 μs isomer. Lifetimes analysis, performed by fast-timing techniques with LaBr₃(Ce) scintillators, revealed a difference of almost two orders of magnitude in B(M1) strength for transitions between positive-parity medium-spin yrast states. The data are interpreted by a newly developed microscopic model which takes into account couplings between core excitations (both collective and non-collective) of the doubly magic nucleus ¹³²Sn and the valence proton, using the Skyrme effective interaction in a consistent way. The results point to a fast change in the nature of particle-core excitations with increasing spin

Factors Influencing Largemouth Bass Recruitment: Implications for the Illinois Management and Stocking Program

Annual Progress Report, Federal Aid Project F-135-R, July 1, 2005 - June 30, 2006Report issued on: August 2006INHS Technical Report submitted to the Illinois Department of Natural Resources, Division of Fisherie