Platelet activation and aggregation are critical to the initiation of hemostasis after trauma with hemorrhage. Platelet dysfunction is a well-recognized phenomenon contributing to trauma-induced ...coagulopathy. The goal of this study was to evaluate the timing and severity of platelet dysfunction in massively transfused, traumatically injured patients during the first 72 hours after injury and its association with 30-day survival.
A retrospective secondary cohort study of platelet count and function was performed using samples from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial. Platelet characteristics were measured at 8 timepoints during the first 72 hours of hospitalization and compared between 30-day survivors and nonsurvivors. Platelet counts were assessed via flow cytometry. Platelet function was analyzed with the use of serial thrombelastography and impedance aggregometry with agonists arachidonic acid, adenosine diphosphate, collagen, thrombin receptor activating peptide, and ristocetin.
In total, 680 patients were included for analysis. Platelet counts were significantly lower from baseline to 72 hours after hospital admission with further 1.3 to 2-fold reductions noted in nonsurvivors compared to survivor patients. Platelet aggregation via adenosine diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, and ristocetin was significantly lower in nonsurvivors at all time points. The nadir of platelet aggregation was 2 to 6 hours after admission with significant improvements in viscoelastic maximum clot formation and agonist-induced aggregation by 12 hours without concomitant improvement in platelet count.
Platelet aggregability recovers 12 hours after injury independent of worsening thrombocytopenia. Failure of platelet function to recover portends a poor prognosis.
Although early balanced blood product resuscitation has improved mortality after traumatic injury, many patients still suffer from inflammatory complications. The goal of this study was to identify ...inflammatory mediators associated with death and multiorgan system failure following severe injury after patients undergo blood product resuscitation.
A retrospective secondary analysis of inflammatory markers from the Pragmatic Randomized Optimal Platelet and Plasma Ratios study was performed. Twenty-seven serum biomarkers were measured at 8 time points in the first 72 hours of care and were compared between survivors and nonsurvivors. Biomarkers with significant differences were further analyzed by adjudicated cause of 30-day mortality.
Biomarkers from 680 patients were analyzed. Seven key inflammatory markers (IL-1ra, IL-6, IL-8, IL-10, eotaxin, IP-10, and MCP-1) were further analyzed. These cytokines were also noted to have the highest hazard ratios of death. Stepwise selection was used for multivariate analysis of survival by time point. MCP-1 at 2 hours, eotaxin and IP-10 at 12 hours, eotaxin at 24 hours, and IP-10 at 72 hours were associated with all-cause mortality.
Early systemic inflammatory markers are associated with increased risk of mortality after traumatic injury. Future studies should use these biomarkers to prospectively calculate risks of morbidity and causes of mortality for all trauma patients.
Abstract
Gliomas are the most common malignant brain tumors and characterized by high recurrence rate and therapeutic resistance. Gliomas are clinically separated by mutations in isocitrate ...dehydrogenase (IDH) genes, but all subtypes have an altered energy metabolism. Mitochondria are essential cellular organelles that mediate many biological processes associated with tumorigenesis, such as energy metabolism and cell death, that can be impacted by mitochondrial mutations and copy number. As part of the Glioma Longitudinal AnalyiSiS consortium, we characterized mitochondrial genome evolution in response to treatment, using whole-genome sequencing data and associated RNA sequencing data from 152 paired tumor samples from 76 patients. Mitochondrial mutations are unequally distributed across the mitochondrial glioma genome, with only 4 of 13 mtDNA genes harboring a mutation across the cohort. Previous consortium analyses have investigated nuclear DNA hypermutation and changes in aneuploidy in response to chemotherapy and radiation treatment. Previous findings have identified hypermutation and copy number alterations as mechanisms of therapeutic resistance in glioma, but did not include analyses on mitochondrial DNA. Our analysis identified key differences between mitochondrial genome evolution and nuclear genome evolution. The mitochondrial mutational burden was not correlated with an increase in nuclear mutational burden. Unlike the nuclear DNA, we did not observe any samples with treatment-associated hypermutation. Mitochondrial copy number varied greatly but was increased at recurrence in IDH wild-type tumors. In tumors with a mutation in the IDH1 gene, mitochondrial copy number decreases were associated with an increase in aneuploidy score in samples that received radiation therapy. Expression analyses highlighted key differences in the active repair mechanisms between mtDNA and nuclear DNA. Our findings shed light on the variations in DNA repair mechanisms between the nucleus and the cytoplasm in glioma and lay the foundation for further analyses on the co-evolution of the mitochondrial and nuclear genomes in treatment-resistant tumors.
Citation Format: Taylor E. Wade, Frederick S. Varn, Kevin C. Johnson, Roel G. Verhaak. Mitochondrial genome evolution in gliomas under therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5786.
We review the ecology and conservation of three lesser‐known chars (genus Salvelinus): Dolly Varden (S. malma), white‐spotted char (S. leucomaenis), and bull trout (S. confluentus). Dolly Varden is ...distributed across the northern Pacific Rim and co‐occurs with bull trout and white‐spotted char at the southern extremes of its range. In contrast, bull trout and white‐spotted char are naturally isolated, with the former restricted to North America and the latter distributed in northeastern Asia. Though the range of Dolly Varden overlaps with the two other chars, it is most closely related to Arctic char (S. alpinus), whereas bull trout and white‐spotted char are sister taxa. Each species exhibits diverse life histories with respect to demographic characteristics, trophic ecology, and movement. This diversity appears to be tied to environmental variability (e.g., temperature, habitat connectivity), resource availability (e.g., food), and species interactions. Increasingly, these interactions involve nonnative species including nonnative salmonines and changes in food webs related to establishment of species such as Mysis shrimp in large lakes. As humans expand into the remote and pristine habitats that support these three chars, we encourage proactive consideration of the lessons learned where chars have already declined and internationally‐based research and conservation.
In a study of genetic variation in the AIDS virus, HTLV-III/LAV, sequential virus isolates from persistently infected individuals were examined by Southern blot genomic analysis, molecular cloning, ...and nucleotide sequencing. Four to six virus isolates were obtained from each of three individuals over a 1-year or 2-year period. Changes were detected throughout the viral genomes and consisted of isolated and clustered nucleotide point mutations as well as short deletions or insertions. Results from genomic restriction mapping and nucleotide sequence comparisons indicated that viruses isolated sequentially had evolved in parallel from a common progenitor virus. The rate of evolution of HTLV-III/LAV was estimated to be at least 10$^{-3}$ nucleotide substitutions per site per year for the env gene and 10$^{-4}$ for the gag gene, values a millionfold greater than for most DNA genomes. Despite this relatively rapid rate of sequence divergence, virus isolates from any one patient were all much more related to each other than to viruses from other individuals. In view of the substantial heterogeneity among most independent HTLV-III/LAV isolates, the repeated isolation from a given individual of only highly related viruses raises the possibility that some type of interference mechanism may prevent simultaneous infection by more than one major genotypic form of the virus.
Abstract
Diffuse glioma is characterized by a poor prognosis and a universal resistance to therapy, though the evolutionary processes behind this resistance remain unclear. The Glioma Longitudinal ...Analysis (GLASS) Consortium has previously demonstrated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single-cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the microenvironment and the administration of standard-of-care therapy. To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA- and/or DNA-sequencing data from temporally separated tumor pairs of over 300 adult patients with IDH-wild-type or IDH-mutant glioma. In a subset of these tumor pairs, we additionally performed multiplex immunofluorescence to capture the spatial relationship between tumor cells and their microenvironment. Recurrent tumors exhibited diverse changes that were attributable to changes in histological features, somatic alterations, and microenvironment interactions. IDH-wild-type tumors overall were more invasive at recurrence and exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. In contrast, recurrent IDH-mutant tumors exhibited a significant increase in proliferative expression programs that correlated with discrete genetic changes. Hypermutation and acquired CDKN2A homozygous deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor expansion. A transition to the mesenchymal phenotype was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells, providing opportunities to target this transition through therapy. Collectively, our results uncover recurrence-associated changes in genetics and the microenvironment that can be targeted to shape disease progression following initial diagnosis.
Citation Format: Frederick S. Varn, Kevin C. Johnson, Jan Martinek, Jason T. Huse, MacLean P. Nasrallah, Pieter Wesseling, Lee A. Cooper, Tathiane M. Malta, Taylor E. Wade, Thais S. Sabedot, Daniel J. Brat, Peter V. Gould, Adelheid Wöehrer, Kenneth Aldape, Azzam Ismail, Floris P. Barthel, Hoon Kim, Emre Kocakavuk, Nazia Ahmed, Kieron White, Santhosh Sivajothi, Indrani Datta, Jill S. Barnholtz-Sloan, Spyridon Bakas, Fulvio D'Angelo, Hui K. Gan, Luciano Garofano, Mustafa Khasraw, Simona Migliozzi, D. Ryan Ormond, Sun Ha Paek, Erwin G. Van Meir, Annemiek M. Walenkamp, Colin Watts, Michael Weller, Tobias Weiss, Karolina Palucka, Lucy F. Stead, Laila M. Poisson, Houtan Noushmehr, Antonio Iavarone, Roel G. Verhaak, The GLASS Consortium. Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2168.
BACKGROUND Clinically abnormal retinal vessels unique to cerebral malaria have previously been shown to be associated with a poor outcome in African children. There have been no studies of the ...histopathological correlates of these vessels. DESIGN This is a descriptive study of the clinical-histopathological correlates of the retinal vessels of 11 children who died with cerebral malaria. RESULTS The retinal vessels in children with cerebral malaria contained many parasitized red blood cells; these cells tended to cluster at the periphery of vessels or, in the case of capillaries, to fill the vessel. Those with late-stage parasites had markedly reduced amounts of hemoglobin. The pattern of dehemoglobinization corresponds to the pattern of clinically abnormal vessels. CONCLUSIONS The sequestration of late-stage parasitized red blood cells with reduced amounts of hemoglobin accounts for the unique white and pale orange retinal vessels seen in cerebral malaria. Clinical examination of these "marked" vessels offers a method to monitor a basic pathophysiological process of cerebral malaria in vivo.Arch Ophthalmol. 2000;118:924-928-->
Land‐based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of ...crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co‐benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay‐loam agricultural soil with a high loading (10 kg/m2) of relatively coarse‐grained crushed basalt significantly increased the yield (21 ± 9.4%, SE) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds. Yield increases resulted from the basalt treatment after 120 days without P‐ and K‐fertilizer addition. Shoot silicon concentrations also increased significantly (26 ± 5.4%, SE), with potential benefits for crop resistance to biotic and abiotic stress. Elemental budgets indicate substantial release of base cations important for inorganic carbon removal and their accumulation mainly in the soil exchangeable pools. Geochemical reactive transport modelling, constrained by elemental budgets, indicated CO2 sequestration rates of 2–4 t CO2/ha, 1–5 years after a single application of basaltic rock dust, including via newly formed soil carbonate minerals whose long‐term fate requires assessment through field trials. This represents an approximately fourfold increase in carbon capture compared to control plant–soil systems without basalt. Our results build support for ERW deployment as a CDR technique compatible with spreading basalt powder on acidic loamy soils common across millions of hectares of western European and North American agriculture.
Amending a UK clay‐loam agricultural soil with a high loading (10 kg/m2) of relatively coarse‐grained crushed basalt significantly increased the yield (21 ± 9.4%) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds, and CO2 sequestration potential.
Offspring of older mothers are at increased risk of adverse birth outcomes, childhood cancers, type 1 diabetes, and neurodevelopmental disorders. The underlying biologic mechanisms for most of these ...associations remain obscure. One possibility is that maternal aging may produce lasting changes in the epigenetic features of a child's DNA. To test this, we explored the association of mothers' age at pregnancy with methylation in her offspring, using blood samples from 890 Norwegian newborns and measuring DNA methylation at more than 450,000 CpG sites across the genome. We examined replication of a maternal-age finding in an independent group of 1062 Norwegian newborns, and then in 200 US middle-aged women. Older maternal age was significantly associated with reduced methylation at four adjacent CpGs near the 2nd exon of KLHL35 in newborns (p-values ranging from 3x10-6 to 8x10-7). These associations were replicated in the independent set of newborns, and replicated again in women 40 to 60 years after their birth. This study provides the first example of parental age permanently affecting the epigenetic profile of offspring. While the specific functions of the affected gene are unknown, this finding opens the possibility that a mother's age at pregnancy could affect her child's health through epigenetic mechanisms.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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