•Internal (eg, design) and external (eg, SCT) factors affect endpoint interpretation.•OS is the gold standard in AML endpoints, but other endpoints are gaining ground.•Time-to-event endpoints are ...often interpreted using the HR and associated P values.
Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial’s statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.
Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that ...supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington's disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders.
Argyrosomus regius (commonly referred to as meagre), is one of Europe's largest coastal bony fish species and supports important recreational and commercial fisheries in the Atlantic and ...Mediterranean coasts. Demand for this species, and more recently for their swim bladders, has led to regional population declines and growing importance as an aquaculture species. Despite intense research in captivity, little is known about the spatial ecology of A. regius's wild population, including basic information such as vertical migrations and depth/temperature preferences. Previous research based on indirect data suggests a seasonal habitat shift from shallow to deeper waters, but this has never been validated through direct high-resolution movement data. In this study, we tagged 13 adult A. regius with pop-up satellite archival tags in the South of Portugal, which successfully returned data from 11 individuals including high-resolution data from six recovered tags (mean, range: 167 days, 28-301 days). We found that adults of this population spend 95.2% of their time between 5 and 75 m depth (mean ± SD, 30.9m ± 18.3m) and do not venture beyond 125 m. Across seasons, A. regius move across water temperatures between 13.3 and 24.8°C with a preferred thermal range between 14 and 18°C where they spent 75.4% of their time. The inferential modelling using this electronic data validated previous hypotheses by showing significant differences between a shallower and warmer summer habitat vs. a deeper and cooler winter habitat. Visual investigation of the diel effects on depth preferences suggests subtle changes in depth use between day and night during the warmer months of the year. We speculate that these patterns are in response to the species' behavioural ecology and physiology, reflecting the seasonal changes in water stratification and presence of prey, as well as on the species reproduction, which results in summer spawning aggregations in shallower areas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional ...profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV– and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV– and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.
Display omitted
•Single-cell RNA-seq revealed distinct immune profiles in HPV– and HPV+ HNSCC•B cells, myeloid cells, and CD4+ Tconv cells were divergent by high-dimensional analysis•Multispectral imaging uncovered immune structures (TLSs) associated with HPV+ disease•T follicular helper signature was associated with favorable survival in TCGA patients
Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or human papillomavirus (HPV). Cillo et al. determine single-cell transcriptional profiles of peripheral and intra-tumoral immune populations from patients with HPV– and HPV+ HNSCC and healthy donors. These datasets, accompanied by spatial organization information, provide a resource for further study of immunity to viral- and carcinogen-induced cancers.
The intense use of herbicides for weed control in agriculture causes selection pressure on soil microbiota and water ecosystems, possibly resulting in changes to microbial processes, such as ...biogeochemical cycles. These xenobiotics may increase the production of reactive oxygen species and consequently affect the survival of microorganisms, which need to develop strategies to adapt to these conditions and maintain their ecological functionality. This study analyzed the adaptive responses of bacterial isolates belonging to the same species, originating from two different environments (water and soil), and subjected to selection pressure by herbicides. The effects of herbicide Callisto and its active ingredient, mesotrione, induced different adaptation strategies on the cellular, enzymatic, and structural systems of two Bacillus megaterium isolates obtained from these environments. The lipid saturation patterns observed may have affected membrane permeability in response to this herbicide. Moreover, this may have led to different levels of responses involving superoxide dismutase and catalase activities, and enzyme polymorphisms. Due to these response systems, the strain isolated from water exhibited higher growth rates than did the soil strain, in evaluations made in oligotrophic culture media, which would be more like that found in semi-pristine aquatic environments. The influence of the intracellular oxidizing environments, which changed the mode of degradation of mesotrione in our experimental model and produced different metabolites, can also be observed in soil and water at sites related to agriculture. Since the different metabolites may present different levels of toxicity, we suggest that this fact should be considered in studies on the fate of agrochemicals in different environments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, ...nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings. Patients receiving TKI agents for CML should be monitored for signs and symptoms of toxicity throughout therapy. Preemptive assessment, early toxicity recognition, and prompt management of cardiovascular, metabolic, and pulmonary toxicities can minimize treatment-limiting complications and improve outcomes in patients with CML.
A new extraction phase based on hydrogel disks of polyvinyl alcohol (PVOH) and pectin was proposed, characterized and evaluated for the extraction of six steroidal hormones (estriol, estrone, ...17β-estradiol, 17α-ethinylestradiol, progesterone, and testosterone) in aqueous samples with subsequent determination by gas chromatography-tandem mass spectrometry (GC-MS/MS) after the derivatization procedure. The developed extraction procedure was based on the solid phase extraction (SPE) technique, but employed hydrogel as the sorbent phase. The effects of several parameters, including the amount and composition of the sorbent phase, pH, sample volume, flow rate, and gel swelling over the extraction efficiency, were evaluated. Gels with lower swelling indexes and larger amounts of sorbent ensured higher extraction yields of analytes. The main benefits of using the PVOH/pectin-based hydrogel as the extraction phase are the ease of synthesis, low-cost preparation, and the possibility of reusing the extraction disks. Limits of quantification of 0.5 μg L
for estrone and 17β-estradiol, and 1 μg L
for testosterone, 17α-ethinylestradiol, progesterone, and estriol were obtained. Accuracy values ranged from 80% to 110%, while the inter-assay precision ranged from 0.23% to 22.2% and the intra-assay from 0.55% to 12.3%. Since the sorbent phase has an amphiphilic character, the use of hydrogels is promising for the extraction of medium-to-high polarity compounds.
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in ...DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.
•Enasidenib, a selective inhibitor of mutant IDH2 enzymes, was safe and well tolerated in patients with IDH2-mutated myeloid malignancies.•Enasidenib induced hematologic responses in patients with relapsed/refractory AML in this dose-escalation and expansion study.
We describe the Einstein Toolkit, a community-driven, freely accessible computational infrastructure intended for use in numerical relativity, relativistic astrophysics, and other applications. The ...toolkit, developed by a collaboration involving researchers from multiple institutions around the world, combines a core set of components needed to simulate astrophysical objects such as black holes, compact objects, and collapsing stars, as well as a full suite of analysis tools. The Einstein Toolkit is currently based on the Cactus framework for high-performance computing and the Carpet adaptive mesh refinement driver. It implements spacetime evolution via the BSSN evolution system and general relativistic hydrodynamics in a finite-volume discretization. The toolkit is under continuous development and contains many new code components that have been publicly released for the first time and are described in this paper. We discuss the motivation behind the release of the toolkit, the philosophy underlying its development, and the goals of the project. A summary of the implemented numerical techniques is included, as are results of numerical test covering a variety of sample astrophysical problems.
Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine ...clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort.
PDF
