Abstract Purpose The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was ...evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Methods Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Findings Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. Implications The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.
Research on humor is carried out in a number of areas in psychology, including the cognitive (What makes something funny?), developmental (when do we develop a sense of humor?), and social (how is ...humor used in social interactions?) Although there is enough interest in the area to have spawned several societies, the literature is dispersed in a number of primary journals, with little in the way of integration of the material into a book. Dr. Martin is one of the best known researchers in the area, and his research goes across subdisciplines in psychology to be of wide appeal. This is a singly authored monograph that provides in one source, a summary of information researchers might wish to know about research into the psychology of humor. The material is scholarly, but the presentation of the material is suitable for people unfamiliar with the subject-making the book suitable for use for advanced undergraduate and graduate level courses on the psychology of humor-which have not had a textbook source.2007 AATH Book Award for Humor/Laughter Research category!
*Up-to-date coverage of research on humor and laughter in every area of psychology*Research findings are integrated into a coherent conceptual framework*Includes recent brain imaging studies, evolutionary models, and animal research*Draws on contributions from sociology, linguistics, neuroscience, and anthropology*Provides an overview of theories of humor and early research*Explores applications of humor in psychotherapy, education, and the workplace*Points out interesting topics for further research and promising research methodologies*Written in a scholarly yet easily accessible style*2007 AATH Book Award for Humor/Laughter Research category
An oral inhibitor of BCL2 produces substantial responses in the majority of patients with refractory chronic lymphocytic leukemia. The agent is so effective that precautions are necessary to protect ...patients against the tumor lysis syndrome at therapy initiation.
The landscape of treatment for relapsed chronic lymphocytic leukemia (CLL) has recently changed with the introduction of agents that inhibit intracellular B-cell receptor signaling.
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Ibrutinib monotherapy
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and idelalisib in combination with rituximab
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induce responses in the majority of patients in whom chemoimmunotherapy has failed, and these patients have improved outcomes. Treatment is given indefinitely, and complete remission is uncommon, particularly in the first 2 years after the initiation of therapy. Persistent disease is a concern because of the potential development of resistance.
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Although many responses are durable and may deepen over time, relapses accumulate with ongoing follow-up, . . .
Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, ...pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.
The availability of thousands of complete rice genome sequences from diverse varieties and accessions has laid the foundation for in-depth exploration of the rice genome. One drawback to these ...collections is that most of these rice varieties have long life cycles, and/or low transformation efficiencies, which limits their usefulness as model organisms for functional genomics studies. In contrast, the rice variety Kitaake has a rapid life cycle (9 weeks seed to seed) and is easy to transform and propagate. For these reasons, Kitaake has emerged as a model for studies of diverse monocotyledonous species.
Here, we report the de novo genome sequencing and analysis of Oryza sativa ssp. japonica variety KitaakeX, a Kitaake plant carrying the rice XA21 immune receptor. Our KitaakeX sequence assembly contains 377.6 Mb, consisting of 33 scaffolds (476 contigs) with a contig N50 of 1.4 Mb. Complementing the assembly are detailed gene annotations of 35,594 protein coding genes. We identified 331,335 genomic variations between KitaakeX and Nipponbare (ssp. japonica), and 2,785,991 variations between KitaakeX and Zhenshan97 (ssp. indica). We also compared Kitaake resequencing reads to the KitaakeX assembly and identified 219 small variations. The high-quality genome of the model rice plant KitaakeX will accelerate rice functional genomics.
The high quality, de novo assembly of the KitaakeX genome will serve as a useful reference genome for rice and will accelerate functional genomics studies of rice and other species.
All published research examining effects of humor and laughter on physical health is reviewed. Potential causal mechanisms and methodological issues are discussed. Laboratory experiments have shown ...some effects of exposure to comedy on several components of immunity, although the findings are inconsistent and most of the studies have methodological problems. There is also some evidence of analgesic effects of exposure to comedy, although similar findings are obtained with negative emotions. Few significant correlations have been found between trait measures of humor and immunity, pain tolerance, or self-reported illness symptoms. There is also little evidence of stress-moderating effects of humor on physical health variables and no evidence of increased longevity with greater humor. More rigorous and theoretically informed research is needed before firm conclusions can be drawn about possible health benefits of humor and laughter.
The present study investigated correlations between four humor styles and the Dark Triad traits of personality. Participants were 114 pairs of adult twins from North America who completed the Humor ...Styles Questionnaire, the Narcissistic Personality Inventory, the Self-Report Psychopathy Scale, and the MACH-IV. Results revealed that participants who scored higher on sub-clinical psychopathy and Machiavellianism exhibited a greater tendency to employ negative humor styles (aggressive, self-defeating), whereas individuals who obtained higher scores on narcissism were more prone to employing a positive affiliative humor style. These results help to clarify the nature of the Dark Triad traits and shed light on the interpersonal styles employed by individuals who exhibit these traits.
Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 ...prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.
Cognitive distortions are negative biases in thinking that are theorized to represent vulnerability factors for depression and dysphoria. Despite the emphasis placed on cognitive distortions in the ...context of cognitive behavioural theory and practice, a paucity of research has examined the mechanisms through which they impact depressive symptomatology. Both adaptive and maladaptive styles of humor represent coping strategies that may mediate the relation between cognitive distortions and depressive symptoms. The current study examined the correlations between the frequency and impact of cognitive distortions across both social and achievement-related contexts and types of humor. Cognitive distortions were associated with reduced use of adaptive Affiliative and Self-Enhancing humor styles and increased use of maladaptive Aggressive and Self-Defeating humor. Reduced use of Self-Enhancing humor mediated the relationship between most types of cognitive distortions and depressed mood, indicating that distorted negative thinking may interfere with an individual's ability to adopt a humorous and cheerful outlook on life (i.e., use Self-Enhancing humor) as a way of regulating emotions and coping with stress, thereby resulting in elevated depressive symptoms. Similarly, Self-Defeating humor mediated the association of the social impact of cognitive distortions with depression, such that this humor style may be used as a coping strategy for dealing with distorted thinking that ultimately backfires and results in increased dysphoria.
Red clover (Trifolium pratense L.) is a globally significant forage legume in pastoral livestock farming systems. It is an attractive component of grassland farming, because of its high yield and ...protein content, nutritional value and ability to fix atmospheric nitrogen. Enhancing its role further in sustainable agriculture requires genetic improvement of persistency, disease resistance, and tolerance to grazing. To help address these challenges, we have assembled a chromosome-scale reference genome for red clover. We observed large blocks of conserved synteny with Medicago truncatula and estimated that the two species diverged ~23 million years ago. Among the 40,868 annotated genes, we identified gene clusters involved in biochemical pathways of importance for forage quality and livestock nutrition. Genotyping by sequencing of a synthetic population of 86 genotypes show that the number of markers required for genomics-based breeding approaches is tractable, making red clover a suitable candidate for association studies and genomic selection.
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