Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial.

PURPOSE: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). PATIENTS AND METHODS: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. RESULTS: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. CONCLUSIONS: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

The connections of the insular VEN area in great apes: A histologically-guided ex vivo diffusion tractography study.

We mapped the connections of the insular von Economo neuron (VEN) area in ex vivo brains of a bonobo, an orangutan and two gorillas with high angular resolution diffusion MRI imaging acquired in 36 h imaging sessions for each brain. The apes died of natural causes without neurological disorders. The localization of the insular VEN area was based on cresyl violet-stained histological sections from each brain that were coregistered with structural and diffusion images from the same individuals. Diffusion MRI tractography showed that the insular VEN area is connected with olfactory, gustatory, visual and other sensory systems, as well as systems for the mediation of appetite, reward, aversion and motivation. The insular VEN area in apes is most strongly connected with frontopolar cortex, which could support their capacity to choose voluntarily among alternative courses of action particularly in exploring for food resources. The frontopolar cortex may also support their capacity to take note of potential resources for harvesting in the future (prospective memory). All of these faculties may support insight and volitional choice when contemplating courses of action as opposed to rule-based decision-making.

Gle1 mediates stress granule-dependent survival during chemotoxic stress.

Stress granules (SGs) are non-membrane bound organelles that form in response to multiple different stress stimuli, including exposure to sodium arsenite. SGs are postulated to support cells during periods of stress and provide a protective effect, allowing survival. Gle1 is a highly conserved, essential modulator of RNA-dependent DEAD-box proteins that exists as at least two distinct isoforms in human cells. Gle1A is required for proper SG formation, whereas Gle1B functions in mRNA export at the nuclear pore complex. Since Gle1A is required for SG function, we hypothesized that SG-dependent survival responses would also be Gle1-dependent. We describe here an experimental system for quantifying and testing the SG-associated survival response to sodium arsenite stress in HeLa cells. Gle1A was required for the sodium arsenite survival response, and overexpression of Gle1A supported the survival response. Overexpression of the SG-component G3BP also enabled the response. Next, we analyzed whether cells undergoing multiple rounds of stress yield a subpopulation with a higher propensity for SG formation and an increased resistance to undergoing apoptosis. After ten doses of sodium arsenite treatment, cells became resistant to sodium arsenite and to diclofenac sodium (another SG-inducing drug). The sodium arsenite-resistant cells exhibited changes in SG biology and had an increased survival response that was conferred in a paracrine manner. Changes in secreted factors occurred including a significantly lower level of MCP-1, a known regulator of stress granules and stress-induced apoptosis. This study supports models wherein SGs play a role in cell evasion of apoptosis and further reveal Gle1A and SG functions as targets for clinical approaches directed at chemoresistant/refractory cells.

Genetic and neuronal regulation of sleep by neuropeptide VF.

Sleep is an essential and phylogenetically conserved behavioral state, but it remains unclear to what extent genes identified in invertebrates also regulate vertebrate sleep. RFamide-related neuropeptides have been shown to promote invertebrate sleep, and here we report that the vertebrate hypothalamic RFamide neuropeptide VF (NPVF) regulates sleep in the zebrafish, a diurnal vertebrate. We found that NPVF signaling and npvf-expressing neurons are both necessary and sufficient to promote sleep, that mature peptides derived from the NPVF preproprotein promote sleep in a synergistic manner, and that stimulation of npvf-expressing neurons induces neuronal activity levels consistent with normal sleep. These results identify NPVF signaling and npvf-expressing neurons as a novel vertebrate sleep-promoting system and suggest that RFamide neuropeptides participate in an ancient and central aspect of sleep control.

Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells.

The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA-dependent DEAD-box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP6 )-bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure-function analysis in S. cerevisiae and human (h) cells, and find that the high-affinity Nup42-Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site. A nup42-CTD/gle1-CTD/Dbp5 trimeric complex forms in the presence of IP6 . Deletion of NUP42 abrogates Gle1-Dbp5 interaction, and disruption of the Nup42 or IP6 binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42-CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42-hGle1B interaction.

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms.

Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP6) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insertion, generating an altered protein. Like hGle1A, at steady state, the altered protein termed hGle1-IVS14-2A>C is absent from the nuclear envelope rim and localizes to the cytoplasm. hGle1A performs essential cytoplasmic functions in translation and stress granule regulation. Therefore, we speculated that the ALS disease pathology results from altered cellular pools of hGle1 and increased cytoplasmic hGle1 activity. GFP-hGle1-IVS14-2A>C localized to stress granules comparably to GFP-hGle1A, and rescued stress granule defects following siRNA-mediated hGle1 depletion. As described for hGle1A, overexpression of the hGle1-IVS14-2A>C protein also induced formation of larger SGs. Interestingly, hGle1A and the disease associated hGle1-IVS14-2A>C overexpression induced the formation of distinct cytoplasmic protein aggregates that appear similar to those found in neurodegenerative diseases. Strikingly, the ALS-linked hGle1-IVS14-2A>C protein also rescued mRNA export defects upon depletion of endogenous hGle1, acting in a potentially novel bi-functional manner. We conclude that the ALS-linked hGle1-c.1965-2A>C mutation generates a protein isoform capable of both hGle1A- and hGle1B-ascribed functions, and thereby uncoupled from normal mechanisms of hGle1 regulation.

Intrinsic susceptibility MRI identifies tumors with ALKF1174L mutation in genetically-engineered murine models of high-risk neuroblastoma.

The early identification of children presenting ALK(F1174L)-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALK(F1174L)/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALK(F1174L)-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R2* (s(-1)) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALK(F1174L) mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALK(F1174L) mutation at the time of diagnosis.

Administration order effects on the test of memory malingering.

Using a sample of 72 university students, we determined whether administering the Boston Naming Test (BNT) before the Test of Memory Malingering (TOMM) affects scores on the latter test and whether administration of a visual test during the interval between TOMM Trial 2 and the TOMM Retention Trial (TOMM-R) influences results on TOMM-R. Four orders of administration were used. A series of nonparametric tests indicated that when the BNT was given before the TOMM, a lower median TOMM Trial 1 (TOMM-1) score emerged. However, of the 36 participants who completed the BNT prior to administration of the TOMM, only one achieved a score < 45 on TOMM-1. There were no other significant findings. Overall, the results suggest that order of test administration is probably not a determinant of TOMM scores.

Substitution of supplementary subtests for core subtests on composite reliability of WAIS--IV Indexes.

The effects of replacing core subtests with supplementary subtests on composite-score reliabilities were evaluated for the WAIS-IV Indexes. Composite score reliabilities and SEMs (i.e., confidence intervals around obtained scores) are provided for the 13 unique Index scores calculated following the subtest substitution guidelines of Wechsler in 2008. In all instances, unique Index composite-score reliabilities were comparable to their respective core Index score composite reliabilities, and measurement error never increased by more than 1 point. Using the standard Verbal Comprehension Index and Perceptual Reasoning Index and the unique subtest combinations for the Working Memory and Processing Speed indexes, which have the lowest composite-score reliabilities, decreased Full Scale composite reliability by .01, while the associated confidence interval of +/- 6 represents an increase in measurement error of 1 IQ point.

Stability of the WISC-IV in a sample of elementary and middle school children.

This study investigated test-retest stability of the Wechsler Intelligence Scale for Children, Fourth Edition, in 43 elementary/middle school students tested on two occasions approximately 11 months apart. Subtest stability coefficients ranged from .26 (Picture Concepts) to .84 (Vocabulary [VC]). Composite stabilities ranged from .54 (Processing Speed Index) to .88 (Full Scale Intelligence Quotient [FSIQ]). On 11 subtests and three indexes, the standardization sample stability coefficients were significantly larger than those of the present sample, with only the VC subtest and FSIQ having high levels of test-retest stability. Mean practice effects were not significant, but range of gain or loss for some individuals was large. On the FSIQ, 42% changed > +/-5 points on retest. The FSIQ is less stable than one might infer from the large stability coefficient and small mean practice effect.

Base rates of "10 to 11" clocks in Alzheimer's and Parkinson's disease.

We extended the work of Rouleau et al. (I. Rouleau, D. P. Salmon, N. Butters, C. Kennedy, & K. McGuire, Quantitative and qualitative analyses of clock drawings in Alzheimer's and Huntington's disease. Brain and Cognition, 18, 1992, 70-87) and Ryan et al. (J. J. Ryan, S. J. Lopez, & S. W. Sumerall, Base rate of "10 to 11" clocks among patients referred for neuropsychological evaluation. Perceptual and Motor Skills, 81, 1995, 1138) by providing base rates for "10 to 11" clocks in samples of healthy elderly (n = 168), Alzheimer's disease (AD; n = 81), and Parkinson's disease (PD; n = 105). Groups were comparable in age and education. Stimulus bound clocks occurred in 3.0% of controls, 30.9% of AD, 5.7% of PD, and 10.2% of the combined sample. The 10.2% base rate is consistent with Ryan et al. for a mixed sample and Rouleau et al. for healthy elderly and patients with AD or Huntington's disease.

Perceptions of psychology as a science among university students: the influence of psychology courses and major of study.

The goal was to examine the relationship between the number of psychology courses students have taken and their perceptions of psychology as a science. Additionally, differences in perceptions of psychology among psychology, education, and natural science majors were examined. Results indicated that students who had taken four or more psychology courses had more favorable perceptions of psychology as a science compared to those who had taken no courses or one course and those who had taken two to three courses. No significant differences in overall perceptions of psychology emerged among students in the three majors.

Internal consistency reliability of the WISC-IV among primary school students'.

Internal consistency reliabilities of the WISC-IV subtest and index scores were estimated for a sample of 76 primary school students from a small Midwestern community. Means for age and Full Scale IQ were 8.2 yr. (SD = 23) and 110.5 (SD = 11.7), respectively. Internal consistency reliabilities were compared with those for the WISC-IV standardization sample of 200. The range of reliabilities for the subtests was from .76 for Picture Concepts to .94 for Arithmetic and from .92 for Perceptual Reasoning Index to .96 for Verbal Comprehension Index and Full Scale IQ. The Full Scale IQ internal consistency reliability is comparable to that of the standardization sample. However, in all but one instance the reliabilities were greater than those of the normative sample.

Predicting neuropsychological test performance on the basis of temporal orientation.

Temporal orientation is often disrupted in the context of psychiatric or neurological disease; tests assessing this function are included in most mental status examinations. The present study examined the relationship between scores on the Temporal Orientation Scale (TOS) and performance on a battery of tests that assess memory, language, and cognitive functioning in a sample of patients with Alzheimer's disease (N = 55). Pearson-product moment correlations showed that, in all but two instances, the TOS was significantly correlated with each neuropsychological measure, p values < or = .05. Also, severely disoriented (i.e., TOS score < or = -8) patients were consistently 'impaired' on memory tests but not on tests of language and general cognitive functioning.

WAIS-III FSIQ and GAI in ability-memory discrepancy analysis.

The present investigation compares WAIS-III FSIQ-WMS-III with GAI-WMS-III discrepancies in 135 male inpatients with suspected memory impairment. Full Scale IQ and GAI scores were highly correlated, r= .96, with mean values of 92.10 and 93.59, respectively. Additional analyses with the ability composites compared to each WMS-III index (IMI, GMI, and DMI), the GAI consistently produced larger difference scores than did the FSIQ; however, effect sizes were relatively small (ES= .12). Lastly, case-by-case analyses demonstrated concordance rates of 86% for the FSIQ-IMI and GAI-IMI comparisons, 85% for the FSIQ-GMI and GAI-GMI, and 82% for the FSIQ-DMI and GAI-DMI.

Administration frequencies of WAIS-III supplementary and optional subtests of board-certified clinical neuropsychologists.

The present investigation surveyed board-certified clinical neuropsychologists in four geographic regions of the United States regarding their administration practices of the WAIS-III supplementary subtests (Letter-Number Sequencing, Symbol Search), optional subtest (Object Assembly), and optional procedures (Digit Symbol-Incidental Learning and Digit Symbol-Copy). Approximately 56% of the surveys were returned and usable. Regardless of geographic region, Letter-Number Sequencing and Symbol Search were the most popular of the supplementary/optional components because they were administered more than 70% of the time. The Digit Symbol-Incidental Learning and Digit Symbol-Copy procedures were the second most frequently administered tasks. Object Assembly was the least frequently administered component by practitioners across the four geographic regions.

Estimating WISC-IV indexes: proration versus linear scaling.

This investigation compared proration and linear scaling for estimating Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) verbal comprehension (VCI) and perceptual reasoning (PRI) composites from all relevant two subtest combinations. Using 57 primary school students and 41 clinical referrals, actual VCI and PRI scores were highly correlated with estimated index scores based on proration and linear scaling (all rs> or =.90). In the school sample, significant mean score differences between the actual and estimated composites were found in two comparisons; however, differences between mean scores were less than three points. No significant differences emerged in the clinical sample. Results indicate that any of the two subtest combinations produced reasonably accurate estimates of actual indexes. There was no advantage of one computational method over the other.

Effective, robust design of community mitigation for pandemic influenza: a systematic examination of proposed US guidance.

BACKGROUND: The US government proposes pandemic influenza mitigation guidance that includes isolation and antiviral treatment of ill persons, voluntary household member quarantine and antiviral prophylaxis, social distancing of individuals, school closure, reduction of contacts at work, and prioritized vaccination. Is this the best strategy combination? Is choice of this strategy robust to pandemic uncertainties? What are critical enablers of community resilience? METHODS AND FINDINGS: We systematically simulate a broad range of pandemic scenarios and mitigation strategies using a networked, agent-based model of a community of explicit, multiply-overlapping social contact networks. We evaluate illness and societal burden for alterations in social networks, illness parameters, or intervention implementation. For a 1918-like pandemic, the best strategy minimizes illness to <1% of the population and combines network-based (e.g. school closure, social distancing of all with adults' contacts at work reduced), and case-based measures (e.g. antiviral treatment of the ill and prophylaxis of household members). We find choice of this best strategy robust to removal of enhanced transmission by the young, additional complexity in contact networks, and altered influenza natural history including extended viral shedding. Administration of age-group or randomly targeted 50% effective pre-pandemic vaccine with 7% population coverage (current US H5N1 vaccine stockpile) had minimal effect on outcomes. In order, mitigation success depends on rapid strategy implementation, high compliance, regional mitigation, and rigorous rescinding criteria; these are the critical enablers for community resilience. CONCLUSIONS: Systematic evaluation of feasible, recommended pandemic influenza interventions generally confirms the US community mitigation guidance yields best strategy choices for pandemic planning that are robust to a wide range of uncertainty. The best strategy combines network- and case-based interventions; network-based interventions are paramount. Because strategies must be applied rapidly, regionally, and stringently for greatest benefit, preparation and public education is required for long-lasting, high community compliance during a pandemic.

Social contact networks for the spread of pandemic influenza in children and teenagers.

BACKGROUND: Influenza is a viral infection that primarily spreads via fluid droplets from an infected person's coughs and sneezes to others nearby. Social contact networks and the way people interact within them are thus important to its spread. We developed a method to characterize the social contact network for the potential transmission of influenza and then applied the method to school aged children and teenagers. METHODS: Surveys were administered to students in an elementary, middle and high-school in the United States. The social contact network of a person was conceptualized as a set of groups to which they belong (e.g., households, classes, clubs) each composed of a sub-network of primary links representing the individuals within each group that they contact. The size of the group, number of primary links, time spent in the group, and level of contact along each primary link (near, talking, touching, or kissing) were characterized. Public activities done by groups venturing into the community where random contacts occur (e.g., friends viewing a movie) also were characterized. RESULTS: Students, groups and public activities were highly heterogeneous. Groups with high potential for the transmission of influenza were households, school classes, friends, and sports; households decreased and friends and sports increased in importance with grade level. Individual public activity events (such as dances) were also important but lost their importance when averaged over time. Random contacts, primarily in school passing periods, were numerous but had much lower transmission potential compared to those with primary links within groups. Students are highly assortative, interacting mainly within age class. A small number of individual students are identified as likely "super-spreaders". CONCLUSION: High-school students may form the local transmission backbone of the next pandemic. Closing schools and keeping students at home during a pandemic would remove the transmission potential within these ages and could be effective at thwarting its spread within a community. Social contact networks characterized as groups and public activities with the time, level of contact and primary links within each, yields a comprehensive view, which if extended to all ages, would allow design of effective community containment for pandemic influenza.