Venetoclax induces BCL-2-dependent Treg to TH17 plasticity to enhance the antitumor efficacy of anti-PD-1 checkpoint blockade.

The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T (Treg) cells, which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediateed Treg plasticity towards a TH17-like Treg phenotype, resulting in increased IL-17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.

PU.1 and BCL11B sequentially cooperate with RUNX1 to anchor mSWI/SNF to poise the T cell effector landscape.

Adaptive immunity relies on specialized effector functions elicited by lymphocytes, yet how antigen recognition activates appropriate effector responses through nonspecific signaling intermediates is unclear. Here we examined the role of chromatin priming in specifying the functional outputs of effector T cells and found that most of the cis-regulatory landscape active in effector T cells was poised early in development before the expression of the T cell antigen receptor. We identified two principal mechanisms underpinning this poised landscape: the recruitment of the nucleosome remodeler mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) by the transcription factors RUNX1 and PU.1 to establish chromatin accessibility at T effector loci; and a 'relay' whereby the transcription factor BCL11B succeeded PU.1 to maintain occupancy of the chromatin remodeling complex mSWI/SNF together with RUNX1, after PU.1 silencing during lineage commitment. These mechanisms define modes by which T cells acquire the potential to elicit specialized effector functions early in their ontogeny and underscore the importance of integrating extrinsic cues to the developmentally specified intrinsic program.

The Relationship between Fatigue and a Clinically Accessible Measure of Switching in Individuals with Multiple Sclerosis.

OBJECTIVE: We examined whether fatigue in multiple sclerosis (MS) is linked to switching processes when switching is measured by the Trail Making Test (TMT). METHOD: Eighty-three participants with MS were administered a battery of standardized tests of switching, working memory, and processing speed. Ordinary least squares regression models were used to estimate the association between fatigue severity and switching above and beyond attention, working memory, and processing speed. RESULTS: We found a negative association between TMT performance and fatigue severity score. When measures of processing speed and working memory were included in the model, the switching measure continued to uniquely contribute to fatigue severity. CONCLUSIONS: There may be a unique relationship between fatigue and switching processes identifiable by clinical measures of switching. Future research should continue to investigate this relationship by using both behavioral and neural markers to test models of fatigue to eventually identify specific intervention targets.

Selective reminding of prospective memory in Multiple Sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is associated with prospective memory (PM) deficits, which may increase the risk of poor functional/health outcomes such as medication non-adherence. This study examined the potential benefits of selective reminding to enhance PM functioning in persons with MS. METHOD: Twenty-one participants with MS and 22 healthy adults (HA) underwent a neuropsychological battery including a Selective Reminding PM (SRPM) experimental procedure. Participants were randomly assigned to either: (1) a selective reminding condition in which participants learn (to criterion) eight prospective memory tasks in a Selective Reminding format; or (2) a single trial encoding condition (1T). RESULTS: A significant interaction was demonstrated, with MS participants receiving greater benefit than HAs from the SR procedure in terms of PM performance. Across diagnostic groups, participants in the SR conditions (vs. 1T conditions) demonstrated significantly better PM performance. Individuals with MS were impaired relative to HAs in the 1T condition, but performance was statistically comparable in the SR condition. CONCLUSIONS: This preliminary study suggests that selective reminding can be used to enhance PM cue detection and retrieval in MS. The extent to which selective reminding of PM is effective in naturalistic settings and for health-related behaviours in MS remains to be determined.

Multitasking in multiple sclerosis: can it inform vocational functioning?

OBJECTIVE: To examine associations between multitasking ability defined by performance on a complex task integrating multiple cognitive domains and vocational functioning in multiple sclerosis (MS). DESIGN: Survey data collection. SETTING: Laboratory with referrals from an outpatient clinic. PARTICIPANTS: Community-dwelling individuals with MS (N=30) referred between October 2011 and June 2012. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The modified Six Elements Test (SET) to measure multitasking ability, Fatigue Severity Scale to measure fatigue, several neuropsychological measures of executive functioning, and vocational status. RESULTS: Among the sample, 60% of individuals have reduced their work hours because of MS symptoms (cutback employment group) and 40% had maintained their work hours. Among both groups, SET performance was significantly associated with performance on several measures of neuropsychological functioning. Individuals in the cutback employment group demonstrated significantly worse overall performance on the SET (P=.041). Logistic regression was used to evaluate associations between SET performance and vocational status, while accounting for neuropsychological performance and fatigue. The overall model was significant (χ(2)3=8.65, P=.032), with fatigue [Exp(B)=.83, P=.01] and multitasking ability [Exp(B)=.60, P=.043] retained as significant predictors. CONCLUSIONS: Multitasking ability may play an important role in performance at work for individuals with MS. Given that multitasking was associated with vocational functioning, future efforts should assess the usefulness of incorporating multitasking ability into rehabilitation planning.

Driver performance while texting: even a little is too much.

OBJECTIVE: To examine the impact of text messaging and other in-car behaviors on driving performance under simple and naturalistic road conditions in a driving simulator. METHODS: Data from 28 healthy individuals (12 female) are presented. Participant age ranged from 18 to 28 (mean = 21.0). Average driving experience was 3.8 years (SD = 2.5). Participants completed a baseline loop condition in which they drove normally through a realistic virtual environment. Next, participants drove an identical loop, and at 3 specified points during this drive, participants were required to (1) complete a radio-tuning task; (2) type and send a text message containing "Drexel University"; and (3) type and send "I am driving to the store." Driving performance and task duration was compared between conditions. RESULTS: Across all tasks, both lane management, F(1,27) = 11.1, P = .002, and velocity, F(1,27) = 10.3, P = .003, varied significantly more while task-engaged. Average lane deviation was significantly greater during a text messaging task than during the baseline drive of the same road segment, t(27) = -2.9, P = .007. Comparison of task durations indicated that both texting tasks took significantly longer to complete than the radio task, with the "Drexel University" text (118 s) taking almost twice as long as the radio-tuning task (60 s). Unexpected and novel findings emerged in the evaluation of duration of texting tasks using the varying text-entry methods, with touch-screen modality taking significantly longer than others. CONCLUSIONS: Engaging in secondary tasks while operating a motor vehicle may have deleterious effects on driving performance and increase risk, even under the simplest of driving conditions. Text messaging may constitute a "perfect storm" of risk compared to other in-vehicle tasks such as tuning the car radio. The current investigation demonstrated detrimental effects of text messaging on driving behaviors such as lane maintenance, speed maintenance, and shifts of attention, even under relatively ideal and naturalistic driving conditions (e.g., familiar route, good weather, no traffic).

Preserved frontal memorial processing for pictures in patients with mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) has been conceptualized as a transitional stage between healthy aging and Alzheimer's disease (AD). Therefore, understanding which aspects of memory are impaired and which remain relatively intact in these patients can be useful in determining who will ultimately go on to develop AD, and subsequently designing interventions to help patients live more engaged and independent lives. The dual-process model posits that recognition memory decisions can rely on either familiarity or recollection. Whereas research is fairly consistent in showing impaired recollection in patients with aMCI, the results have been mixed regarding familiarity. A noted difference between these studies investigating familiarity has been stimulus type. The goal of the current investigation was to use high-density event-related potentials (ERPs) to help elucidate the neural correlates of recognition decisions in patients with aMCI for words and pictures. We also hoped to help answer the question of whether patients can rely on familiarity to support successful recognition. Patients and controls participated in separate recognition memory tests of words and pictures while ERPs were recorded during retrieval. Results showed that ERP components typically associated with familiarity and retrieval monitoring were similar between groups for pictures. However, these components were diminished in the patient group for words. Based on recent work, the authors discuss the possibility that implicit conceptual priming could have contributed to the enhanced ERP correlate of familiarity. Further, the authors address the possibility that enhanced retrieval monitoring may be needed to modulate increased familiarity engendered by pictures.

Parietal contributions to recollection: electrophysiological evidence from aging and patients with parietal lesions.

There has been much recent investigation into the role of parietal cortex in memory retrieval. Proposed hypotheses include attention to internal memorial representations, an episodic working memory-type buffer, and an accumulator of retrieved memorial information. The current investigation used event-related potentials (ERPs) to test the episodic buffer hypothesis, and to assess the memorial contribution of parietal cortex in younger and older adults, and in patients with circumscribed lateral parietal lesions. In a standard recognition memory paradigm, subjects studied color pictures of common objects. One-third of the test items were presented in the same viewpoint as the study phase, one-third were presented in a 90 degrees rotated viewpoint, and one-third were presented in a noncanonical viewpoint. Conflicting with the episodic buffer hypothesis, results revealed that the duration of the parietal old/new effect was longest for the canonical condition and shortest for the noncanonical condition. Results also revealed that older adults demonstrated a diminished parietal old/new effect relative to younger adults. Consistent with previous data reported by Simons et al., patients with lateral parietal lesions showed no behavioral impairment compared to controls. Behavioral and ERP data from parietal lesion patients are presented and discussed. From these results, the authors speculate that the parietal old/new effect may be the neural correlate of an individual's subjective recollective experience.

Aging memory for pictures: using high-density event-related potentials to understand the effect of aging on the picture superiority effect.

High-density event-related potentials (ERPs) were used to understand the effect of aging on the neural correlates of the picture superiority effect. Pictures and words were systematically varied at study and test while ERPs were recorded at retrieval. Here, the results of the word-word and picture-picture study-test conditions are presented. Behavioral results showed that older adults demonstrated the picture superiority effect to a greater extent than younger adults. The ERP data helped to explain these findings. The early frontal effect, parietal effect, and late frontal effect were all indistinguishable between older and younger adults for pictures. In contrast, for words, the early frontal and parietal effects were significantly diminished for the older adults compared to the younger adults. These two old/new effects have been linked to familiarity and recollection, respectively, and the authors speculate that these processes are impaired for word-based memory in the course of healthy aging. The findings of this study suggest that pictures allow older adults to compensate for their impaired memorial processes, and may allow these memorial components to function more effectively in older adults.