Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

PURPOSE: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. MATERIALS AND METHODS: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. RESULTS: Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. CONCLUSIONS: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. SIGNIFICANCE: We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Effects of Aerobic and Flexibility Training on Physiological and Psychosocial Function in a Patient with Anaplastic Oligodendroglioma: A Case Report.

OBJECTIVE: Diagnoses of anaplastic oligodendrogliomas are rare. For cancer rehabilitation practitioners, anaplastic oligodendroglioma may impact on the development and maintenance of prescriptive exercise. Exercise interventions for healthy individuals and cancer patients have been shown to increase functional capacity, psychosocial functioning, and aspects of cognitive function. However, there is a lack of research into exercise interventions among patients with anaplastic oligodendroglioma. This case report of a patient with anaplastic oligodendroglioma, measures the effects of aerobic and flexibility training on physiological, psychosocial, and cognitive functioning. PATIENT: A 44-year old woman diagnosed with class III anaplastic oligodendroglioma with 1p19q genetic co-deletion underwent left-frontal craniotomy, chemotherapy, and radiation treatment. Comprehensive physical, psychosocial, and cognitive assessments were completed before and after a 36-session exercise intervention. RESULTS: Following the intervention improvements were observed in 9 of the 14 physiological measures. Fatigue decreased by 20% and quality of life increased by almost 70%. Improvements were also observed in 6 of the 12 cognitive assessment variables. CONCLUSION: The 36 sessions of aerobic and flexibility training were well-tolerated by the subject. The results demonstrate the feasibility and importance of aerobic and flexibility training for the attenuation of cancer-related decrements in physiological and psychosocial variables in patients with anaplastic oligodendroglioma. The effects on cognitive function were uncertain.

Detection of quantitative trait loci associated with drought tolerance in St. Augustinegrass.

St. Augustinegrass (Stenotaphrum secundatum) is a warm-season grass species commonly utilized as turf in the southeastern US. Improvement in the drought tolerance of St. Augustinegrass has significant value within the turfgrass industry. Detecting quantitative trait loci (QTL) associated with drought tolerance will allow for advanced breeding strategies to identify St. Augustinegrass germplasm with improved performance for this trait. A multi-year and multi-environment study was performed to identify QTL in a 'Raleigh' x 'Seville' mapping population segregating for phenotypic traits associated with drought tolerance. Phenotypic data was collected from a field trial and a two-year greenhouse study, which included relative water content (RWC), chlorophyll content (CHC), leaf firing (LF), leaf wilting (LW), green cover (GC) and normalized difference vegetative index (NDVI). Significant phenotypic variance was observed and a total of 70 QTL were detected for all traits. A genomic region on linkage group R6 simultaneously harbored QTL for RWC, LF and LW in different experiments. In addition, overlapping QTL for GC, LF, LW and NDVI were found on linkage groups R1, R5, R7 and S2. Sequence alignment analysis revealed several drought response genes within these regions. The QTL identified in this study have potential to be used in the future to identify genes associated with drought tolerance and for use in marker-assisted breeding.

GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells.

Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein-coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell-derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.

Validation of the 6-min Walk Test for Predicting Peak V˙O2 in Cancer Survivors.

PURPOSE: To assess the quality of the relationship between V˙O2peak estimated from patient outcomes on the 6-min walk test (6MWT) and the V˙O2peak calculated from patient outcomes on the University of Northern Colorado Cancer Rehabilitation Institute (UNCCRI) treadmill protocol. METHODS: Cancer survivors (N = 187) completed the UNCCRI treadmill protocol and a 6MWT 1 wk apart in randomized order to obtain V˙O2peak. Values from the UNCCRI treadmill protocol were compared against four common 6MWT V˙O2peak prediction equations. RESULTS: All four 6MWT prediction equations significantly (P < 0.001) underestimated V˙O2peak with predicted values ranging from 8.0 ± 4.1 mL·kg·min to 18.6 ± 3.1 mL·kg·min, whereas the UNCCRI treadmill protocol yielded a significantly higher value of 23.9 ± 7.6 mL·kg·min. A positive strong correlation occurred between estimated V˙O2peak derived from the UNCCRI treadmill protocol and only one of the V˙O2peak values derived from the 6MWT prediction equations (r = 0.81), and all four equations consistently underpredicted V˙O2peak. CONCLUSIONS: These findings suggest that the 6MWT is not a valid test for predicting V˙O2peak in the cancer population due to its consistent underestimation of V˙O2peak regardless of the prediction equation. Obtaining an accurate and valid V˙O2peak value is necessary to correctly prescribe an individualized exercise rehabilitation regimen for cancer survivors. It is recommended that clinicians avoid the 6MWT and instead implement treadmill testing to volitional fatigue to quantify V˙O2peak in cancer survivors.

Feasibility of a combined aerobic and cognitive training intervention on cognitive function in cancer survivors: a pilot investigation.

BACKGROUND: Cancer-related cognitive impairment (CRCI) may negatively affect upwards of 75% of cancer patients. Exercise and cognitive training, independently, may increase functional capacity and aspects of cognitive function. Yet, combined training protocols have not been evaluated in cancer survivor populations. Therefore, the aim of this study was to explore the feasibility of a quasi-randomized, controlled, exploratory, repeated-measures aerobic and cognitive training intervention on cognitive function in participants undergoing treatment for cancer (N = 28). METHODS: Pre- and post-physical and cognitive assessments were administered. A 36-session (approximately 12 weeks) computer-based cognitive (COG), aerobic (AER), cognitive and aerobic (AER + COG), and flexibility (CON) training intervention was completed. Dependent measures t tests and pre- to post percentages were then calculated to address within-group changes for each dependent variable. RESULTS: Within-group measures revealed that the AER logical memory scores (pre- to post mean difference [2.3], 95.0% CI [0.9, 3.7], percentage change [32.7%]), delayed recall scores (pre- to post mean difference [2.1], 95.0% CI [0.3, 3.9], percentage change [27.2%]), block design scores (pre- to post mean difference [1.7], 95.0% CI [0.2, 3.2], percentage change [19.0%]), and letter-number sequencing scores (pre- to post mean difference [1.0], 95.0% CI [0.2, 1.8], percentage change [12.3%]) all increased. Aspects of verbal fluidity scores increased in the CON group. However, all cognitive scores (AER + COG and COG groups) failed to increase. CONCLUSIONS: Aerobic training for CRCI may positively impact cognitive function. Individually, these methods may appropriately address CRCI, but combined training of this nature may be too demanding for patients undergoing treatment for cancer. However, larger randomized trials are needed to substantiate this protocol in large-scale cancer rehabilitation centers.

Do dysfunctional coping modes mediate the relationship between perceived parenting style and disordered eating behaviours?

BACKGROUND: Preliminary studies suggest that both childhood experiences and coping behaviours may be linked to eating disorder symptoms. METHODS: In this study maladaptive schema coping modes were investigated as mediators in the relationship between perceived negative parenting and disordered eating. A total of 174 adults with eating and/or body image concerns completed questionnaires measuring parenting experiences, schema modes, and disordered eating behaviours. RESULTS: Perfectionistic Overcontroller, Self-Aggrandiser, Compliant Surrenderer, Detached Protector and Detached Self-Soother coping modes partially explained the variance in the relationships between perceived negative parenting experiences and the behaviours of restricting and compensation (purging and overexercising). CONCLUSIONS: Our findings suggest that Overcompensatory, Avoidant and Surrender coping mechanisms all appear to play a role in the maintenance of eating disorder symptoms, and that there are multiple complex relationships between these and Early Maladaptive Schemas that warrant further investigation.

Linking air pollution data and adverse birth outcomes: environmental public health tracking in New York State.

BACKGROUND: Studies investigating associations between ambient air pollution and fetal growth and gestational duration have reported inconclusive findings. OBJECTIVES: The study goal was to use the Environmental Public Health Tracking Network to describe the association between exposure to particulate matter (PM2.5) and ozone and term low birth weight (TLBW) in New York State. METHODS: Birth data for the years 2001-2006 were linked to Census data and hierarchical Bayesian modeled air pollution data. Daily 8-hour maximums for ozone and daily average PM2.5 estimates were averaged by trimester and exposure quartiles. The Environmental Public Health Tracking Academic Center for Excellence at Rutgers University partnered with New York and several other states to create a statistical program that uses logistic regression to determine the association between air pollution exposure and TLBW. RESULTS: There were no consistent dose-response relationships between the pollutants and TLBW. Ozone exposure was associated with a higher risk of TLBW only in the first trimester, but these results were not statistically significant. Exposure to the third quartile of ozone for the full gestational period had negative associations with TLBW (odds ratio = 0.86; 95% confidence interval, 0.81-0.92). CONCLUSION: Collaboration within the Environmental Public Health Tracking Network to share methods and data for research proved feasible and efficient in assessing the relationship of air pollutants to adverse birth outcomes. This study finds little evidence to support positive associations between exposure to ozone or PM2.5 and TLBW in New York State.

Cancer type does not affect exercise-mediated improvements in cardiorespiratory function and fatigue.

PURPOSE: Despite mounting evidence indicating that exercise training has a positive effect on cancer recovery, the influence of cancer type on the response to exercise training remains uncharacterized. Therefore, the adaptations to exercise training were compared between groups composed of 7 different forms of cancer. METHODS: A total of 319 cancer survivors completed fatigue inventories and participated in assessments of cardiorespiratory function, which encompassed aerobic capacity (VO2 peak), pulmonary function (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]), and resting blood pressure and heart rate. Participants were divided into 7 groups based on cancer type, including breast cancer (BC, n = 170), prostate cancer and other male urogenital neoplasia (PC, n = 38), hematological malignancies (HM, n = 34), colorectal cancer (CC, n = 25), gynecological cancers (GC, n = 20), glandular and epithelial neoplasms (GEN, n = 20), and lung cancer (LC, n = 12). All participants completed an individualized, multimodal exercise intervention consisting of cardiorespiratory, flexibility, balance, and muscular strength training 3 days per week for 3 months. Following the intervention, all subjects were reassessed. Generalized Estimating Equations with exchangeable working correlation structure was used to model each response; the group by time interaction effect represented the effect of cancer type on exercise-associated improvements. RESULTS: No significant (P > .05) group by time interaction effects were observed between different types of cancer for any parameter. Pre- to postexercise contrasts revealed significant improvements in VO2 peak in BC, PC, HM, and GEN at the Bonferroni adjusted significance level (.00714). Heart rate was significantly lowered in the BC and CC groups. Mean fatigue indices decreased by at least 17% in all groups, but these changes were only significant in the BC, HM, CC, and GC groups. Systolic blood pressure decreased significantly in BC and GC, and diastolic blood pressure decreased significantly only in the BC group while pulmonary function remained unchanged in all cancer types. CONCLUSION: Although trends toward improved cardiorespiratory and fatigue parameters only reached significance in some groups, there were no significant differences between cancer types. This suggests that cardiorespiratory and fatigue improvements following rehabilitative exercise are not dependent on cancer type. Further research investigating alternative physiological parameters are needed to confirm the relationship between cancer type and exercise-mediated rehabilitation.

Pushrim kinetics during advanced wheelchair skills in manual wheelchair users with spinal cord injury.

OBJECTIVE: To assess the peak force during wheelchair propulsion of individuals with spinal cord injury propelling over obstacles from the Wheelchair Skills Test. PARTICIPANTS/METHODS: Twenty-three individuals with spinal cord injury (SCI) who are full-time manual wheelchair users were included in this prospective study. A SmartWheel (Three Rivers Holdings, LLC) was used to analyze each push while subjects negotiated standardized obstacles used in the Wheelchair Skills Test, including tile, carpet, soft surface, 5° and 10° ramps, 2 cm, 5 cm, and 15 cm curbs. RESULTS: When the peak forces of the advanced skills were compared to level 10 m tile/10 m carpet, there was a statistically significant increase in all peak forces (P value ranged from .0001 to .0268). DISCUSSION: It is well documented that a large number of individuals with SCI develop upper limb pain. One of the recommendations to preserve the upper limb is to minimize force during repetitive tasks. CONCLUSION: Advanced wheelchair skills require an increase in force to accomplish. The increase in forces ranged from 18% to 130% over that required for level 10 m tile/10 m carpet.

Risk of coronary heart disease events over 15 years among older adults with depressive symptoms.

OBJECTIVES: To determine whether depression status is associated with an increased risk of coronary heart disease (CHD) events, defined as CHD death or nonfatal acute myocardial infarction (MI). DESIGN: Prospective cohort study. SETTING: An urban primary care practice. PARTICIPANTS: Two thousand seven hundred twenty-eight adults (71.4% women, 65.5% black), age 60 years and older, who were screened for depression between 1991 and 1993. MEASUREMENTS: Depressive symptom severity at baseline was assessed by the Center for Epidemiologic Studies Depression Scale (CES-D). Data regarding baseline demographic and clinical variables, as well as laboratory evidence of acute MI, were obtained from an electronic medical record system. All-cause mortality and CHD death were determined from the National Death Index through 2006. RESULTS: A total of 423 (15.5%) participants reported elevated symptoms of depression (CES-D score ≥16). During the 13 to 16 years of follow-up, 1,646 (60.3%) individuals died from any cause, and 727 (26.6%) died from CHD or suffered an acute MI. Cox proportional hazards models revealed that individuals with elevated depressive symptoms were more likely to experience a CHD event, even after adjustment for demographics and comorbid health conditions (relative risk = 1.46, 95% confidence interval: 1.20-1.77). Depression status was also a significant predictor of all-cause mortality in adjusted models. CONCLUSIONS: We report the longest prospective study to date to examine depression status as an independent risk factor for CHD among a cohort of older adults including large numbers of women and underrepresented minorities. The present findings underscore the need to consider depression as a common and modifiable risk factor for CHD events among older adults.

Differential modulation of synaptic strength and timing regulate synaptic efficacy in a motor network.

Neuromodulators modify network output by altering neuronal firing properties and synaptic strength at multiple sites; however, the functional importance of each site is often unclear. We determined the importance of monoamine modulation of a single synapse for regulation of network cycle frequency in the oscillatory pyloric network of the lobster. The pacemaker kernel of the pyloric network receives only one chemical synaptic feedback, an inhibitory synapse from the lateral pyloric (LP) neuron to the pyloric dilator (PD) neurons, which can limit cycle frequency. We measured the effects of dopamine (DA), octopamine (Oct), and serotonin (5HT) on the strength of the LP→PD synapse and the ability of the modified synapse to regulate pyloric cycle frequency. DA and Oct strengthened, whereas 5HT weakened, LP→PD inhibition. Surprisingly, the DA-strengthened LP→PD synapse lost its ability to slow the pyloric oscillations, whereas the 5HT-weakened LP→PD synapse gained a greater influence on the oscillations. These results are explained by monoamine modulation of factors that determine the firing phase of the LP neuron in each cycle. DA acts via multiple mechanisms to phase-advance the LP neuron into the pacemaker's refractory period, where the strengthened synapse has little effect. In contrast, 5HT phase-delays LP activity into a region of greater pacemaker sensitivity to LP synaptic input. Only Oct enhanced LP regulation of cycle period simply by enhancing LP→PD synaptic strength. These results show that modulation of the strength and timing of a synaptic input can differentially affect the synapse's efficacy in the network.

Correction: Activation of Akt signaling reduces the prevalence and intensity of malaria parasite infection and lifespan in Anopheles stephensi mosquitoes.

Malaria (Plasmodium spp.) kills nearly one million people annually and this number will likely increase as drug and insecticide resistance reduces the effectiveness of current control strategies. The most important human malaria parasite, Plasmodium falciparum, undergoes a complex developmental cycle in the mosquito that takes approximately two weeks and begins with the invasion of the mosquito midgut. Here, we demonstrate that increased Akt signaling in the mosquito midgut disrupts parasite development and concurrently reduces the duration that mosquitoes are infective to humans. Specifically, we found that increased Akt signaling in the midgut of heterozygous Anopheles stephensi reduced the number of infected mosquitoes by 60-99%. Of those mosquitoes that were infected, we observed a 75-99% reduction in parasite load. In homozygous mosquitoes with increased Akt signaling parasite infection was completely blocked. The increase in midgut-specific Akt signaling also led to an 18-20% reduction in the average mosquito lifespan. Thus, activation of Akt signaling reduced the number of infected mosquitoes, the number of malaria parasites per infected mosquito, and the duration of mosquito infectivity.

Activation of Akt signaling reduces the prevalence and intensity of malaria parasite infection and lifespan in Anopheles stephensi mosquitoes.

Malaria (Plasmodium spp.) kills nearly one million people annually and this number will likely increase as drug and insecticide resistance reduces the effectiveness of current control strategies. The most important human malaria parasite, Plasmodium falciparum, undergoes a complex developmental cycle in the mosquito that takes approximately two weeks and begins with the invasion of the mosquito midgut. Here, we demonstrate that increased Akt signaling in the mosquito midgut disrupts parasite development and concurrently reduces the duration that mosquitoes are infective to humans. Specifically, we found that increased Akt signaling in the midgut of heterozygous Anopheles stephensi reduced the number of infected mosquitoes by 60-99%. Of those mosquitoes that were infected, we observed a 75-99% reduction in parasite load. In homozygous mosquitoes with increased Akt signaling parasite infection was completely blocked. The increase in midgut-specific Akt signaling also led to an 18-20% reduction in the average mosquito lifespan. Thus, activation of Akt signaling reduced the number of infected mosquitoes, the number of malaria parasites per infected mosquito, and the duration of mosquito infectivity.

Identification and characterization of the catalytic subunit of phosphatidylinositol 3-kinase in the yellow fever mosquito Aedes aegypti.

We characterized the catalytic subunit of phosphatidylinositol 3-kinase in Aedes aegypti (Aaegp110). Aaegp110 is an essential component of the insulin/ insulin growth factor I signaling (IIS) cascade, which regulates aging, reproduction, and other physiological processes in diverse organisms. The Aaegp110 gene encodes five putative domains (adapter binding, ras binding, C2, helical, and PI3-kinase) identified by sequence homology with other p110 proteins. Aaegp110 transcript was expressed during all A. aegypti life stages except late pupae, with particularly high levels in embryos. In female tissues, Aaegp110 transcript and protein were strongly expressed in ovaries, and moderately expressed in midguts, fat bodies and heads. The importance of IIS in mosquito reproduction led us to examine Aaegp110 ovarian expression during reproduction. Aaegp110 was expressed in ovaries prior to and during the first 24h post-bloodmeal, but undetectable 36-48 h post-bloodmeal. Following oviposition Aaegp110 protein levels returned to pre-bloodmeal levels. In reproductively arrested ovaries, Aaegp110 was present predominantly in the cytoplasm of follicle cells surrounding the oocyte. In vitro stimulation of the ovaries with 17 microM bovine insulin resulted in translocation of Aaegp110 from the cytoplasm to cell membrane in 15s. Lower concentrations (0.17 microM) also recruited Aaegp110 to the cell membrane.

Characterization of phosphatase and tensin homolog expression in the mosquito Aedes aegypti: six splice variants with developmental and tissue specificity.

Phosphatase and tensin homologue (PTEN), an inhibitor of insulin signalling, was characterized in Aedes aegypti. Surprisingly, six splice variants were identified: three with alternative terminal exons (AaegPTEN2 : 3 : 6) and three formed by intron retention (AaegPTEN1 : 4 : 5). All variants encoded active phosphatase domains. Variants with alternative terminal exons also encoded C2 and COOH-domains, and AaegPTEN6 encoded a PDZ binding motif. These three variants also had unique expression patterns. AaegPTEN2 was expressed primarily in the ovary. AaegPTEN3 was predominant in heads and midguts, and throughout development, except early embryogenesis. AaegPTEN6 was expressed in fat body, ovaries, and throughout development. Intron retention variants were weakly expressed in most samples. These expression patterns suggest that AaegPTEN variants play unique roles in regulating insulin's pleiotropic effects.