Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.

PURPOSE: Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer. EXPERIMENTAL DESIGN: Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer. Tumors from susceptible and resistant congenics were analyzed by RNAseq to identify candidate genes. Candidates were prioritized by correlation with outcome, using a consensus of three breast cancer patient cohorts. NNAT was transgenically expressed in ER+ breast cancer lines (T47D and ZR75), followed by transcriptomic and phenotypic characterization. RESULTS: We identified a region on rat chromosome 3 (142-178 Mb) that modified mammary tumor incidence. RNAseq of the mammary tumors narrowed the candidate list to three differentially expressed genes: NNAT, SLC35C2, and FAM210B. NNAT mRNA and protein also correlated with survival in human breast cancer patients. Quantitative immunohistochemistry of NNAT protein revealed an inverse correlation with survival in a univariate analysis of patients with invasive ER+ breast cancer (training cohort: n = 444, HR = 0.62, p = 0.031; validation cohort: n = 430, HR = 0.48, p = 0.004). NNAT also held up as an independent predictor of survival after multivariable adjustment (HR = 0.64, p = 0.038). NNAT significantly reduced proliferation and migration of ER+ breast cancer cells, which coincided with altered expression of multiple related pathways. CONCLUSIONS: Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.

The irrelevant speech effect among younger and older adults: The influence of background noises on reading comprehension.

BACKGROUND: Aging could exacerbate the decreases in cognitive functioning already caused by noise pollution. According to the inhibitory deficit hypothesis, older adults have more difficulty than do younger adults keeping irrelevant information from interfering with processing of relevant information. However, irrelevant speech studies typically fail to support this hypothesis. The present study aimed to quantify the effects of age and noise pollution on reading comprehension. METHODS: Seventeen younger (age 21-29) and 15 older (age 62-77) adults completed a reading task (reading discourse material for a follow-up comprehension test) in the presence of six irrelevant background noise conditions. Repeated measures ANOVAs and t tests were used to analyze participant accuracy on the follow-up comprehension tests. RESULTS: Contrary to the inhibitory deficit hypothesis, but congruent with previous irrelevant speech studies, younger and older adults did not have significantly different reading comprehension scores, and both groups' accuracy was greatest when asked to read in silence. Noise conditions that contained English speech, regardless of whether this background noise was spoken or sung, were most disruptive. CONCLUSION: Younger and older adults appear to be equally influenced by irrelevant background material when reading. Regardless of age, reading in a distraction-free environment whenever possible is the best way to maximize reading comprehension.

Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer.

PURPOSE: Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. METHODS: To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains. RESULTS: Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping. CONCLUSIONS: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.

Spatial and temporal assessment of cumulative disturbance impacts due to military training, burning, haying, and their interactions on land condition of Fort Riley.

The effects of military training activities on the land condition of Army installations vary spatially and temporally. Training activities observably degrade land condition while also increasing biodiversity and stabilizing ecosystems. Moreover, other anthropogenic activities regularly occur on military lands such as prescribed burns and agricultural haying-adding to the dynamics of land condition. Thus, spatially and temporally assessing the impacts of military training, prescribed burning, agricultural haying, and their interactions is critical to the management of military lands. In this study, the spatial distributions and patterns of military training-induced disturbance frequency were derived using plot observation and point observation-based method, at Fort Riley, Kansas from 1989 to 2001. Moreover, spatial and variance analysis of cumulative impacts due to military training, burning, haying, and their interactions on the land condition of Fort Riley were conducted. The results showed that: (1) low disturbance intensity dominated the majority of the study area with exception of concentrated training within centralized areas; (2) high and low values of disturbance frequency were spatially clustered and had spatial patterns that differed significantly from a random distribution; and (3) interactions between prescribed burning and agricultural haying were not significant in terms of either soil erosion or disturbance intensity although their means and variances differed significantly between the burned and non-burned areas and between the hayed and non-hayed areas.

Using action research and a community-academic partnership to understand clinical trial participation: a patient-centered perspective.

BACKGROUND: Clinical trials that are patient-centered appear to be more successful (e.g., clinical outcomes, improved communication, mutual empowerment, changed attitudes), thus, action research may be a field of importance. The current study explores the Formation and Execution of Activities phases of a community-academic partnership (CAP). METHODS: Members consisted of industry stakeholders, a healthcare/academic institution, and patients/families with lived experiences as cancer survivors and/or caregivers. Retrospectively, CAP members described the facilitating and/or hindering factors present in the partnership development. A document review process was used. Field notes from three CAP meetings, which focused on understanding clinical trial participation, were analyzed using a thematic approach. RESULTS: Seven facilitating and three hindering factors were present. Interpersonal (vs. operational) processes were referenced as influential facilitating factors more often. Themes that emerged included 'trials as a treatment option', 'leaving a legacy', and 'timing is critical.' CONCLUSION: This study provides a patient-centered perspective on barriers/challenges of clinical trial participation and how to improve future perceptions.

Clinical trials are more successful when patients are engaged, and their perspectives have been considered in the study design. Community-academic partnerships (CAPs) are one way to ensure patients are more engaged in the research process by creating a collaboration where all parties involved play an equitable role. We provide an example of a CAP with an industry stakeholder, a healthcare/academic institution, and patients as well as families with lived experiences as cancer survivors and/or caregivers. Described here two phases of the CAP: the Formation and the Execution of Activities phases. The Formation phase covers the collaboration process and development of the CAP. In our study, to better understand this phase, CAP members described what did and did not go well during the partnership development. We found more aspects went well than did not and that processes related to the quality of the relationship and communication among CAP members were important. The Execution of Activities phase focuses on how the CAP is working towards an agreed upon outcome. In our study, to better understand this phase, we reviewed notes taken at previous CAP meetings that focused on exploring participation in clinical trials as a treatment option. We found that when it comes to participation in clinical trials, patients and/or caregivers with lived experiences with cancer, felt that timing of this treatment option was important and that reasons for participation included wanting to leave a legacy. In this paper we describe some challenges of clinical trial participation, identified by patients and caregivers, and discuss how to improve views of clinical trial participation in the future.

A patient perspective on applying intermittent fasting in gynecologic cancer.

OBJECTIVE: Researchers sought patient feedback on a proposed randomized controlled trial (RCT) in which gynecological cancer patients would modify their diets with intermittent fasting to gain insight into patients' perspectives, receptivity, and potential obstacles. A convenience sample of 47 patients who met the inclusion criteria of the proposed RCT provided their feedback on the feasibility and protocols of the RCT using a multi-method approach consisting of focus groups (n = 8 patients) and surveys (n = 36 patients). RESULTS: Patients were generally receptive to the concept of intermittent fasting, and many expressed an interest in attempting it themselves. Patients agreed that the study design was feasible in terms of study assessments, clinic visits, and biospecimen collection. Feedback on what could facilitate adherence included convenient appointment scheduling times and the availability of the research team to answer questions. Regarding recruitment, patients offered suggestions for study advertisements, with the majority concurring that a medical professional approaching them would increase their likelihood of participation.

"Healing Can Be a Very Jagged Line": Reflections on Life as a COVID-19 Long Hauler.

"Long COVID" - a term referring to COVID-19-associated symptoms and conditions (ie, sequelae) that remain or emerge after resolution of a SARS-CoV-2 infection - is a multifaceted condition about which little is known. As part of formalized patient-engaged research at a large Midwestern health system, patient stakeholders with long COVID (N=5) wrote stories based on their lived experience, as this was their preferred format for detailing their experience with the condition. These patient stakeholders reviewed one another's stories, identified relevant quotes, and provided opportunities for elaboration. Independently, a trained researcher extracted quotes from the stories, identified themes, and wove the quotes together to share the independent, yet similar, stories. Emergent themes were that of uncertainty about the symptomatology of long COVID and its effects on patients' mental health, physical functioning, family unit, self-identity, and future outlook. Further patient-engaged research on understanding the lived experience of long COVID may serve to advance knowledge and treatment. Health care providers caring for those with long COVID can benefit from listening and validating the stories of individuals suffering from this condition.

Bridging the Patient Engagement Gap in Research and Quality Improvement Utilizing the Henry Ford Flexible Engagement Model.

PURPOSE: This paper was intended to share a flexible engagement model (FEM) for organizing a structure to obtain patient input regarding health care operations and research, provide greater detail on recruitment, retention, and dissemination strategies, and demonstrate successes and potential applications in other health care settings. METHODS: Utilizing a pragmatic approach, the Patient-Engaged Research Center (PERC) at Henry Ford Health System developed the FEM, a 7-step process to introduce interested patients/caregivers to the patient advisor program and to follow up with placements. PERC developed a meeting evaluation to measure participant satisfaction. Retention and dissemination methods to keep participants consistently engaged included monthly email blasts, an annual patient advisor retreat, and inviting patient advisors to attend/present at local and national conferences. RESULTS: As of January 2020, the program had 419 patient advisors. Almost 50% self-reported as Caucasian and 31% as African American; 73% were women, and most were 45-74 years of age. Recruitment methods proved effective, as 85% of advisors were initially engaged through print and digital marketing. Mean advisor orientation workshop evaluation scores regarding content, facilitators, and logistics were high, with all 4.5 or higher on a Likert scale of 1 (strongly negative) to 5 (strongly positive). CONCLUSIONS: Given the FEM's flexible nature and adaptability, PERC has been successful in effectively leveraging the patient voice and experiences in research and health care delivery. Further research could investigate the model's generalizability, return on investment, and how to formally embed its methodology institutionally.

ZATPAC: a model consortium evaluates teen programs.

How do we advance the environmental literacy of young people, support the next generation of environmental stewards and increase the diversity of the leadership of zoos and aquariums? We believe it is through ongoing evaluation of zoo and aquarium teen programming and have founded a consortium to pursue those goals. The Zoo and Aquarium Teen Program Assessment Consortium (ZATPAC) is an initiative by six of the nation's leading zoos and aquariums to strengthen institutional evaluation capacity, model a collaborative approach toward assessing the impact of youth programs, and bring additional rigor to evaluation efforts within the field of informal science education. Since its beginning in 2004, ZATPAC has researched, developed, pilot-tested and implemented a pre-post program survey instrument designed to assess teens' knowledge of environmental issues, skills and abilities to take conservation actions, self-efficacy in environmental actions, and engagement in environmentally responsible behaviors. Findings from this survey indicate that teens who join zoo/aquarium programs are already actively engaged in many conservation behaviors. After participating in the programs, teens showed a statistically significant increase in their reported knowledge of conservation and environmental issues and their abilities to research, explain, and find resources to take action on conservation issues of personal concern. Teens also showed statistically significant increases pre-program to post-program for various conservation behaviors, including "I talk with my family and/or friends about things they can do to help the animals or the environment," "I save water...," "I save energy...," "When I am shopping I look for recycled products," and "I help with projects that restore wildlife habitat."

Why do older adults have difficulty following conversations?

Age-related declines in understanding conversation may be largely a consequence of perceptual rather than cognitive declines. B. A. Schneider, M. Daneman, D. R. Murphy, and S. Kwong-See (2000) showed that age-related declines in comprehending single-talker discourse could be eliminated when adjustments were made to compensate for the poorer hearing of older adults. The authors used B. A. Schneider et al.'s methodology to investigate age-related differences in comprehending 2-person conversations. Compensating for hearing difficulties did not eliminate age-related differences when the 2 talkers were spatially separated by 9 degrees or 45 degrees azimuth, but it did when the talkers' contributions came from one central location. These findings suggest that dialogue poses more of a problem for older than for younger adults, not because of the additional cognitive requirements of having to follow 2 talkers rather than 1, but because older adults are not as good as younger adults at making use of the auditory cues that are available for helping listeners perceptually segregate the contributions of 2 spatially separated talkers.

A comparison of higher order auditory processes in younger and older adults.

The authors conducted 3 experiments investigating the effects of aging on higher order auditory processes. They compared younger and older adults with respect to (a) their auditory channel capacity, (b) the extent of their top-down control over auditory gain, and (c) their ability to focus attention on a narrow band of frequencies. To ensure that subclinical cochlear processing deficits in older adults (e.g., higher thresholds, poorer discrimination of frequency and intensity differences) did not limit performance, the authors used only stimuli that were perfectly discriminable by all participants. No age differences were found in any of these experiments, suggesting that some higher order auditory processes (e.g., top-down control over auditory gain, auditory attention) are preserved in normal aging, despite numerous age-related declines in peripheral auditory functionality.

Speech comprehension difficulties in older adults: cognitive slowing or age-related changes in hearing?

Speech comprehension declines more rapidly in older adults than in younger adults as speech rate increases. This effect is usually attributed to a slowing of brain function with age. Alternatively, this Age X Speed interaction could reflect the inability of the older adult's auditory system to cope with speed-induced stimulus degradation. When the authors speeded speech in a way that produced minimal degradation, both age groups were equally affected. However, when speech was speeded using other methods, word identification declined more in older than in younger adults. Hence, auditory decline rather than cognitive slowing may be responsible for older adults' poorer performance in speeded conditions.

Comparing the effects of aging and background noise on short-term memory performance.

Paired associate recall was tested as a function of serial position for younger and older adults for five word pairs presented aurally in quiet and in noise. In Experiment 1, the addition of noise adversely affected recall in young adults, but only in the early serial positions. Experiments 2 and 3 suggested that the recall of older adults listening to the words in quiet was nearly equivalent to that of younger adults listening in noise. In Experiment 4, we determined the signal-to-noise ratio (S/N) such that, on average, younger and older adults were able to correctly hear the same percentage of words when words were presented one at a time in noise. In Experiment 5, younger adults were tested under this S/N. Compared with older adults from Experiment 3, younger adults in this experiment recalled more words at all serial positions. The results are interpreted as showing that encoding in secondary memory is impaired by aging and noise either as a function of degraded sensory representations, or as a function of reduced processing resources.

Making sense of age-related distractibility: the critical role of sensory modality.

Older adults are known to have reduced inhibitory control and therefore to be more distractible than young adults. Recently, we have proposed that sensory modality plays a crucial role in age-related distractibility. In this study, we examined age differences in vulnerability to unimodal and cross-modal visual and auditory distraction. A group of 24 younger (mean age=21.7 years) and 22 older adults (mean age=65.4 years) performed visual and auditory n-back tasks while ignoring visual and auditory distraction. Whereas reaction time data indicated that both young and older adults are particularly affected by unimodal distraction, accuracy data revealed that older adults, but not younger adults, are vulnerable to cross-modal visual distraction. These results support the notion that age-related distractibility is modality dependent.

A model of top-down gain control in the auditory system.

To evaluate a model of top-down gain control in the auditory system, 6 participants were asked to identify 1-kHz pure tones differing only in intensity. There were three 20-session conditions: (1) four soft tones (25, 30, 35, and 40 dB SPL) in the set; (2) those four soft tones plus a 50-dB SPL tone; and (3) the four soft tones plus an 80-dB SPL tone. The results were well described by a top-down, nonlinear gain-control system in which the amplifier's gain depended on the highest intensity in the stimulus set. Individual participants' identification judgments were generally compatible with an equal-variance signal-detection model in which the mean locations of the distribution of effects along the decision axis were determined by the operation of this nonlinear amplification system.

Aging and distraction by irrelevant speech: does emotional valence matter?

OBJECTIVES: From prior studies, we know that older adults are rarely more distracted by irrelevant speech than younger adults, which is remarkable in light of the inhibitory deficit view of aging. We tested the hypothesis that older adults are more distracted by emotional irrelevant speech during a visual cognitive task than younger adults. METHODS: Forty-eight younger (mean age = 21.9 years) and 48 older individuals (mean age = 68.1 years) performed a visual counting task while being exposed to irrelevant speech consisting of random numbers intermixed with neutral, positive, or negative words. Performance in these conditions was compared with that in a silence condition. RESULTS: Irrelevant speech increased counting time and decreased accuracy similarly for younger and older adults. Furthermore, the emotional conditions did not elicit a stronger effect than the neutral condition. Finally, we found implicit memory for irrelevant speech, but its level was independent of emotional valence and age. DISCUSSION: We conclude that emotional irrelevant speech has no disproportionate impact on cognitive performance in older adults. This can be regarded as a challenge to the inhibitory deficit hypothesis.

The effects of age on channel capacity for absolute identification of tonal duration.

We compared the ability of younger and older adults to identify which 2-kHz tones of eight varying durations was presented on a trial with their ability to discriminate between adjacent pairs of duration-varying tones drawn from the same set. We used signal detection analyses to construct scales of perceived duration for both tasks. Scales derived from pairwise comparisons of adjacent durations were related linearly to the logarithm of stimulus duration; these were essentially identical in younger and older adults. However, scales derived from the eight-alternative absolute identification experiments, which were also linearly related to the logarithm of duration, indicated that older adults outperformed younger adults on this task. These results suggest that the ability to process large numbers of stimuli that differ only in duration is at least as good, if not better, in older than in younger adults, relative to the ability of each group to discriminate between two stimuli differing only in duration.

The role of sensory modality in age-related distraction: a critical review and a renewed view.

Selective attention requires the ability to focus on relevant information and to ignore irrelevant information. The ability to inhibit irrelevant information has been proposed to be the main source of age-related cognitive change (e.g., Hasher & Zacks, 1988). Although age-related distraction by irrelevant information has been extensively demonstrated in the visual modality, studies involving auditory and cross-modal paradigms have revealed a mixed pattern of results. A comparative evaluation of these paradigms according to sensory modality suggests a twofold trend: Age-related distraction is more likely (a) in unimodal than in cross-modal paradigms and (b) when irrelevant information is presented in the visual modality, rather than in the auditory modality. This distinct pattern of age-related changes in selective attention may be linked to the reliance of the visual and auditory modalities on different filtering mechanisms. Distractors presented through the auditory modality can be filtered at both central and peripheral neurocognitive levels. In contrast, distractors presented through the visual modality are primarily suppressed at more central levels of processing, which may be more vulnerable to aging. We propose the hypothesis that age-related distractibility is modality dependent, a notion that might need to be incorporated in current theories of cognitive aging. Ultimately, this might lead to a more accurate account for the mixed pattern of impaired and preserved selective attention found in advancing age.

Top-down gain control in the auditory system: evidence from identification and discrimination experiments.

The influence of intensity range in auditory identification and intensity discrimination experiments is well documented and is usually attributed to nonsensory factors. Recent studies, however, have suggested that the stimulus range effect might be sensory in origin. To test this notion, in one set of experiments, we had listeners identify the individual tones in a set. One baseline condition consisted of identifying four 1-kHz, low-intensity tones; the other consisted of identifying four 1-kHz, high-intensity tones. In the experimental conditions, these baseline tone sets were augmented by adding a fifth tone at either 1 or 5 kHz. Added 5-kHz tones had little effect on identification accuracy for the four baseline tones. When an added 1-kHz tone differed substantially in intensity from the four baseline tones, it adversely affected performance, with the addition of a high-intensity tone to a set of low-intensity tones having a more deleterious effect than the addition of a low-intensity tone to a set of high-intensity tones. These and further results, obtained in an exploration of this asymmetrical range effect in a third identification experiment and in two intensity-discrimination experiments, were consistent with the notion of a nonlinear amplifier under top-down control whose functions include protection against sensory overload from loud sounds. The identification data were well described by a signal-detection model using equal-variance Laplace distributions instead of the usual Gaussian distributions.