Resistance and Tolerance Screening of Spring Wheat Cultivars to Cereal Cyst Nematode (Heterodera avenae) in Southeastern Idaho.

Increased populations of Heterodera avenae in southeastern Idaho are associated with increased planting of susceptible cereal cultivars and lack of crop rotation. Identifying high-yield, resistant spring wheat cultivars with tolerance requires testing new genotypes and susceptibility assessments of marketed cultivars. We conducted two experiments to determine whether cultivars with putative resistance could maintain acceptable yield in the presence of H. avenae. We also evaluated the tolerance response in relation to previously tested cultivars. Seven spring wheat cultivars were planted in two irrigated commercial fields that were naturally infested with high populations of H. avenae. Measures of resistance, tolerance, and grain yield were assessed in aldicarb-treated versus nontreated plots. In aldicarb-treated plots in both years, grain yield of the susceptible cultivars Snow Crest, WestBred 936, WB9411, Patwin-515, and WB9668 was significantly increased. The expected yield increase with aldicarb was limited for the moderately susceptible Expresso due to water stress. 'WB-Rockland', carrying the Cre5 resistance gene, maintained its standard yield, while none of the other cultivars in the experiment showed resistance or tolerance. Our results indicated that aldicarb improves wheat grain yield in irrigated crop production systems, and although removed from the market, it is effective and has utility for research. The results also support the hypothesis that high yield susceptible cultivars can mask the effect of H. avenae on grain yield when managed appropriately.

Fate and Management of Incompletely Excised Solitary Fibrous Tumor of the Orbit: A Case Series and Literature Review.

PURPOSE: There is an imperfect correlation between the histology and behavior of solitary fibrous tumor (SFT). In addition, recurrence is common, and dedifferentiation may occur over time. Preferred primary treatment is intact excision, but friable pseudocapsules and tenacious attachments can thwart this goal in the crowded, visually sensitive orbit. This study addresses the fate and appropriate management of incompletely excised orbital SFT. METHODS: Among a single surgeon's 7-case experience with orbital SFT, 3 cases involved incomplete primary excision, either before (2 cases) or after (1 case) referral. We reviewed the clinicopathologic data in these 3 cases, with follow-up intervals of 18, 21, and 52 years after initial presentation. We reviewed the English-language literature on SFT, with special attention to evolving nomenclature, orbital involvement, recurrence, malignant transformation, and management options. RESULTS: Benign versus malignant designations of SFT vary with histological and behavioral criteria. Approximately 150 orbital cases have been reported. Published rates of primary malignancy and recurrence across all histologic categories are 6% to 12% and 30% to 37%, respectively. We identified 43 well-documented recurrences (range, 6 months-33 years; median, 3 years) and 10 cases of histological dedifferentiation (range, 14 months-33 years). Because of SFT's rarity and needed follow-up intervals, the value of adjuvant therapy is not yet proven. In follow up of 18, 21, and 52 years after initial presentation, our 3 cases with incomplete excision showed either no recurrence (Case 1) or no morphological dedifferentiation (Cases 2, 3). CONCLUSION: A treatment algorithm is predicated on the completeness of surgical excision and histological features. However, we recommend case-by-case multidisciplinary decisions in a tumor-board setting.

Impact of puberty on the evolution of cerebral perfusion during adolescence.

Puberty is the defining biological process of adolescent development, yet its effects on fundamental properties of brain physiology such as cerebral blood flow (CBF) have never been investigated. Capitalizing on a sample of 922 youths ages 8-22 y imaged using arterial spin labeled MRI as part of the Philadelphia Neurodevelopmental Cohort, we studied normative developmental differences in cerebral perfusion in males and females, as well as specific associations between puberty and CBF. Males and females had conspicuously divergent nonlinear trajectories in CBF evolution with development as modeled by penalized splines. Seventeen brain regions, including hubs of the executive and default mode networks, showed a robust nonlinear age-by-sex interaction that surpassed Bonferroni correction. Notably, within these regions the decline in CBF was similar between males and females in early puberty and only diverged in midpuberty, with CBF actually increasing in females. Taken together, these results delineate sex-specific growth curves for CBF during youth and for the first time to our knowledge link such differential patterns of development to the effects of puberty.

The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort.

BACKGROUND: Diffusion tensor imaging (DTI) is applied in investigation of brain biomarkers for neurodevelopmental and neurodegenerative disorders. However, the quality of DTI measurements, like other neuroimaging techniques, is susceptible to several confounding factors (e.g., motion, eddy currents), which have only recently come under scrutiny. These confounds are especially relevant in adolescent samples where data quality may be compromised in ways that confound interpretation of maturation parameters. The current study aims to leverage DTI data from the Philadelphia Neurodevelopmental Cohort (PNC), a sample of 1601 youths with ages of 8-21 who underwent neuroimaging, to: 1) establish quality assurance (QA) metrics for the automatic identification of poor DTI image quality; 2) examine the performance of these QA measures in an external validation sample; 3) document the influence of data quality on developmental patterns of typical DTI metrics. METHODS: All diffusion-weighted images were acquired on the same scanner. Visual QA was performed on all subjects completing DTI; images were manually categorized as Poor, Good, or Excellent. Four image quality metrics were automatically computed and used to predict manual QA status: Mean voxel intensity outlier count (MEANVOX), Maximum voxel intensity outlier count (MAXVOX), mean relative motion (MOTION) and temporal signal-to-noise ratio (TSNR). Classification accuracy for each metric was calculated as the area under the receiver-operating characteristic curve (AUC). A threshold was generated for each measure that best differentiated visual QA status and applied in a validation sample. The effects of data quality on sensitivity to expected age effects in this developmental sample were then investigated using the traditional MRI diffusion metrics: fractional anisotropy (FA) and mean diffusivity (MD). Finally, our method of QA is compared with DTIPrep. RESULTS: TSNR (AUC=0.94) best differentiated Poor data from Good and Excellent data. MAXVOX (AUC=0.88) best differentiated Good from Excellent DTI data. At the optimal threshold, 88% of Poor data and 91% Good/Excellent data were correctly identified. Use of these thresholds on a validation dataset (n=374) indicated high accuracy. In the validation sample 83% of Poor data and 94% of Excellent data was identified using thresholds derived from the training sample. Both FA and MD were affected by the inclusion of poor data in an analysis of an age, sex and race matched comparison sample. In addition, we show that the inclusion of poor data results in significant attenuation of the correlation between diffusion metrics (FA and MD) and age during a critical neurodevelopmental period. We find higher correspondence between our QA method and DTIPrep for Poor data, but we find our method to be more robust for apparently high-quality images. CONCLUSION: Automated QA of DTI can facilitate large-scale, high-throughput quality assurance by reliably identifying both scanner and subject induced imaging artifacts. The results present a practical example of the confounding effects of artifacts on DTI analysis in a large population-based sample, and suggest that estimates of data quality should not only be reported but also accounted for in data analysis, especially in studies of development.

The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth.

The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment.

Circadian perinatal photoperiod has enduring effects on retinal dopamine and visual function.

Visual system development depends on neural activity, driven by intrinsic and light-sensitive mechanisms. Here, we examined the effects on retinal function due to exposure to summer- and winter-like circadian light cycles during development and adulthood. Retinal light responses, visual behaviors, dopamine content, retinal morphology, and gene expression were assessed in mice reared in seasonal photoperiods consisting of light/dark cycles of 8:16, 16:8, and 12:12 h, respectively. Mice exposed to short, winter-like, light cycles showed enduring deficits in photopic retinal light responses and visual contrast sensitivity, but only transient changes were observed for scotopic measures. Dopamine levels were significantly lower in short photoperiod mice, and dopaminergic agonist treatment rescued the photopic light response deficits. Tyrosine hydroxylase and Early Growth Response factor-1 mRNA expression were reduced in short photoperiod retinas. Therefore, seasonal light cycles experienced during retinal development and maturation have lasting influence on retinal and visual function, likely through developmental programming of retinal dopamine.

Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells.

Spatial variation in light intensity, called spatial contrast, comprises much of the visual information perceived by mammals, and the relative ability to detect contrast is referred to as contrast sensitivity (Purves et al., 2012). Recently, retinal dopamine D4 receptors (D4Rs) have been implicated in modulating contrast sensitivity (Jackson et al., 2012); however, the cellular and molecular mechanisms have not been elucidated. Our study demonstrates a circadian rhythm of contrast sensitivity that peaks during the daytime, and that its regulation involves interactions of D4Rs, the clock gene Npas2, and the clock-controlled gene adenylyl cyclase 1 (Adcy1) in a subset of retinal ganglion cells (RGCs). Targeted disruption of the gene encoding D4Rs reduces the amplitude of the contrast sensitivity rhythm by reducing daytime sensitivity and abolishes the rhythmic expression of Npas2 and Adcy1 mRNA in the ganglion cell layer (GCL) of the retina. Npas2(-/-) and Adcy1(-/-) mice show strikingly similar reductions in the contrast sensitivity rhythm to that in mice lacking D4Rs. Moreover, Adcy1 transcript rhythms were abolished in the GCL of Npas2(-/-) mice. Luciferase reporter assays demonstrated that the Adcy1 promoter is selectively activated by neuronal PAS-domain protein 2 (NPAS2)/BMAL1. Our results indicate that the contrast sensitivity rhythm is modulated by D4Rs via a signaling pathway that involves NPAS2-mediated circadian regulation of Adcy1. Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing.

Functional maturation of the executive system during adolescence.

Adolescence is characterized by rapid development of executive function. Working memory (WM) is a key element of executive function, but it is not known what brain changes during adolescence allow improved WM performance. Using a fractal n-back fMRI paradigm, we investigated brain responses to WM load in 951 human youths aged 8-22 years. Compared with more limited associations with age, WM performance was robustly associated with both executive network activation and deactivation of the default mode network. Multivariate patterns of brain activation predicted task performance with a high degree of accuracy, and also mediated the observed age-related improvements in WM performance. These results delineate a process of functional maturation of the executive system, and suggest that this process allows for the improvement of cognitive capability seen during adolescence.

Neuroimaging of the Philadelphia neurodevelopmental cohort.

The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale, NIMH funded initiative to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness, and understand how genetics impacts this process. As part of this study, 1445 adolescents ages 8-21 at enrollment underwent multimodal neuroimaging. Here, we highlight the conceptual basis for the effort, the study design, and the measures available in the dataset. We focus on neuroimaging measures obtained, including T1-weighted structural neuroimaging, diffusion tensor imaging, perfusion neuroimaging using arterial spin labeling, functional imaging tasks of working memory and emotion identification, and resting state imaging of functional connectivity. Furthermore, we provide characteristics regarding the final sample acquired. Finally, we describe mechanisms in place for data sharing that will allow the PNC to become a freely available public resource to advance our understanding of normal and pathological brain development.

Retinal dopamine mediates multiple dimensions of light-adapted vision.

Dopamine is a key neuromodulator in the retina and brain that supports motor, cognitive, and visual function. Here, we developed a mouse model on a C57 background in which expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase, is specifically disrupted in the retina. This model enabled assessment of the overall role of retinal dopamine in vision using electrophysiological (electroretinogram), psychophysical (optokinetic tracking), and pharmacological techniques. Significant disruptions were observed in high-resolution, light-adapted vision caused by specific deficits in light responses, contrast sensitivity, acuity, and circadian rhythms in this retinal dopamine-depleted mouse model. These global effects of retinal dopamine on vision are driven by the differential actions of dopamine D1 and D4 receptors on specific retinal functions and appear to be due to the ongoing bioavailability of dopamine rather than developmental effects. Together, our data indicate that dopamine is necessary for the circadian nature of light-adapted vision as well as optimal contrast detection and acuity.

Heterogeneous impact of motion on fundamental patterns of developmental changes in functional connectivity during youth.

Several independent studies have demonstrated that small amounts of in-scanner motion systematically bias estimates of resting-state functional connectivity. This confound is of particular importance for studies of neurodevelopment in youth because motion is strongly related to subject age during this period. Critically, the effects of motion on connectivity mimic major findings in neurodevelopmental research, specifically an age-related strengthening of distant connections and weakening of short-range connections. Here, in a sample of 780 subjects ages 8-22, we re-evaluate patterns of change in functional connectivity during adolescent development after rigorously controlling for the confounding influences of motion at both the subject and group levels. We find that motion artifact inflates both overall estimates of age-related change as well as specific distance-related changes in connectivity. When motion is more fully accounted for, the prevalence of age-related change as well as the strength of distance-related effects is substantially reduced. However, age-related changes remain highly significant. In contrast, motion artifact tends to obscure age-related changes in connectivity associated with segregation of functional brain modules; improved preprocessing techniques allow greater sensitivity to detect increased within-module connectivity occurring with development. Finally, we show that subject's age can still be accurately estimated from the multivariate pattern of functional connectivity even while controlling for motion. Taken together, these results indicate that while motion artifact has a marked and heterogeneous impact on estimates of connectivity change during adolescence, functional connectivity remains a valuable phenotype for the study of neurodevelopment.

Spring Wheat Tolerance and Resistance to Heterodera avenae in the Pacific Northwest.

The cereal cyst nematode Heterodera avenae reduces wheat yields in the Pacific Northwest. Previous evaluations of cultivar resistance had been in controlled environments. Cultivar tolerance had not been evaluated. Seven spring wheat trials were conducted in naturally infested fields in three states over 2 years. A split-plot design was used for all trials. Five trials evaluated both tolerance and resistance in 1.8-by-9-m plots treated or not treated with nematicides. Two trials evaluated resistance in 1-m head rows where each wheat entry was paired with an adjacent row of a susceptible cultivar. Cultivars with the Cre1 resistance gene ('Ouyen' and 'Chara') reduced the postharvest density of H. avenae under field conditions, confirming Cre1 parents as useful for germplasm development. Ouyen was resistant but it was also intolerant, producing significantly lower grain yield in controls than in plots treated with nematicides. Susceptible cultivars varied in tolerance. Undefined resistance was identified in one commercial cultivar ('WB-Rockland) and four breeding lines (UC1711, SO900163, SY-B041418, and SY-97621-05). This research was the first systematic field demonstration of potential benefits to be derived through development and deployment of cultivars with resistance plus tolerance to cereal cyst nematode in North America.

Dopamine D4 receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina.

In the mammalian retina, dopamine binding to the dopamine D4 receptor (D4R) affects a light-sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark-adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D4R. The present investigation provides evidence that D4R activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild-type mouse retina. Also, rhythms in the Ca²âº-stimulated AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D4R. Pharmacologically activating the D4R 4 h before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the D4R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D4R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina.

Adaptation and validation of a computerized neurocognitive battery in the Xhosa of South Africa.

OBJECTIVE: Large-scale studies have revolutionized biomedical research, and neurocognitive tests can help elucidate the biological basis of neuropsychiatric diseases. However, studies have predominantly been conducted in Western settings. We describe the development and validation of a computerized battery (PennCNB) with the Xhosa population of South Africa. METHOD: Individuals with schizophrenia (n = 525) and a normative comparison group (n = 744) were balanced on age, sex, education, and region. Participants provided blood samples, were assessed psychiatrically, and were administered a PennCNB translation to isiXhosa, including measures of executive functions, episodic memory, complex cognition, social cognition, and sensorimotor speed. Feasibility was examined with test completion rates and input from administrators, and psychometric structural validity and associations with clinical and demographic characteristics were examined. RESULTS: Tests were well tolerated by participants, as >87% had one (or fewer) test missing. Results suggested a similar factor structure to prior PennCNB studies in Western contexts, and expected age and sex effects were apparent. Furthermore, a similar profile of schizophrenia was observed, with neurocognitive deficits most pronounced for executive functions, especially attention, as well as memory, social cognition, and motor speed relative to complex cognition and sensorimotor speed. CONCLUSIONS: Results support the feasibility of implementing a culturally adapted computerized neurocognitive battery in sub-Saharan African settings and provide evidence supporting the concurrent validity of the translated instrument. Thus, the PennCNB is implementable on a large scale in non-Western contexts, shows expected factor structure, and can detect cognitive deficits associated with neuropsychiatric disorders. Obtaining valid measures of cognition by nonspecialized proctors is especially suitable in resource-limited settings, where traditional testing is prohibitive. Future work should establish normative standards, test-retest reliability, and sensitivity to treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.

Photoperiodic effects on monoamine signaling and gene expression throughout development in the serotonin and dopamine systems.

Photoperiod or the duration of daylight has been implicated as a risk factor in the development of mood disorders. The dopamine and serotonin systems are impacted by photoperiod and are consistently associated with affective disorders. Hence, we evaluated, at multiple stages of postnatal development, the expression of key dopaminergic (TH) and serotonergic (Tph2, SERT, and Pet-1) genes, and midbrain monoamine content in mice raised under control Equinox (LD 12:12), Short winter-like (LD 8:16), or Long summer-like (LD 16:8) photoperiods. Focusing in early adulthood, we evaluated the midbrain levels of these serotonergic genes, and also assayed these gene levels in the dorsal raphe nucleus (DRN) with RNAScope. Mice that developed under Short photoperiods demonstrated elevated midbrain TH expression levels, specifically during perinatal development compared to mice raised under Long photoperiods, and significantly decreased serotonin and dopamine content throughout the course of development. In adulthood, Long photoperiod mice demonstrated decreased midbrain Tph2 and SERT expression levels and reduced Tph2 levels in the DRN compared Short photoperiod mice. Thus, evaluating gene × environment interactions in the dopaminergic and serotonergic systems during multiple stages of development may lead to novel insights into the underlying mechanisms in the development of affective disorders.

Essential roles of dopamine D4 receptors and the type 1 adenylyl cyclase in photic control of cyclic AMP in photoreceptor cells.

Light and dopamine regulate many physiological functions in the vertebrate retina. Light exposure decreases cyclic AMP formation in photoreceptor cells. Dopamine D(4) receptor (D(4)R) activation promotes light adaptation and suppresses the light-sensitive pool of cyclic AMP in photoreceptor cells. The key signaling pathways involved in regulating cyclic AMP in photoreceptor cells have not been identified. In the present study, we show that the light- and D(4)R-signaling pathways converge on the type 1 Ca(2+)/calmodulin-stimulated adenylyl cyclase (AC1) to regulate cyclic AMP synthesis in photoreceptor cells. In addition, we present evidence that D(4)R activation tonically regulates the expression of AC1 in photoreceptors. In retinas of mice with targeted deletion of the gene (Adcy1) encoding AC1, cyclic AMP levels and Ca(2+)/calmodulin-stimulated adenylyl cyclase activity are markedly reduced, and cyclic AMP accumulation is unaffected by either light or D(4)R activation. Similarly, in mice with disruption of the gene (Drd4) encoding D(4)R, cyclic AMP levels in the dark-adapted retina are significantly lower compared to wild-type retina and are unresponsive to light. These changes in Drd4-/- mice were accompanied by significantly lower Adcy1 mRNA levels in photoreceptor cells and lower Ca(2+)/calmodulin-stimulated adenylyl cyclase activity in retinal membranes compared with wild-type controls. Reduced levels of Adcy1 mRNA were also observed in retinas of wild-type mice treated chronically with a D(4)R antagonist, L-745870. Thus, activation of D(4)R is required for normal expression of AC1 and for the regulation of its catalytic activity by light. These observations illustrate a novel mechanism for cross-talk between dopamine and photic signaling pathways regulating cyclic AMP in photoreceptor cells.

Impact of a Non-small Cell Lung Cancer Educational Program for Interdisciplinary Teams.

BACKGROUND: Successful implementation of non-small cell lung cancer (NSCLC) evidence-based guideline recommendations requires effective educational programs that target all clinicians from interdisciplinary teams. This study describes and evaluates the Engaging an Interdisciplinary Team for NSCLC (GAIN 3.0) experiential learning-based educational curriculum. METHODS: GAIN 3.0 was designed to enhance interdisciplinary collaboration for effective NSCLC diagnosis, assessment, and treatment. The program used a flipped classroom model that included an e-learning component prior to a live 6-hour interactive program. The interactive program included hands-on simulations, small group workshops, gamification, and case discussions. Participants included academic and community members of multidisciplinary lung cancer teams. Assessments included an online baseline survey, a pretest and posttest, a program evaluation, a long-term survey (LTS), and on-site faculty evaluation of participants. RESULTS: Of 416 attendees to 13 live GAIN 3.0 programs (nine in the United States and four in Europe), 304 (73%) completed the pretest and 187 (45%) completed the posttest. Out of a perfect score of 12 points, program participants had a mean test score of 6.3 ± 2.1 on the pretest (52%) and 7.8 ± 2.1 on the posttest (65%) (P = .03). There was an overall knowledge increase of 13% from pretest to posttest. Most LTS respondents (65%) rated the GAIN 3.0 live programs as "high impact." On the LTS, the areas with the greatest gains in participants who had very high confidence were communication across disciplines, use of a team-based approach, and personalized treatment. CONCLUSIONS: GAIN 3.0 was a highly successful interdisciplinary activity that improved participants' knowledge, competence, and likely the clinical care provided to patients with NSCLC.

Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer.

PURPOSE: The transforming growth factor-beta (TGF-beta) signaling pathway has been frequently implicated in breast cancer. An intronic variant (Int7G24A) of TGF-beta receptor type I (TGFBR1) is associated with kidney and bladder cancers in our recent study. We hypothesize that this germline variant may be involved in development and progression of breast cancer. EXPERIMENTAL DESIGN: Case-control studies were designed from archived paraffin-embedded tissue specimens from the same geographic area with a homogenous ethnic population. We analyzed 223 patients (25 with preinvasive tumors and 198 with invasive and metastatic breast cancers) and 153 noncancer controls. The Int7G24A was identified by PCR-RFLP. Another germline deletion (TGFBR1*6A) and somatic mutations in the TGFBR1 were also analyzed by PCR and single-strand conformational polymorphism. RESULTS: The Int7G24A allele was evident in 32% of patients with preinvasive neoplasms and 48% of patients with invasive breast cancers compared with 26% controls (P = 0.00008). In addition, 11 (5.6%) homozygous Int7G24A carriers were found in patients with invasive breast cancers, whereas only 3 (2%) homozygous carriers were found in the control group. The TGFBR1*6A allele was not significantly associated with breast cancer patients and only one somatic mutation was found in 71 breast cancers. CONCLUSION: These data suggest that the germline Int7G24A variant may represent a risk factor for invasive breast cancer and a marker for breast cancer progression. A separate study with a larger sample size is warranted to validate the association of the Int7G24A with human breast cancer.

Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.

BACKGROUND: Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed. METHODS: Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice. RESULTS: Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates. CONCLUSIONS: These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.