Characterization of glycine-N-acyltransferase like 1 (GLYATL1) in prostate cancer.

BACKGROUND: Recent microarray and sequencing studies of prostate cancer showed multiple molecular alterations during cancer progression. It is critical to evaluate these molecular changes to identify new biomarkers and targets. We performed analysis of glycine-N-acyltransferase like 1 (GLYATL1) expression in various stages of prostate cancer in this study and evaluated the regulation of GLYATL1 by androgen. METHOD: We performed in silico analysis of cancer gene expression profiling and transcriptome sequencing to evaluate GLYATL1 expression in prostate cancer. Furthermore, we performed immunohistochemistry using specific GLYATL1 antibody using high-density prostate cancer tissue microarray containing primary and metastatic prostate cancer. We also tested the regulation of GLYATL1 expression by androgen and ETS transcription factor ETV1. In addition, we performed RNA-sequencing of GLYATL1 modulated prostate cancer cells to evaluate the gene expression and changes in molecular pathways. RESULTS: Our in silico analysis of cancer gene expression profiling and transcriptome sequencing we revealed an overexpression of GLYATL1 in primary prostate cancer. Confirming these findings by immunohistochemistry, we show that GLYATL1 is overexpressed in primary prostate cancer compared with metastatic prostate cancer and benign prostatic tissue. Low-grade cancers had higher GLYATL1 expression compared to high-grade prostate tumors. Our studies showed that GLYATL1 is upregulated upon androgen treatment in LNCaP prostate cancer cells which harbors ETV1 gene rearrangement. Furthermore, ETV1 knockdown in LNCaP cells showed downregulation of GLYATL1 suggesting potential regulation of GLYATL1 by ETS transcription factor ETV1. Transcriptome sequencing using the GLYATL1 knockdown prostate cancer cell lines LNCaP showed regulation of multiple metabolic pathways. CONCLUSIONS: In summary, our study characterizes the expression of GLYATL1 in prostate cancer and explores the regulation of its regulation in prostate cancer showing role for androgen and ETS transcription factor ETV1. Future studies are needed to decipher the biological significance of these findings.

Current status of treating neurodegenerative disease with induced pluripotent stem cells.

Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease.

CACNA1C hypermethylation is associated with bipolar disorder.

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation.

Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling.

Insulin-like growth factor-binding protein 7 (IGFBP7) is a selective biomarker of glioblastoma (GBM) vessels, strongly expressed in tumor endothelial cells and vascular basement membrane. IGFBP7 gene regulation and its potential role in tumor angiogenesis remain unclear. Mechanisms of IGFBP7 induction and its angiogenic capacity were examined in human brain endothelial cells (HBECs) exposed to tumor-like conditions. HBEC treated with GBM cell (U87MG)-conditioned media (-CM) exhibited fourfold upregulation of IGFBP7 mRNA and protein compared to control cells. IGFBP7 gene regulation in HBEC was methylation independent. U87MG-CM analysed by enzyme-linked immunosorbent assay contained approximately 5 pM transforming growth factor (TGF)-beta1, a concentration sufficient to stimulate IGFBP7 in HBEC to similar levels as U87MG-CM. Both pan-TGF-beta-neutralizing antibody (1D11) and the TGF-beta1 receptor (activin receptor-like kinase 5, ALK5) antagonist, SB431542, blocked U87MG-CM-induced IGFBP7 expression in HBEC, indicating that TGF-beta1 is an important tumor-secreted effector capable of IGFBP7 induction in endothelial cells. HBEC exposed to either U87MG-CM or IGFBP7 protein exhibited increased capillary-like tube (CLT) formation in Matrigel. Both TGF-beta1- and U87MG-CM-induced Smad-2 phosphorylation and U87MG-CM-induced CLT formation in HBEC were inhibited by the ALK5 antagonist, SB431542. These data suggest that proangiogenic IGFBP7 may be induced in brain endothelial cells by TGF-betas secreted by GBM, most likely through TGF-beta1/ALK5/Smad-2 pathway.

English Language Narratives of Filipino Children.

PURPOSE: The current study focuses on describing the English language narrative skills of children who have been exposed to the Filipino language. METHOD: Eight children between the ages of 6;0 (years;months) and 7;7 who spoke primarily English but who were exposed to the Filipino language at home participated. Each child produced three narrative samples based on wordless picture books. Samples were analyzed for narrative complexity as well as measures of productivity and grammaticality. RESULTS: The complexity of children's narratives was comparable to that reported in the literature for monolingual English-speaking children. Grammaticality measures show use of an average of 16.55% Filipino-influenced English forms across three stories. The observed patterns of Filipino-influenced English were predictable based on the comparison of English and Filipino structures. Variability in maze use was related to the amount of exposure to Filipino. CLINICAL IMPLICATIONS: Care should be taken to evaluate grammaticality with respect to nonstandard English forms predicted by the rules of the language in contact with English. Further, maze use may be related to level of exposure to another language and should be further explored when using such information in language evaluation.

Conceptual Versus Monolingual Scoring: When Does It Make a Difference?

PURPOSE: This study evaluates the extent to which bilingual children produce the same or overlapping responses on tasks assessing semantic skills in each of their languages and whether classification analysis based on monolingual or conceptual scoring can accurately classify the semantic development of typically developing (TD) bilingual children. METHOD: In Study 1, 55 TD children (ages 4;0 [years;months] to 7;11) from bilingual backgrounds named characteristic properties of familiar items. The extent to which children produced overlapping responses in each of their languages and their errors were examined. In Study 2, 40 TD children (ages 5;0 to 6;1), group matched for age and bilingual language exposure, responded to the Phase 2 version of the Bilingual English Spanish Assessment (BESA; E. D. Peña, V. Gutierrez-Clellen, A. Iglesias, B. A. Goldstein, & L. M. Bedore, in development). Conceptual and monolingual scores were compared to determine the extent to which these were comparable for groups of children. RESULTS: The results of Study 1 indicated that TD children from bilingual backgrounds are more likely to produce unique than overlapping responses when they respond to test items. Children were more likely to code switch when tested in Spanish than in English, but they were more likely to produce errors in English. In Study 2, monolingual and bilingual children achieved comparable conceptual scores. For Spanish-speaking bilingual children, the conceptual score was more likely to be in the average range of the monolingual children than was their monolingual score. For testing in English, monolingual and conceptual scores were similar. CLINICAL IMPLICATIONS: Bilingual children will benefit from conceptual scoring, especially when they are tested in Spanish.

Narrative Discourse in Bilingual Children: Language and Task Effects.

PURPOSE: This study investigated the effect of language on Spanish-English bilingual children's production of narrative samples elicited in two ways. METHOD: Twelve bilingual (Spanish-English-speaking) children ranging in age from 4;0 (years;months) to 6;11 who were fluent speakers of English as a second language produced two narratives-one elicited by using a wordless picture book and another by using a static picture. The children produced stories for each task in each language, for a total of four stories. For the book task, the story complexities were compared across both languages. Stories were scored for complexity of story grammar and the inclusion of specific narrative elements. Both stories in each language were further analyzed for productivity (total words, number of C-units, and mean length of C-unit). The grammaticality (proportion of grammatically acceptable C-units) and the proportion of utterances influenced by the nontarget language was compared across each language and story task. RESULTS: Children produced narratives of equal complexity for the book task regardless of language. However, children used more attempts and initiating events in Spanish, while producing more consequences in English. The picture task yielded mixed results, and these were not compared quantitatively. There were differences in the two task conditions with respect to the children's use of Spanish influenced English and English-influenced Spanish. Although children were equally productive in both languages, they used proportionally more Spanish-influenced utterances in the book task. CLINICAL IMPLICATIONS: The results demonstrate the importance of considering the test language when eliciting narratives from bilingual children and the type of the narrative task for eliciting a productive and complex narrative.

Measures of Language Development in Fictional Narratives of Latino Children.

PURPOSE: This preliminary study was designed to determine whether commonly used measures of language productivity, sentence organization, and story structure were sensitive to developmental differences in narratives produced by Latino preschool children from a low-socioeconomic status (SES) community. METHOD: Twenty-four children, divided equally into younger and older groups, produced oral narratives that corresponded with the wordless picture book, Frog, Where Are You? (Mayer, 1969). Their narratives were analyzed for productivity (total number of words, total number of different words), sentence organization (number of utterances, mean length of C unit in words, and percentage of grammatically acceptable utterances), and story structure (complete and incomplete narrative episodes). RESULTS: The length of children's narratives did not differ significantly by age. However, older Latino children produced stories that contained longer sentences, a higher proportion of grammatically acceptable sentences, and more complete episodes than did younger children. CLINICAL IMPLICATIONS: These results suggest that measures of language productivity (such as total number of words and number of different words) that reflect developmental differences in monolingual mainstream preschoolers may not be sensitive indicators of narrative language development in young Latino children from low-SES environments. However, measures of syntactic accuracy and episodic structure are likely to be valid indicators of developmental changes in these children's narrative abilities.

Comparison of Spanish, English, and Bilingual Children's Performance Across Semantic Tasks.

PURPOSE: This study investigated predominantly Spanish-speaking, predominantly English-speaking, and Spanish-English bilingual children's performance on a battery of semantic tasks. METHOD: Six semantic tasks (associations, characteristic properties, categorization, functions, linguistic concepts, and similarities and differences) were developed in Spanish and English. The tasks contained comparable items but were not direct translations of each other. Each task consisted of expressive and receptive items. Predominantly Spanish-speaking children completed the tasks in Spanish, predominantly English-speaking children completed the tasks in English, and bilingual children completed the tasks in Spanish and English. RESULTS: Children in all three groups achieved similar average levels of performance on the assessment battery. However, there were differences in the patterns of performance for English and Spanish, as well as group performance differences when compared in the same language. CLINICAL IMPLICATIONS: These findings highlight the importance of testing bilingual children in both of their languages and across a variety of semantic tasks in order to gain insight into bilingual children's semantic knowledge.

Dynamic Assessment of Diverse Children: A Tutorial.

Dynamic assessment (DA) has been advocated as an alternative and/or supplemental approach to traditional standardized testing with children who are culturally and linguistically diverse (CLD). However, there is great variability across DA methods and applications, as well as limited information concerning which methods and procedures may be best suited to differentiate language disorder from difference. In this tutorial, DA methods are compared with respect to their assessment applications. Next, an assessment protocol recommended for the identification of language disorder versus difference is described. Finally, examples of two Spanish-English bilingual children are used to show how the protocol may be useful to assess children's language-learning potential and to minimize misdiagnosis.

Language Sample Analysis in Spanish-Speaking Children: Methodological Considerations.

The purposes of this article are (a) to discuss issues related to the selection and development of language assessment procedures for children who speak Spanish and English based on spontaneous language samples and (b) to show how available procedures can be applied to research and clinical aims with these children. Sociolinguistic influences in the language performance of Spanish-speaking children, including patterns of language shift, differences in the amount of exposure to each of a bilingual's languages, and contextual effects of different language-learning environments, are discussed. Methodological issues and effects of codeswitching and dialect are examined concerning use of the Developmental Assessment of Spanish Grammar (DASG), mean length of response in words (MLR-w), mean length of terminable unit (MLTU), and mean length of utterance in morphemes (MLU-m). Measures of Spanish grammar with diagnostic potential are proposed. Clinical suggestions for the language assessment of Spanish-speaking children with different levels of English proficiency and research implications are discussed.

An educational implementation of a cancer pain algorithm for ambulatory care.

Algorithms are proposed as a means of operationalizing guidelines or standards for cancer pain management. Professional education is used as the means to translate knowledge into practice. Outcomes measurement is the gold standard for validating improvement. This study used an educational intervention to transfer knowledge on implementing a previously tested algorithm for cancer pain management into community outpatient oncology clinics and, subsequently, measuring patient outcomes. Physicians and nurses from 9 Puget Sound clinics were randomized by institution blocks to either "training" or "no training." Role model physician/nurse teams were the core faculty for a day-long seminar. Written reference materials and documentation tools were provided to the trained physician/nurse teams. A total of 105 patients of trained and untrained providers were accrued and assessed over 4 months. Patients of trained providers had a significant reduction in usual pain over the 4 months of data collection compared with patients of untrained providers (t = 2.0; p = .05). Improvements were modest in the prescription of opioid analgesics and dramatic in the prescription of co-analgesics for neuropathic pain. There was a clear deterioration in the impact of the training over time. The most significant effect occurred within the first 140 days after the intervention and was followed by a gradual return to baseline practice. In conclusion, algorithmic interventions can be successfully transferred into community practice, but further work must be performed to develop methods for securing retention of knowledge and maintaining improved outcomes.

Implementing guidelines for cancer pain management: results of a randomized controlled clinical trial.

PURPOSE: Pain and symptom management is an integral part of the clinical practice of oncology. A number of guidelines have been developed to assist the clinician in optimizing comfort care. We implemented clinical guidelines for cancer pain management in the community setting and evaluated whether these guidelines improved care. PATIENTS AND METHODS: Eighty-one cancer patients, aged 37 to 76 years, were enrolled onto a prospective, longitudinal, randomized controlled study from the outpatient clinic settings of 26 western Washington-area medical oncologists. A multilevel treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management was compared with standard-practice (control) pain and symptom management therapies used by community oncologists. The primary outcome of interest was pain (Brief Pain Inventory); secondary outcomes of interest were all other symptoms (Memorial Symptom Assessment Scale) and quality of life (Functional Assessment of Cancer Therapy Scale). RESULTS: Patients randomized to the pain algorithm group achieved a statistically significant reduction in usual pain intensity, measured as slope scores, when compared with standard community practice (P < .02). Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences in other symptoms or quality of life between the two treatment groups. CONCLUSION: This guideline implementation study supports the use of algorithmic decision making in the management of cancer pain. These findings suggest that comprehensive pain assessment and evidence-based analgesic decision-making processes do enhance usual pain outcomes.

Factors hindering patients' use of medications for cancer pain.

OBJECTIVES: The purpose of this study was to explore the reasons that cancer patients with pain find it difficult to adhere to analgesic therapy. MATERIALS AND METHODS: Twenty-one patients with advanced cancer with pain were interviewed using a semistructured schedule of questions. Participants were asked to describe their decision making regarding analgesics and the factors that made it difficult for them to take analgesics prescribed for their pain. They also were asked to describe their relationships with their healthcare providers. Themes were identified and refined using qualitative analytic techniques. Two investigators independently coded all data to ensure that findings accurately reflected participants' experiences. RESULTS: Findings reveal several factors that hindered analgesic use and the specific ways in which patients evaluated these factors in making decisions about taking pain medication. The provider-patient factors that impeded analgesic use also were described. Finally, the common use of nonpharmacologic methods of pain control offers insight into the role of these therapeutic strategies in achieving pain relief and decreasing analgesic use. CONCLUSIONS: The findings underscore the importance of early intervention to address barriers to analgesic use. Some barriers may be overcome through educational efforts. The findings suggest, however, that consistent, repeated patient education often may not be sufficient to subdue patients' negative thoughts about taking the medication. Other approaches, such as changing medications or assisting the patient to use nonpharmacologic pain strategies, may prove more successful.

Task Familiarity: Effects on the Test Performance of Puerto Rican and African American Children.

Two studies compared the performance of Puerto Rican and African American Head Start children on presumably familiar (description) and unfamiliar (one-word labeling) test tasks. Results indicated that children performed significantly better on the familiar test task, and that the familiar task was more sensitive in differentiating children who were typically developing from those with low language ability. Implications for the use of standardized tests, local norms, and dynamic assessment with culturally/linguistically diverse children are discussed.