Deciphering the role of tlx in dorsal neural progenitors and its contribution to brain structure and behavior

Tlx (Nr2E1) is an orphan nuclear receptor transcription factor expressed in neural progenitor cells (PCs) in the forebrain throughout development and in regions of adult neurogenesis. Tlx regulates proliferation in both embryonic and adult PCs. Loss of tlx leads to abnormalities in limbic structures resulting in alterations in emotional and cognitive behaviors. However, the precise role of tlx in the developing forebrain and how tlx contributes to the normal development of adult anatomy and behavior are not fully understood. Tlx is expressed in PCs throughout the dorsal and ventral telencephalon and the diencephalon that give rise to structures including the cerebral cortex, hippocampus, amygdala, septum, striatum, and hypothalamus. Detailed examination of tlx expression revealed that within the dorsal PC population tlx is expressed specifically in radial glial progenitors but is absent from intermediate progenitor cells (IPCs). However, in the absence of tlx IPCs are reduced throughout development, suggesting that tlx promotes the production of IPCs. To examine the role of tlx specifically in dorsal PCs we generated mice with a conditional mutation of tlx in cortical, Emx1-expressing PCs (tlxcKO). In these animals functional recombination of the floxed tlx allele occurs prior to embryonic day 12.5. TlxcKO animals show similar changes in PCs as nulls, indicating a requirement for tlx within dorsal PCs. The cerebral cortex of tlxcKO animals is reduced in surface area and thickness from birth, persisting into adulthood. As in tlx null mutants, superficial layers are specifically affected and caudal functional cortical areas, including visual cortex, are disproportionately reduced. Other dorsally-derived structures, including the hippocampus, specific nuclei of the amygdala, and the septum are reduced, whereas ventrally-derived structures are relatively unaffected. These animals exhibit a subset of the behavioral abnormalities observed in nulls, with the primary phenotype being a reduction in anxiety. Together, these findings suggest an important role for tlx in the regulation of dorsal PCs. I propose that tlx promotes divisions that produce IPCs, and that disruption of this population leads to specific alterations in adult brain structure and behavior. This model allows us to begin to make connections between early development and behavior

Agreement Between Clinician and Patient Ratings of Adaptive Functioning and Developmental History

Objective: Psychiatric researchers rely heavily on patient report data for clinical research. However, patient reports are prone to defensive and self-presentation biases. Recent research using practice networks has relied on clinician reports, and both forensic and personality disorder researchers have recently turned to quantified data from clinically expert observers as well. However, critics have raised legitimate concerns about the reliability and validity of data from clinician informants. The aim of this study was to assess the validity and diagnostic efficiency of clinician reports of their patients\u27 adaptive functioning and developmental histories, using patient reports as the comparative standard traditionally used in psychiatric research. Method: Eighty-four clinicians and their patients completed a clinical data form designed to assess a range of patient functioning, clinical history, and developmental relationship variables used in multiple clinician report studies. The authors correlated clinician and patient reports across a number of clinically relevant adaptive functioning variables and calculated diagnostic efficiency statistics for a range of clinical history variables, including suicide attempts, hospitalizations, arrests, interpersonal conflicts affecting employment, and childhood physical and sexual abuse. Results: Across variables, patient-therapist correlations (0.40-0.66) and overall correct classification statistics (0.74-0.96) were high. Conclusions: The data demonstrate that clinicians\u27 judgments about their patients\u27 functioning and histories agree with patients\u27 self-reports and that in areas of discrepancy, clinicians tend to make appropriately conservative judgments in the absence of clear data. These findings suggest that quantified clinical judgment provides a vast untapped potential for large-sample research on psychopathology and treatment

Assessment of Clinical Information: Comparison of the Validity of a Structured Clinical Interview (the Scid) and the Clinical Diagnostic Interview

Adaptive functioning is a key aspect of psychiatric diagnosis and assessment in research and practice. This study compared adaptive functioning validity ratings from Structured Clinical Interviews (SCIDs, symptom-focused structured diagnostic interviews), and Clinical Diagnostic Interviews (CDIs, systematic diagnostic interviews modeling naturalistic clinical interactions focusing on relational narratives). Two hundred forty-five patients (interviewed by two independent interviewers) and their interviewers completed the Clinical Data Form which assesses adaptive functioning and clinical information. Both interviews converged strongly with patient-reports, with no significant differences in validity of the interviews in measuring global and specific domains of adaptive functioning variables. Findings suggest that CDIs provide adaptive functioning data comparable to SCIDs (often considered gold standard for assessment but difficult to use in practice) and have important implications for bridging the research-practice gap. By incorporating clinicians\u27 everyday methods, CDIs yield information that is psychometrically sound for empirical investigation, diagnostically practical, and clinically meaningful and valid

Effect of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats

OBJECTIVE: Deficiencies of vitamin A and iodine are common in many developing countries. Vitamin A deficiency (VAD) may adversely affect thyroid metabolism. The study aim was to investigate the effects of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats. DESIGN: Weanling rats (n = 56) were fed diets deficient in vitamin A (VAD group), iodine (ID group), vitamin A and iodine (VAD + ID group), or sufficient in both vitamin A and iodine (control) for 30 days in a pair-fed design. Serum retinol (SR), thyroid hormones (FT(4), TT(4), FT(3), and TT(3)), serum thyrotropin (TSH), pituitary TSHbeta mRNA expression levels, and thyroid weights were determined at the end of the depletion period. MAIN OUTCOME: Compared to the control and ID groups, SR concentrations were about 35% lower in the VAD and VAD + ID groups (p < 0.001), indicating moderate VA deficiency. Comparing the VAD and control groups, there were no significant differences in TSH, TSHbeta mRNA, thyroid weight, or thyroid hormone levels. Compared to the control group, serum TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.05), and FT4 and TT4 were lower (p < 0.001), in the VAD + ID and ID groups. Compared to the ID group, TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.01) and FT(4) and TT(4) were lower (p < 0.001) in the VAD + ID group. There were no significant differences in TT3 or FT3 concentrations among groups. CONCLUSION: Moderate VAD alone has no measurable effect on the pituitary-thyroid axis. Concurrent ID and VAD produce more severe primary hypothyroidism than ID alone

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development. Comprehensive, integrated molecular analysis identifies molecular relationships across a large diverse set of human cancers, suggesting future directions for exploring clinical actionability in cancer treatment