Disrupting Essentialism in Medical Genetics Education.

Many traditional practices in medical genetics education need review to counteract messages of essentialism, or the belief in an underlying natural structure differentiating social categories. While genomics research increasingly disproves a genetic foundation for race, research from educational scholars demonstrates that current medical genetics instruction may actually reinforce racial bias in learners. In this monograph, we outline seven recommendations for medical educators to actively counteract essentialism, racial, and otherwise, in the genetics classroom. In particular, we emphasize the importance of engaging learners in nuanced discussions around stereotyping and its negative consequences for both accurate diagnoses and promoting health equity.

Using the "Hallmarks of Cancer" as a framework for medical students and clinicians to understand oncogenesis.

Two landmark reviews in 2000 and 2011, describing the "Hallmarks of Cancer", provided a new and valuable framework for understanding the process of oncogenesis as a progressive accumulation of characteristics, each characteristic essential for a tumor to become a clinically relevant, metastatic neoplasia. The process of oncogenesis is conceptually important for physicians, both for clinical reasons, and for their engagement in oncological research. However, these reviews are written for specialists in the field, which presents barriers for novice learners. Therefore, to allow students, and also clinicians external to the oncological field, to access this valuable framework for understanding oncogenesis, we have created a condensed summary of the original reviews. Our institutions use a "flipped" approach to the large-group components of our preclinical education. We have successfully used our Hallmarks of Cancer summary as the prework for sessions on oncogenesis for five years at one institution, and nine years at the other, typically at the end of cancer blocks within integrated, multidisciplinary courses. We report here survey results indicating learners strongly appreciate the summary as both preparation material for participation in relevant flipped classroom sessions, and as a general review of oncogenesis. This condensed summary of the original Hallmarks of Cancer reviews makes many of the key concepts of oncogenesis available to medical students in their preclinical years, as well as to physicians outside the field of oncology.

Words of advice: preparing to teach.

You have spent most of your training learning how to be successful in a research laboratory. But are you ready to step in front of a class and teach? This Words of Advice article provides guidance and resources for designing a course using backward design and for becoming an effective teacher, especially in today's new format of large, interactive classes.

Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer.

Alternative processing of pre-mRNA transcripts is a major source of protein diversity in eukaryotes and has been implicated in several disease processes including cancer. In this study we have performed a genome wide analysis of alternative splicing events in lung adenocarcinoma. We found that 2369 of the 17 800 core Refseq genes appear to have alternative transcripts that are differentially expressed in lung adenocarcinoma versus normal. According to their known functions the largest subset of these genes (30.8%) is believed to be cancer related. Detailed analysis was performed for several genes using PCR, quantitative RT-PCR and DNA sequencing. We found overexpression of ERG variant 2 but not variant 1 in lung tumors and overexpression of CEACAM1 variant 1 but not variant 2 in lung tumors but not in breast or colon tumors. We also identified a novel, overexpressed variant of CDH3 and verified the existence and overexpression of a novel variant of P16 transcribed from the CDKN2A locus. These findings demonstrate how analysis of alternative pre-mRNA processing can shed additional light on differences between tumors and normal tissues as well as between different tumor types. Such studies may lead to the development of additional tools for tumor diagnosis, prognosis and therapy.

Mouse models of Wolf-Hirschhorn syndrome.

Subtelomeric deletion syndromes represent a significant cause of mental retardation and craniofacial disease. However, for most of these syndromes the pathogenic genes have yet to be identified. Currently there is every indication that identification of these genes will be a slow process if we continue to rely strictly upon clinical data. An alternative approach is the use of mouse models to complement the patient studies. Wolf-Hirschhorn syndrome (WHS), caused by deletions in 4p16.3, is the first recognized subtelomeric deletion syndrome. As with other syndromes of this class, WHS has not yet been subjected to an intensive, systematic analysis using mouse models. Nonetheless, a significant number of targeted mutations have been introduced into mouse genomic region, 5B1, which is orthologous to 4p16.3. Included among these mutations are a series of deletions approximating the deletions in some patients. The mouse lines carrying these deletions display a remarkable concordance of phenotypes with the human patient's characteristics, strongly indicating that the mouse models can be used to phenocopy WHS. In this review, we will catalog the currently existing targeted mutations in mice in the regions orthologous to the WHS critical regions. For each mutation we will discuss the resulting phenotype and its potential relevance to the pathogenesis of the syndrome. Further, we will describe how the phenotypes of some of the mutations suggest new directions for the clinical studies. Finally we will outline approaches for the efficient creation of new mouse models of WHS going forward.

Tuberculosis induced changes to the osseous cranial base and its potential effect on hearing.

Our prior work suggested that petro-occipital fissure (POF) ossification may be altered in clinicopathologies of the cranial base such as hearing loss (Balboni et al., 2005). Here we demonstrate an accelerated and statistically significant ossification of the POF and cochlear aqueduct (CA) in a historical population of patients diagnosed with tuberculosis (TB). While a number of studies have sought to reduce the importance of the POF/CA to hearing, given its anatomical location, evolutionary conservation across mammals and the mounting data linking morphological changes of the POF/CA to the temporal onset of hearing loss and tinnitus, it is becoming difficult to maintain that its function is not related to inner ear homeostasis.

Homeobox gene Sax2 deficiency causes an imbalance in energy homeostasis.

The brain, in particular the hypothalamus and the brainstem, plays a critical role in the regulation of energy homeostasis by incorporating signals from the periphery and translating them into feeding behavior. Here we show that the homeobox gene Sax2, which is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, contributes to this physiological balance. Sax2 deficiency results in a decrease of fat and glycogen storage, reduced blood glucose levels, and raised serotonin levels in the hindbrain. Surprisingly, in the brainstem the expression levels of pro-opiomelanocortin and neuropeptide Y were indicative of a fasting condition, opposed to the observed high serotonin levels implying satiation. Furthermore, Sax2-directed lacZ expression reveals a dramatic change of the distribution of Sax2-expressing cells in the null mutant occurring during perinatal development. These data strongly suggest that Sax2 is required for the coordinated crosstalk of factors involved in the maintenance of energy homeostasis.

Mechanism of DNA binding and localized strand separation by Pur alpha and comparison with Pur family member, Pur beta.

Pur alpha is a single-stranded (ss) DNA- and RNA-binding protein with three conserved signature repeats that have a specific affinity for guanosine-rich motifs. Pur alpha unwinds a double-stranded oligonucleotide containing purine-rich repeats by maintaining contact with the purine-rich strand and displacing the pyrimidine-rich strand. Mutational analysis indicates that arginine and aromatic residues in the repeat region of Pur alpha are essential for both ss- and duplex DNA binding. Pur alpha binds either linearized or supercoiled plasmid DNA, generating a series of regularly spaced bands in agarose gels. This series is likely due to localized unwinding by quanta of Pur alpha since removal of Pur alpha in the gel eliminates the series and since Pur alpha binding increases the sensitivity of plasmids to reaction with potassium permanganate, a reaction specific for unwound regions. Pur alpha binding to linear duplex DNA creates binding sites for the phage T4 gp32 protein, an ss-DNA binding protein that does not itself bind linearized DNA. In contrast, Pur beta lacking the Pur alpha C-terminal region binds supercoiled DNA but not linearized DNA. Similarly, a C-terminal deletion of Pur alpha can bind supercoiled pMYC7 plasmid, but cannot bind the same linear duplex DNA segment. Therefore, access to linear DNA initially requires C-terminal sequences of Pur alpha.

The etiology of Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is defined by a collection of core characteristics, which include mental retardation, epilepsy, growth delay and cranio-facial dysgenesis. The disorder is caused by sub-telomeric deletions in the short arm of chromosome 4. The severity of the core characteristics is highly variable, and additional problems, including midline fusion defects, occur at lower frequency. Only one gene, WHSC1, is deleted in every case. However, recent evidence, from patient studies and mouse models, indicates that deletion of WHSC1 alone is insufficient for full-blown WHS. Instead a model is emerging in which deletion of WHSC1 is essential for pathogenesis, but deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems. In this article, we outline the progress being made in patient studies and in the development of mouse models, and relate the implications of this work for a broad group of sub-telomeric deletion syndromes.

Assessing age-related ossification of the petro-occipital fissure: laying the foundation for understanding the clinicopathologies of the cranial base.

The petro-occipital fissure (POF) lies within a critical interface of cranial growth and development in the posterior cranial fossa. The relationships between skeletal and soft tissues make this region especially important for examining biomechanical and basic biologic forces that may mold the cranial base and contribute to significant clinicopathologies associated with the structures located near the POF. Therefore, this study investigates the POF in adults in both preserved human cadavers and dried crania in order to determine if developmental changes can be observed and, if so, their value in age assessment as a model system for describing normal morphogenesis of the POF. This study demonstrates that tissue within the POF undergoes characteristic changes in ossification with age, the onset of which is considerably later than that of other synchondroses of the cranial base. Statistically, there is a moderate to strong correlation between age and stage of ossification within the POF. Further, male crania were observed to reach greater degrees of ossification at a younger age than female crania and that individual asymmetry in ossification of the tissue within the POF was not uncommon. An understanding of the basic temporal biological processes of the POF may yield insight into the development of clinicopathologies in this region of the cranial base.

Diverse roles for the Eph family of receptor tyrosine kinases in carcinogenesis.

The Eph family of receptor tyrosine kinases and their cell-presented ligands, the ephrins, are frequently overexpressed in a wide variety of cancers, including breast, small-cell lung and gastrointestinal cancers, melanomas, and neuroblastomas. In particular, one Eph family member, EphA2, is overexpressed in many cancers, including 40% of breast cancers. EphA2 can also transform breast epithelial cells in vitro to display properties commonly associated with the development of metastasis. Remarkably, the oncogenic properties of EphA2 contravene traditional dogma with regard to the oncogenic properties of a growth factor and its receptor tyrosine kinase: while stimulation of EphA2 by its ligand (ephrin-A1) results in EphA2 autophosphorylation, the stimulation reverses the oncogenic transformation. As will be discussed in this review, the apparent dependence of oncogenicity on the dephosphorylated state of EphA2 most probably reflects the unique nature of Eph signaling. In particular, oncogenecity may depend on the capacity of unactivated EphA2 to interact with a variety of signaling molecules. As well as acting in oncogenic transformation, a growing body of evidence supports the importance of the concerted actions of ephrins and Eph molecules in tumor angiogenesis. Genetic studies, using targeted mutagenesis in mice, reveal that ephrin-B1, ephrin-B2, and EphB4 are essential for the normal morphogenesis of the embryonic vasculature into a sophisticated network of arteries, veins, and capillaries. Initial studies indicate that these molecules are also angiogenic in tumors, and as such represent important new targets for the development of chemotherapeutic treatments.

Isolation of DNTNP, which encodes a potential nuclear protein that is expressed in the developing, dorsal neural tube.

We have performed a screen to identify genes expressed in a functionally significant anatomic region of the vertebrate dorsal neural tube, the dorsomedial roof of the third ventricle (DMRTV). The DMRTV includes the primordia of a series of circumventricular organs. The screen searched for genes preferentially expressed in the DMRTV of stage 18-25 chicken embryos, relative to their telencephala and ventral diencephalon. Through this screen, we have cloned a series of genes strongly expressed in the dorsal but not ventral neural tube. We describe here the first of these genes, DNTNP (dorsal neural tube nuclear protein). DNTNP is highly expressed in the dorsal regions of the diencephalon, the midbrain, the hindbrain, and the spinal neural tube in the chicken stage 18 embryo. Expression is also observed in the telencephalon, the branchial arches, the heart, and somites, but is absent from the presomitic mesoderm. The amino acid sequence of DNTNP reveals that it belongs to an uncharacterized protein family with at least two additional members. All the members of this family possess a basic region reminiscent of a nuclear localization signal (NLS). We demonstrate that the putative NLS of DNTNP can indeed direct nuclear localization of green fluorescent protein (GFP). The dorsal localization of DNTNP in the early embryonic central nervous system suggests roles for this molecule in specifying dorsal cell fates within the neural tube.