Christopher G. Bunick

Genomic landscape of cutaneous T cell lymphoma.

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs versus 1.0 somatic single-nucleotide variant per CTCL). These findings have implications for new therapeutics.

Structure of the N-terminal Calcium Sensor Domain of Centrin Reveals the Biochemical Basis for Domain-specific Function

Centrin is an essential component of microtubule-organizing centers in organisms ranging from algae and yeast to humans. It is an EF-hand calcium-binding protein with homology to calmodulin but distinct calcium binding properties. In a previously proposed model, the C-terminal domain of centrin serves as a constitutive anchor to target proteins, and the N-terminal domain serves as the sensor of calcium signals. The three-dimensional structure of the N-terminal domain of Chlamydomonas rheinhardtii centrin has been determined in the presence of calcium by solution NMR spectroscopy. The domain is found to occupy an open conformation typical of EF-hand calcium sensors. Comparison of the N- and C-terminal domains of centrin reveals a structural and biochemical basis for the domain specificity of interactions with its cellular targets and the distinct nature of centrin relative to other EF-hand proteins. An NMR titration of the centrin N-terminal domain with a fragment of the known centrin target Sfi1 reveals binding of the peptide to a discrete site on the protein, which supports the proposal that the N-terminal domain serves as a calcium sensor in centrin.

Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi

Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN.

Hemorrhagic complications in dermatologic surgery.

The ability to recognize, manage, and, most importantly, prevent hemorrhagic complications is critical to performing dermatologic procedures that have safe and high quality outcomes. This article reviews the preoperative, intraoperative, and postoperative factors and patient dynamics that are central to preventing such an adverse outcome. Specifically, the role that anticoagulants and anti‐platelet agents, hypertension, and other medical conditions play in the development of postoperative hemorrhage are discussed. In addition, this article provides practical guidelines on managing bleeding during and after surgery.

Chemical burn from topical apple cider vinegar

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When erythema ab igne warrants an evaluation for internal malignancy

2012; 2012: 952753. 4 Humbert P, Pelletier F, Dreno B, et al. Gluten intolerance and skin diseases. Eur J Dermatol 2006; 16: 4–11. 5 Francesco Stefanini G, Resta F, Marsigli L, et al. Prurigo nodularis (Hydes prurigo) disclosing celiac disease. Hepatogastroenterology 1999; 46: 2281–2284. 6 Bonciolini V, Bonciani D, Verdelli A, et al. Newly described clinical and immunopathological feature of dermatitis herpetiformis. Clin Dev Immunol 2012; 2012: 967974. 7 Cannistraci C, Lesnoni La Parola ICardinali G, et al. Co-localization of IgA and TG3 on healthy skin of coeliac patients. J Eur Acad Dermatol Venereol 2007; 21: 509–514.

The X-Ray Crystal Structure of the Keratin 1-Keratin 10 Helix 2B Heterodimer Reveals Molecular Surface Properties and Biochemical Insights into Human Skin Disease.

Keratins 1 (K1) and 10 (K10) are the primary keratins expressed in differentiated epidermis. Mutations in K1/K10 are associated with human skin diseases. We determined the crystal structure of the complex between the distal (2B) helices of K1 and K10 to better understand how human keratin structure correlates with function. The 3.3 Å resolution structure confirms many features inferred by previous biochemical analyses, but adds unexpected insights. It demonstrates a parallel, coiled-coil heterodimer with a predominantly hydrophobic intermolecular interface; this heterodimer formed a higher order complex with a second K1-K10-2B heterodimer via a Cys401K10 disulfide link, although the bond angle is unanticipated. The molecular surface analysis of K1-K10-2B identified several pockets, one adjacent to the disulfide linkage and conserved in K5-K14. The solvent accessible surface area of the K1-K10 structure is 20-25% hydrophobic. The 2B region contains mixed acidic and basic patches proximally (N-terminal), whereas it is largely acidic distally (C-terminal). Mapping of conserved and nonconserved residues between K1-K10 and K5-K14 onto the structure demonstrated the majority of unique residues align along the outer helical ridge. Finally, the structure permitted a fresh analysis of the deleterious effects caused by K1/K10 missense mutations found in patients with phenotypic skin disease.

Vegetative Plaques and Hemorrhagic Pustules

A man with a history of chronic renal insufficiency (baseline creatinine level, 2.8mg/dL) presented for evaluation of a painful forehead erythematous eruption and associated headache. (To convert creatinine to micromoles per liter, multiply by 88.4.) Three days prior to symptom onset he underwent a contrast-enhanced computed tomographic (CT) scan to evaluate abdominal pain. On the central forehead was a tender 5-cm reddish brown plaque composed of numerous coalescing vesicles and hemorrhagic pustules with intermixed serous and hemorrhagic crust. Similar vesicles and pustules were present on the nasal bridge and tip, the bilateral conchal bowls, and on the scalp (Figure, A). Two days later, the patient developed several 0.5to 1.0-cm purpuric macules and hemorrhagic vesicles on the bilateral hands and nail beds. Initial blood tests revealed a white blood cell count of 6400 cells (range, 4000 to 11 000/μL; to convert to ×109/L, multiply by 0.001). The patient denied any new medications, any known contacts with or exposures to individuals who were ill, and any history of skin disease. A punch biopsy of the forehead plaque was performed (Figure, B and C). What is your diagnosis?

Evaporative microdialysis: an effective improvement in an established method of protein crystallization

Evaporative dialysis is a simple variant of conventional microdialysis in which the reservoir solution is allowed to evaporate slowly. The slow increase in precipitant concentration allows crystals to grow without increasing nucleation. The method is useful for proteins that have a very narrow metastable zone (the range of solution conditions under which crystals grow but nuclei do not form at an appreciable rate). The method is demonstrated with the coat protein of potato virus X.

Crystal Structure of Human Profilaggrin S100 Domain and Identification of Target Proteins Annexin II, Stratifin, and HSP27.

The fused-type S100 protein profilaggrin and its proteolytic products including filaggrin are important in the formation of a normal epidermal barrier; however, the specific function of the S100 calcium-binding domain in profilaggrin biology is poorly understood. To explore its molecular function, we determined a 2.2Å-resolution crystal structure of the N-terminal fused-type S100 domain of human profilaggrin with bound calcium ions. The profilaggrin S100 domain formed a stable dimer, which contained two hydrophobic pockets that provide a molecular interface for protein interactions. Biochemical and molecular approaches demonstrated that three proteins, annexin II/p36, stratifin/14-3-3 sigma, and Hsp27, bind to the N-terminal domain of human profilaggrin; one protein (stratifin) co-localized with profilaggrin in the differentiating granular cell layer of human skin. Together, these findings suggest a model where the profilaggrin N-terminus uses calcium-dependent and calcium-independent protein-protein interactions to regulate its involvement in keratinocyte terminal differentiation and incorporation into the cornified cell envelope.