Vulvar Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma.

Cutaneous T-cell lymphomas may present with a clinical course that is incongruent with the associated histologic findings. Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma classically presents as an abrupt eruption of disseminated ulcerated annular plaques with aggressive behavior and a poor prognosis. Herein we describe a vulvar primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with a locally aggressive clinical course that was strikingly responsive to radiation therapy. As aggressive therapy involving systemic chemotherapy is indicated for primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, appropriate clinico-pathologic correlation is crucial for preventing potentially excessive or insufficient therapeutic intervention. Our case also highlights the pivotal role of both radiation therapy and infection control in the management of aggressive cutaneous vulvar lymphomas.

SLC25A22 is a novel gene for migrating partial seizures in infancy.

OBJECTIVE: To identify a genetic cause for migrating partial seizures in infancy (MPSI). METHODS: We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. RESULTS: In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. INTERPRETATION: We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22.

Medical spa facilities and nonphysician operators in aesthetics.

Consumer interest in aesthetic procedures continues to grow. Through savvy marketing, affordable pricing, and minimal wait times, medical spas have grown in number to where they now outnumber physician-based cosmetic practices in 73% of major U.S. cities. To staff these facilities, owners frequently turn to nonphysician operators who have variable levels of training in dermatology and cosmetics. There has been a lack of uniform standardization of training and oversight, which may contribute to adverse events, such as burns, pigmentary alterations, and scarring. As the market for noninvasive and minimally invasive cosmetic procedures continues to grow, physicians should be informed about the current cosmetic landscape in which they practice to improve patient awareness, education, and safety.

miR-181a Promotes Multiple Protumorigenic Functions by Targeting TGFßR3.

Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and has a well-defined progression sequence from precancerous actinic keratosis to invasive cSCC. To identify targets for chemoprevention, we previously reported a cross-species analysis to identify the transcriptional drivers of cSCC development and identified miR-181a as a potential oncomiR. We show that the upregulation of miR-181a promotes multiple protumorigenic properties by targeting an understudied component of TGFß signaling, TGFßR3. miR-181a and TGFßR3 are upregulated and downregulated, respectively, in cSCC. miR-181a overexpression (OE) and TGFßR3 knockdown (KD) significantly suppresses UV-induced apoptosis in HaCaT cells and in primary normal human epidermal keratinocytes. In addition, OE of miR-181a or KD of TGFßR3 by short hairpin RNA enhances anchorage-independent survival. miR-181a OE or TGFßR3 KD enhances cellular migration and invasion and upregulation of epithelial‒mesenchymal transition markers. Luciferase reporter assays demonstrate that miR-181a directly targets the 3'-untranslated region of TGFßR3. miR-181a upregulates phosphorylated SMAD3 levels after TGFß2 administration and results in elevated SNAIL and SLUG expression. Finally, we confirm in vivo that miR-181a inhibition compromises tumor growth. Importantly, these phenotypes can be reversed with TGFßR3 OE or KD in the context of miR-181a OE or KD, respectively, further highlighting the physiologic relevance of this regulation in cSCC.

Genomewide clonal analysis of lethal mutations in the Drosophila melanogaster eye: comparison of the X chromosome and autosomes.

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.

TCF7L1 promotes skin tumorigenesis independently of ß-catenin through induction of LCN2.

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with ß-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

Deficient synthesis of class-switched, HIV-neutralizing antibodies to the CD4 binding site and correction by electrophilic gp120 immunogen.

OBJECTIVE: HIV is vulnerable to antibodies that recognize a linear CD4 binding site epitope of gp120 (C), but inducing C-directed antibody synthesis by traditional vaccine principles is difficult. We wished to understand the basis for deficient C-directed antibody synthesis and validate correction of the deficiency by an electrophilic gp120 analog (E-gp120) immunogen that binds B-cell receptors covalently. METHODS: Serum antibody responses to a C peptide and full-length gp120 epitopes induced by HIV infection in humans and immunization of mice with gp120 or E-gp120 were monitored. HIV neutralization by monoclonal and variable domain-swapped antibodies was determined from tissue culture and humanized mouse infection assays. RESULTS: We describe deficient C-directed IgG but not IgM antibodies in HIV-infected patients and mice immunized with gp120 accompanied by robust synthesis of IgGs to the immunodominant gp120 epitopes. Immunization with the E-gp120 corrected the deficient C-directed IgG synthesis without overall increased immunogenicity of the C or other gp120 epitopes. E-gp120-induced monoclonal IgGs neutralized diverse HIV strains heterologous to the immunogen. A C-directed IgG neutralized HIV more potently compared to its larger IgM counterpart containing the same variable domains, suggesting obstructed access to HIV surface-expressed C. An E-gp120-induced IgG suppressed HIV infection in humanized mice, validating the tissue culture neutralizing activity. CONCLUSION: A C-selective physiological defect of IgM→IgG class-switch recombination (CSR) or restricted post-CSR B-cell development limits the functional utility of the humoral immune response to gp120. The E-gp120 immunogen is useful to bypass the restriction and induce broadly neutralizing C-directed IgGs (see Supplemental Video Abstract, http://links.lww.com/QAD/A551).

Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK.

Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.

The syndrome of perisylvian polymicrogyria with congenital arthrogryposis.

BACKGROUND: Bilateral perisylvian polymicrogyria (BPP) is a well-recognized malformation of cortical development commonly associated with epilepsy, cognitive impairment, and oromotor apraxia. Reports have suggested the association of BPP with arthrogryposis multiplex congenita. We sought to investigate the clinical, electrophysiological, and neuroradiological features of this combined syndrome to determine if there are unique features that distinguish BPP with arthrogryposis from BPP alone. METHODS: Cases of BPP with congenital arthrogryposis were identified from a large research database of individuals with polymicrogyria. Clinical features (including oromotor function, seizures, and joint contractures), MR brain imaging, and results of neuromuscular testing were reviewed. RESULTS: Ten cases of BPP with congenital arthrogryposis were identified. Most cases had some degree of oromotor apraxia. Only a few had seizures, but a majority of cases were still young children. Electrophysiological studies provided evidence for lower motor neuron or peripheral nervous system involvement. On brain imaging, bilateral polymicrogyria (PMG) centered along the Sylvian fissures was seen, with variable extension frontally or parietally; no other cortical malformations were present. We did not identify obvious neuroimaging features that distinguish this syndrome from that of BPP without arthrogryposis. CONCLUSIONS: The clinical and neuroimaging features of the syndrome of BPP with congenital arthrogryposis appear similar to those seen in cases of isolated BPP without joint contractures, but electrophysiological studies often demonstrate coexistent lower motor neuron or peripheral nervous system pathology. These findings suggest that BPP with arthrogryposis may have a genetic etiology with effects at two levels of the neuraxis.