ABSTRACT
We present a case of a 39-year-old Hispanic woman who was referred to our clinic for treatment of several indurated plaques on her buttocks that developed one year prior to presentation, after she received injections of an unknown substance for augmentation. Biopsy of one nodule revealed silicone in the dermis.
Subject(s)
Buttocks/pathology , Cosmetic Techniques/adverse effects , Foreign-Body Reaction/pathology , Silicones/adverse effects , Adult , Female , Humans , Injections, Intradermal , Silicones/administration & dosage , Thigh/pathologyABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Imidazoles/pharmacology , Indoles/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , Oximes/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Signal Transduction/drug effects , Sulfonamides/pharmacology , Animals , Humans , MAP Kinase Kinase 4/metabolism , Mice , Mice, Hairless , VemurafenibABSTRACT
BACKGROUND: Many copy number variants (CNVs) are documented to be associated with neuropsychiatric disorders, including intellectual disability, autism, epilepsy, schizophrenia, and bipolar disorder. Chromosomal deletions of 1q21.1, 3q29, 15q13.3, 22q11.2, and NRXN1 and duplications of 15q11-q13 (maternal), 16p11, and 16p13.3 have the strongest association with schizophrenia. We hypothesized that cases with both schizophrenia and epilepsy would have a higher frequency of disease-associated CNVs and would represent an enriched sample for detection of other mutations associated with schizophrenia. METHODS: We used array comparative genomic hybridization (CGH) to analyze 235 individuals with both schizophrenia and epilepsy, 80 with bipolar disorder and epilepsy, and 191 controls. RESULTS: We detected 10 schizophrenia plus epilepsy cases in 235 (4.3%) with the above mentioned CNVs compared to 0 in 191 controls (p = 0.003). Other likely pathological findings in schizophrenia plus epilepsy cases included 1 deletion 16p13 and 1 duplication 7q11.23 for a total of 12/235 (5.1%) while a possibly pathogenic duplication of 22q11.2 was found in one control for a total of 1 in 191 (0.5%) controls (p = 0.008). The rate of abnormality in the schizophrenia plus epilepsy of 10/235 for the more definite CNVs compares to a rate of 75/7336 for these same CNVs in a series of unselected schizophrenia cases (p = 0.0004). CONCLUSION: We found a statistically significant increase in the frequency of CNVs known or likely to be associated with schizophrenia in individuals with both schizophrenia and epilepsy compared to controls. We found an overall 5.1% detection rate of likely pathological findings which is the highest frequency of such findings in a series of schizophrenia patients to date. This evidence suggests that the frequency of disease-associated CNVs in patients with both schizophrenia and epilepsy is significantly higher than for unselected schizophrenia.
Subject(s)
Chromosome Disorders/complications , Chromosome Disorders/genetics , DNA Copy Number Variations , Epilepsy/complications , Epilepsy/genetics , Schizophrenia/complications , Schizophrenia/genetics , Trisomy/genetics , Bipolar Disorder/complications , Bipolar Disorder/genetics , Case-Control Studies , Chromosome Deletion , Chromosome Duplication , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 22/genetics , Comparative Genomic Hybridization , Female , Humans , MaleABSTRACT
Granuloma annulare (GA) is a common, benign skin condition, which was first described over a century ago, but still remains an enigma with respect to etiology, associated systemic diseases, and treatment. A number of clinical variants have been classified. We report an atypical presentation of GA localized to the palms.
