SUMMARY It is intuitively obvious that the ability of a cell to repair DNA damage is saturable, either by limitation of enzymatic activities, the time allotted to achieve their function, or both. However, very little is known regarding the mechanisms that establish such a threshold. Here we demonstrated that the CUL4A ubiquitin ligase restricts the cellular repair capacity by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector. We generated Cul4a conditional knockout mice and observed that skin-specific Cul4a ablation dramatically increased resistance to UV-induced skin carcinogenesis. Our findings reveal that wild-type cells do not operate at their full DNA repair potential, underscore the critical role of CUL4A in establishing the cellular DNA repair threshold, and highlight the potential augmentation of cellular repair proficiency by pharmacological CUL4A inhibition.

Using high-density oligonucleotide arrays, we measured expression of >12,000 genes in surgical excisions of invasive human squamous cell carcinomas (SCCs) versus site-matched control skin. This analysis defined >1,900 genes with altered expression in SCCs that were statistically different from controls. As SCCs are composed of epithelial cells, which are both hyperplastic and invasive, we sought to define gene sets associated with these biologic processes by comparing gene expression to psoriasis vulgaris, which is a condition of benign keratinocyte hyperplasia without invasiveness or pre-malignant potential. Through this analysis, we found genes that were commonly upregulated in both conditions and unique genes with increased expression in SCCs. Differential gene regulation in these two conditions was confirmed by real-time reverse transcription-PCR and immunohistochemistry. We found that benign hyperplasia is associated with upregulation of genes including DEFB4 (defensin B4), SERPINB3 (serine proteinase inhibitor, member 3), STAT1 (signal transducer and activator of transcription 1), K16 (keratin 16), CEACAMs (carcinoembryonic antigen-related cell adhesion molecules), and WNT 5A (wingless-type MMTV integration site family, member 5A). WNT receptor frizzled homolog 6 (FZD6) and prostaglandin-metabolizing enzyme hydroxyprostaglandin dehydrogenase were increased in SCC alone. Growth factor pleiotrophin (PTN) was expressed at higher levels in non-tumor-bearing skin adjacent to excised SCC. SCC was further characterized by upregulation of matrix metalloproteinases 1, 10, and 13, cathepsin L2, cystatin E/M as well as STAT3 and microseminoprotein, beta (MSMB), and downregulation of inducible nitric oxide synthase, granzyme B, CD8, and CD83. The current study defines a unique gene expression signature for cutaneous SCC in humans and suggests potential roles for WNT, FZD, and PTN in the pathogenesis of SCC.

BACKGROUND The increase in the number of childhood thyroid carcinoma cases in Ukraine after the Chernobyl nuclear accident in 1986 prompted the development of a registry of thyroid carcinoma cases at the Institute of Endocrinology and Metabolism in Kiev. In the current study, the authors report the statistical data and clinicomorphologic features of the cases included in this registry. METHODS To study the incidence, and age and gender distribution of thyroid carcinoma in Ukraine, the authors compiled complete clinical information from cases diagnosed and treated at the Institute of Endocrinology and Metabolism and statistical reports submitted to the registry from 27 regions of Ukraine. Morphologic features of the resected tumors were examined and were included in the database. RESULTS During the 5 years preceding the Chernobyl nuclear accident, a total of 59 cases of thyroid carcinoma were identified in the birth to 18 years age group (25 in children age ≤ 14 years and 34 in adolescents ages 15–18 years). Between 1986 and 1997, the total number of thyroid carcinomas in Ukrainian children and adolescents was 577 (358 children and 219 adolescents). Morphologically, the thyroid tumors overwhelmingly were papillary carcinomas, and the majority of these also showed a follicular and/or solid growth pattern. Lymph node metastases and other extrathyroidal spread were common, thus necessitating total thyroidectomy and lymph node dissections in many patients. CONCLUSIONS Between 1990 and 1997, a significant increase in the incidence of thyroid carcinoma was noted in children and adolescents in Ukraine; the group most affected was comprised of the individuals who were age ≤ 5 years in 1986 (the year of the Chernobyl nuclear accident). The largest number of cases occurred in patients living in areas of thyroid radiation doses of ≥0.50 grays. The morphologic features of those thyroid tumors suggest that they are aggressive tumors with a high frequency of lymph node metastases, venous invasion, and extrathyroidal spread. Cancer 1999;86:149–56. © 1999 American Cancer Society.

Squamous cell carcinoma (SCC) is the second most frequently diagnosed skin cancer. It has a higher incidence in immunosuppressed individuals such as organ transplant recipients and human immunodeficiency virus (HIV) carriers. Recently, a newly described polyoma virus, Merkel cell polyomavirus (MCPyV), was found in Merkel cell carcinoma (MCC), a rare aggressive skin cancer also associated with immunosuppression. We hypothesized that MCPyV would be present in SCCs. To test for the presence of MCPyV in immunocompetent SCC patients, we used PCR primer sets directed against the large T (LT) antigen and VP1 gene of MCPyV. We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied. We did not detect MCPyV in any matched normal blood DNA (0/57), but observed the presence of MCPyV DNA in 1 of 12 normal mouthwash DNAs. All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration. The presence of MCPyV in approximately 15% of SCCs from immunocompetent individuals warrants evaluation of MCPyV as an etiologic agent in the carcinogenesis of SCC.

Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.

BACKGROUND Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but is typically associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die yearly from this disease. METHODS As it is difficult to predict which cSCCs are more likely to metastasize, and because there are no targeted therapies specifically designated for metastatic cSCC, we performed exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. We compared our results to published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs. RESULTS We identified genes showing higher mutation frequencies in metastatic cSCC relative to primary tumors including the chromatin remodeling gene KMT2D and the classic skin tumor suppressor TP53 which was mutated in 54% of primary tumors relative to 85% of metastatic tumors (p <0.0001). CONCLUSIONS These studies uncover potential pathways important in metastatic cSCC that broaden our understanding of the biology contributing to aggressive tumor behavior and may lead to new therapeutic strategies.

Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27Kip1. These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27Kip1 expression in human melanoma cells.

In this randomized, placebo-controlled, crossover trial, pergolide appeared to be a safe and efficacious treatment for Tourette's syndrome in children.