Rapid hair regrowth in an alopecia universalis patient with deucravacitinib: A case report.

Alopecia universalis is a severe, difficult to treat variant of alopecia areata that results in loss of hair on the scalp, eyebrows, eyelashes, and extremities. Deucravacitinib, a selective TYK2 inhibitor, has been recently approved in Canada, opening the door to novel uses of the drug. We present the case of a patient known for psoriasis who developed alopecia universalis resistant to many interventions (topical minoxidil and topical, intralesional, and systemic corticosteroids). We report the first case of successful rapid hair regrowth after starting deucravacitinib, which should prompt further inquiry into the use of TYK2 inhibitors in the management of alopecia areata.

Computational methods for discovering structural variation with next-generation sequencing.

In the last several years, a number of studies have described large-scale structural variation in several genomes. Traditionally, such methods have used whole-genome array comparative genome hybridization or single-nucleotide polymorphism arrays to detect large regions subject to copy-number variation. Later techniques have been based on paired-end mapping of Sanger sequencing data, providing better resolution and accuracy. With the advent of next-generation sequencing, a new generation of methods is being developed to tackle the challenges of short reads, while taking advantage of the high coverage the new sequencing technologies provide. In this survey, we describe these methods, including their strengths and their limitations, and future research directions.

Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma.

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.

Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma.

Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an exploitable cancer vulnerability.

Contact Allergy to Polymyxin B Among Patients Referred for Patch Testing.

BACKGOUND: Polymyxin B is not included in most standard contact allergen series. The aim of this study was to determine the prevalence of contact sensitization to polymyxin B in a population of patients referred for patch testing. METHODS: A retrospective cohort study design was used to collect data on 795 patients referred to the contact dermatitis clinic of the McGill University Health Centre, as well as to the office of one of the authors (L.M.), between March 2014 and November 2015. Patients were patch tested to the North American Contact Dermatitis Group baseline series and polymyxin B sulfate 3% in petrolatum. RESULTS: Out of 795 tested individuals, 18 were allergic to polymyxin B, for a prevalence of 2.3%. The eruptions affected almost all body parts, but mostly the face. The degree of reaction ranged from 1+ to 2+. Isolated reactions to polymyxin B occurred in 9 (50%) patients, whereas reactions to bacitracin and polymyxin B were seen in the other 9. Only 1 patient reacted to bacitracin, polymyxin B, and neomycin (11.1%). Most reactions (12/18) were from past exposure to polymyxin B. CONCLUSIONS: Allergic reactions to polymyxin B are not rare, and this antibiotic warrants inclusion in the standard patch testing series.

Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide.

Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but the disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that in GBM cells, even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of temozolomide resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tumor regression. Using The Cancer Genome Atlas to analyze mRNA expression patterns in tumors from temozolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial temozolomide therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades temozolomide sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide resistance and argue that MMR activity offers a predictive marker for initial therapeutic response to temozolomide treatment.

Unusual case of proximal calciphylaxis without renal failure.

BACKGROUND: Calciphylaxis is a rare syndrome of vascular calcification with subsequent cutaneous and tissue necrosis. It usually manifests as a complication of end-stage renal failure, affecting 1 to 4% of long-term dialysis patients. Very exceptionally, it can occur without chronic renal failure. OBJECTIVE: The goal of this study was to discuss an exceptional case of extensive calciphylaxis in the absence of chronic renal failure and its successful management. METHODS: We present a case of a 31-year-old woman with extensive proximal, ulcerated calciphylaxis without associated chronic renal failure. Our patient had quite a few risk factors associated with the pathogenesis of calciphylaxis, such as obesity, malnutrition, and a transient episode of acute renal failure. RESULTS: She was successfully treated with sodium thiosulfate, extensive wound débridement (more than 30% total body surface), and subsequent skin grafts. The patient has miraculously survived this often fatal condition. CONCLUSION: Calciphylaxis can occur even in the absence of chronic renal failure. This often fatal condition can be managed successfully with a combination of aggressive wound control and the fairly newly described sodium thiosulfate therapy.

Ophthalmologic manifestations of cutaneous conditions.

Many cutaneous conditions have associated ophthalmologic findings, which are important to recognize for both dermatologists and ophthalmologists. This review highlights some important ophthalmologic manifestations associated with neurocutaneous syndromes and inherited connective tissue diseases.

p38 mitogen-activated protein kinase protects glomerular epithelial cells from complement-mediated cell injury.

In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC). We previously showed that sublytic concentration of C5b-9 triggers a variety of biological events in GEC. In the current study, we demonstrate that complement activates p38 MAPK in GEC and address the role of p38 in complement-mediated cell injury. When cultured rat GEC were stimulated with complement, p38 kinase activity and phosphorylation were increased by approximately 2.4-fold, compared with control. Treatment with p38 inhibitors significantly augmented complement-mediated cytotoxicity. In contrast, when the constitutively active mutant of transforming growth factor-beta-activated kinase 1 (TAK1), a kinase upstream of p38, was expressed in GEC in an inducible manner, cytotoxicity was significantly reduced, compared with uninduced cells. p38 inhibitors abolished the protective effect of TAK1 expression. By analogy to cultured cells, p38 activity was also increased in glomeruli from rats with PHN and treatment with the p38 inhibitor FR-167653 increased proteinuria. Complement induced phosphorylation of MAPK-associated protein kinase-2 (MAPKAPK-2), a kinase downstream of p38 in GEC. Heat shock protein (HSP27) is a cytoskeleton-interacting substrate of MAPKAPK-2. Overexpression of the wild-type HSP27, but not a non-phosphorylatable mutant, markedly reduced complement-mediated GEC injury. In summary, complement activates p38 MAPK in GEC in vitro and in glomeruli from rats with PHN. The activation of p38 MAPK appears to be cytoprotective for GEC against complement-mediated GEC injury. Phosphorylation of HSP27 may mediate this cytoprotection.