Two for One: Tuberculid and Leukocytoclastic Vasculitis in an Adolescent.

A 13-year-old girl with fevers, abdominal pain, and vomiting for 4 days presented with a full body pruritic rash that began in the axilla and spread rapidly to the rest of the body. She was recently diagnosed with tuberculosis and had been on rifampin, isoniazid, pyrazinamide and ethambutol (RIPE) therapy for 1 month to treat this infection, raising concern for a severe drug reaction. On exam, there were pink to hemorrhagic crusted papules diffusely on the body; two skin biopsies from the right ankle and right arm showed leukocytoclastic vasculitis and tuberculid pathologies, respectively. Tuberculids are a cutaneous form of tuberculosis that represent a hypersensitivity reaction to Mycobacterium tuberculosis or its antigens. These rashes can mimic other common diseases, and this case highlights the importance of obtaining histopathology early in the disease course for accurate and prompt diagnosis.

Racial disparities in immune-related adverse events of immune checkpoint inhibitors and association with survival based on clinical and biochemical responses.

BACKGROUND: Immune checkpoint inhibitors (ICPi) cause various immune-related adverse events (irAE) with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with < 5% African Americans. AIM: To evaluate the association between development of irAE and survival outcomes among a racially diverse patient population. METHODS: Data on patients with stage IV solid malignancies treated with programmed cell death-protein 1/programmed death ligand 1 blockers between January 2013 and December 2018 across MedStar Georgetown Cancer Institute facilities were retrospectively reviewed. Patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison. RESULTS: Out of 293 patients who met eligibility criteria, 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians vs African Americans (60.4% vs 30.8%), in patients with low programmed death ligand 1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in patients with irAE (30.8% vs 46.0%, P = 0.0140). Median PFS (5.8 vs 3.0 mo, P = 0.0204) and OS (17.1 vs 7.2 mo, P < 0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, P = 0.0002) but not in PFS (5.8 vs 3.3 mo, P = 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of patients with irAE are described. CONCLUSION: Development of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies.

Avelumab: a new standard for treating metastatic Merkel cell carcinoma.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is chemosensitive, responses to traditional chemotherapeutic agents are not durable. Avelumab, a novel anti-PD-L1 immune checkpoint inhibitor, recently became the first FDA-approved agent for the treatment of metastatic MCC and represents a new option to improve patient survival. Areas covered: This article presents an overview of MCC and summarizes the development of avelumab in the treatment of metastatic MCC. Preclinical studies, phase 1 and phase 2 clinical trials, and the safety profile of avelumab are reviewed. Future perspectives and ongoing studies are also discussed. Expert commentary: Avelumab demonstrated rapid and durable responses and a manageable safety profile in the treatment of metastatic MCC. Patient outcomes are favorable when compared to historical responses to standard chemotherapy. Ongoing clinical trials will continue to characterize avelumab and its optimal use in MCC therapy.

A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568.

Insulin-like growth factor 2 (IGF2) is the major fetal growth hormone in mammals. We identify zinc finger protein 568 (ZFP568), a member of the rapidly evolving Kruppel-associated box-zinc finger protein (KRAB-ZFP) family linked primarily to silencing of endogenous retroelements, as a direct repressor of a placental-specific Igf2 transcript (designated Igf2-P0) in mice. Loss of Zfp568, which causes gastrulation failure, or mutation of the ZFP568-binding site at the Igf2-P0 promoter causes inappropriate Igf2-P0 activation. Deletion of Igf2 can completely rescue Zfp568 gastrulation phenotypes through late gestation. Our data highlight the exquisite selectivity with which members of the KRAB-ZFP family repress their targets and identify an additional layer of transcriptional control of a key growth factor regulating fetal and placental development.

A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation.

Much has been learned about transcriptional cascades and networks from large-scale systems analyses of high-throughput datasets. However, analysis methods that optimize statistical power through simultaneous evaluation of thousands of ChIP-seq peaks or differentially expressed genes possess substantial limitations in their ability to uncover mechanistic principles of transcriptional control. By examining nascent transcript RNA-seq, ChIP-seq, and binding motif datasets from lipid A-stimulated macrophages with increased attention to the quantitative distribution of signals, we identified unexpected relationships between the in vivo binding properties of inducible transcription factors, motif strength, and transcription. Furthermore, rather than emphasizing common features of large clusters of co-regulated genes, our results highlight the extent to which unique mechanisms regulate individual genes with key biological functions. Our findings demonstrate the mechanistic value of stringent interrogation of well-defined sets of genes as a complement to broader systems analyses of transcriptional cascades and networks.

High CO2 Leads to Na,K-ATPase Endocytosis via c-Jun Amino-Terminal Kinase-Induced LMO7b Phosphorylation.

The c-Jun amino-terminal kinase (JNK) plays a role in inflammation, proliferation, apoptosis, and cell adhesion and cell migration by phosphorylating paxillin and ß-catenin. JNK phosphorylation downstream of AMP-activated protein kinase (AMPK) activation is required for high CO2 (hypercapnia)-induced Na,K-ATPase endocytosis in alveolar epithelial cells. Here, we provide evidence that during hypercapnia, JNK promotes the phosphorylation of LMO7b, a scaffolding protein, in vitro and in intact cells. LMO7b phosphorylation was blocked by exposing the cells to the JNK inhibitor SP600125 and by infecting cells with dominant-negative JNK or AMPK adenovirus. The knockdown of the endogenous LMO7b or overexpression of mutated LMO7b with alanine substitutions of five potential JNK phosphorylation sites (LMO7b-5SA) or only Ser-1295 rescued both LMO7b phosphorylation and the hypercapnia-induced Na,K-ATPase endocytosis. Moreover, high CO2 promoted the colocalization and interaction of LMO7b and the Na,K-ATPase α1 subunit at the plasma membrane, which were prevented by SP600125 or by transfecting cells with LMO7b-5SA. Collectively, our data suggest that hypercapnia leads to JNK-induced LMO7b phosphorylation at Ser-1295, which facilitates the interaction of LMO7b with Na,K-ATPase at the plasma membrane promoting the endocytosis of Na,K-ATPase in alveolar epithelial cells.

A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer.

Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.