GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.

Recessive dystrophic epidermolysis bullosa (RDEB) is a complex inherited skin disorder caused by loss-of-function mutations in the COL7A1 gene. In order for an effective treatment of this disorder to be realized, both a thorough understanding of the regulation of COL7A1 and an understanding of the underlying nature of the complications of RDEB is needed. Currently, both post-transcriptional regulation of COL7A1 and the underlying causes of fibrosis in RDEB patients are poorly understood. Here, we describe a previously unknown mechanism of regulation by which miR-29 regulates COL7A1 in a complex network: both directly through targeting its 3’ UTR at two distinct seed regions and indirectly through targeting an essential transcription factor required for basal COL7A1 expression, SP1. In turn miR-29 itself is regulated by SP1 activity and TGF-β signaling. RDEB mice express high levels of TGF-β and significantly lower miR-29 when compared to wild-type cohorts. The sustained decrease in miR-29 in RDEB skin leads to an increase of miR-29 target genes expressed in the skin, including pro-fibrotic extracellular matrix collagens. Collectively, we identify miR-29 as an important factor in both regulating COL7A1 and inhibiting TGF-β mediated fibrosis.

Summary Background Recessive dystrophic epidermolysis bullosa (RDEB) is a severe, complicated inherited blistering skin disease with few treatment options currently available. Recently, haematopoietic stem cell transplantation (HCT) has been used as an alternative therapy that can improve skin integrity, but it is not known if the preparative HCT regimen also contributes to the therapeutic response. Objectives To determine whether chemotherapy drugs used in the HCT preparative regimen influence type VII collagen (C7) expression, which is inherently reduced or absent in RDEB skin, and to explore the pathomechanisms of such responses, if present. Methods Drugs from the HCT preparative regimen (busulfan, cyclophosphamide, ciclosporin A, fludarabine and mycophenolate) with inhibitors (PD98059, U0126, LY294002, SR11302, SIS3 and N‐acetyl‐l‐cysteine) were added to normal human dermal and human RDEB fibroblasts. C7 expression was measured using reversetranscription polymerase chain reaction and immunoblotting. Results We uncovered a previously unknown consequence of fludarabine whereby dermal fibroblasts exposed to fludarabine upregulate C7. This effect is mediated, in part, through activation of the mitogen‐activated protein kinase/extracellular signal‐regulated kinase, phosphoinositide 3‐kinase/protein kinase B and transforming growth factor‐β pathways. Activation of these pathways leads to activation of downstream transcription factors, including activator protein 1 (AP‐1) and SMAD. Subsequently, both AP‐1 and SMAD bind the COL7A1 promoter and increase COL7A1 expression. Conclusions Fludarabine influences the production of type VII collagen in RDEB fibroblasts.

Introduction: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC), however limited characterization has been pursued. Methods: Clinicopathologic, genomic, and treatment data were collected for 5172 patients with NSCLC tumors which underwent genomic profiling. ATM immunohistochemistry (IHC) was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATMMUT NSCLC was significantly associated with female sex (P=0.02), ever smoking status (P<0.001), non-squamous histology (P=0.004) and higher tumor mutational burden (DFCI: P<0.0001; MSK: P<0.0001) compared to ATMWT cases. Among 3687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q<0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs 28.6%, P<0.0001) compared to tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N=1522) and chemo-immunotherapy (N=951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusion: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Kobuvirus infections are common among humans, rodents, carnivores, pigs, and ruminants. We report herein the complete genome sequence of a novel caprine kobuvirus (MN604700) from diarrheic kids in Minnesota. Whole-genome sequencing revealed a kobuvirus genome of 8,139 nt with a single ORF region encoding a polyprotein of 2,480 amino acids. Further analysis revealed nt substitutions along the genome compared with that of the caprine kobuvirus reference strain, with 93% identity. Phylogenetic analysis indicated that the clade of the caprine kobuvirus was most closely related to porcine kobuviruses rather than bovine or ovine kobuviruses. Using primers designed from this genome, caprine kobuvirus was identified in the stools of other goats. Sanger sequencing of PCR products indicated 3D and VP1 gene nucleotides of this latter strain were 95% and 91% identical with those of MN604700, respectively. There were 35 and 101 nt substitutions in 3D and VP1 genes, respectively. Findings of kobuvirus over a 2-y period may indicate an endemic state, which needs further research. In addition, screening for kobuviruses over large geographic areas is needed to identify the evolutionary connections among different strains.