Inherited immunodeficiency disorders can be caused by mutations in any one of a large number of genes involved in the function of immune cells. Here, we describe two families with an autosomal recessive inherited immunodeficiency disorder characterized by increased susceptibility to infection and autoimmunity. Genetic linkage studies mapped the disorder to chromosomal region 14q11.2, and a homozygous guanine-to-adenine substitution was identified at the last base of exon 3 immediately following the translational termination codon in the TCRα subunit constant gene (TRAC). RT-PCR analysis in the two affected individuals revealed impaired splicing of the mRNA, as exon 3 was lost from the TRAC transcript. The mutant TCRα chain protein was predicted to lack part of the connecting peptide domain and all of the transmembrane and cytoplasmic domains, which have a critical role in the regulation of the assembly and/or intracellular transport of TCR complexes. We found that T cells from affected individuals were profoundly impaired for surface expression of the TCRαβ complex. We believe this to be the first report of a disease-causing human TRAC mutation. Although the absence of TCRαβ + T cells in the affected individuals was associated with immune dysregulation and autoimmunity, they had a surprising level of protection against infection.

Purpose Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) -positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI), a negative regulator of the Rho GTPase pathway, is associated with Tam resistance. We now discover that androgen receptor (AR) is overexpressed in cells with decreased Rho GDI and seek to determine AR’s contribution to resistance. Methods We engineered ER -positive cell lines with stable knock-down (KD) of Rho GDI (KD cells). Resistance mechanisms were examined using microarray profiling, protein-interaction studies, growth and reporter gene assays, and Western blot analysis combined with a specific AR antagonist and other signaling inhibitors. Results Tam-resistant tumors and cell lines with low Rho GDI levels exhibited upregulated AR expression. Microarray of Rho GDI KD cells indicated that activation of EGFR and ER was associated with Tam treatment. When AR levels were elevated interaction between AR and EGFR was detected. Constitutive and Tam-induced phosphorylation of EGFR and ERK1/2 was blocked by the AR antagonist Enzalutamide, suggesting that AR-mediated EGFR activation was a mechanism of resistance in these cells. Constitutive ERα phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ER. Tam exhibited agonist activity in AR over-expressing cells, stimulating ERα transcriptional activity and proliferation, which was blocked by Enzalutamide and gefitinib. Conclusions We describe a novel model of AR-mediated Tam resistance through activation of EGFR signaling leading to ER activation in ER -positive cells with low expression of Rho GDI.

PURPOSE: The National Lung Screening Trial demonstrated a 20% relative reduction in lung cancer mortality with low-dose computed tomography screening, leading to implementation of lung cancer screening across the United States. The Centers for Medicare and Medicaid Services approved coverage, but questions remained about effectiveness of community-based screening. To assess screening implementation during the first full year of CMS coverage, we surveyed a nationwide network of lung cancer screening centers, comparing results from academic and nonacademic centers. METHODS: One hundred sixty-five lung cancer screening centers that have been designated Screening Centers of Excellence responded to a survey about their 2016 program data and practices. The survey included 21 pretested, closed- and open-ended quantitative and qualitative questions covering implementation, workflow, numbers of screening tests completed, and cancers diagnosed. RESULTS: Centers were predominantly community based (62%), with broad geographic distribution. In both community and academic centers, more than half of lung cancers were diagnosed at stage I or limited stage, demonstrating a clear stage shift compared with historical data. Lung-RADS results were also comparable. There are wide variations in the ways centers address Centers for Medicare and Medicaid Services requirements. The most significant barriers to screening implementation were insurance and billing issues, lack of provider referral, lack of patient awareness, and internal workflow challenges. CONCLUSION: These data validate that responsible screening can take place in a community setting and that lung cancers detected by low-dose computed tomography screening are often diagnosed at an early, more treatable stage. Lung cancer screening programs have developed different ways to address requirements, but many implementation challenges remain.

We have previously found increased expression of thromboxane synthase (TXAS) and thromboxane receptor (TP) beta isoform in the tissues of patients with bladder cancer. Studies in cell lines and mice have indicated a potential significant role of the thromboxane signaling pathway in the pathogenesis of human bladder cancer. This study was designed to determine if the changes observed in the tissues of patients with bladder cancer were mirrored by changes in the urine of these patients. We found increased levels of thromboxane B2, (TXB2) the major metabolite of TXAS and increased levels of the TPβ receptor. These results raised the possibility that patients with bladder cancer may be followed for progression or remission of their disease by quantitation of these substances in their urine.