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To explore the possibility of using a combination of a rapid MALDI-TOF-MS method (Mass-Fix) in conjunction with higher resolution LC-ESI-QTOF-MS (miRAMM) measurements to discriminate the IgG kappa M-protein from daratumumab, elotuzumab and isatuximab in myeloma patients. 86 patients with an IgG kappa M-protein were spiked with therapeutic levels of the drugs and examined by Mass-Fix and miRAMM to establish the percent of cases that could be resolved by each method. The method was then applied to 21 samples from patients receiving one of the drugs. Mass-Fix was capable of resolving the t-mAb from M-protein for 87 percent of the spiked samples. For the cases unresolved by Mass-Fix, miRAMM was capable of resolving the remaining drug interferences. The 21 IgG kappa myeloma patients that were receiving the drugs were all resolved by Mass-Fix. This proposed algorithm allows use of a clinical available assay (Mass-Fix) while maximizing the number of cases that can accurately resolve the t-mAb from the M-protein. [ABSTRACT FROM AUTHOR]

Patients with celiac disease (CeD) carry the major histocompatibility complex class II, HLA-DQ2 or DQ8 haplotype; the absence of these haplotypes excludes a diagnosis of CeD. While the most common and highest risk HLA haplotypes in CeD have been established, the risk profiles of the less common and equivocal HLA haplotypes need further refinement. The aim of this study was to use a large national patient cohort to further stratify the risk gradient of HLA-DQ haplotypes. The study cohort included 24,339 adult patients with suspected CeD and immunoglobulin (Ig)A sufficiency (total IgA ≥ 70 mg/dL) whose samples were assessed at Mayo Clinic Laboratories for HLA-DQ genotyping, total IgA, and tissue transglutaminase (tTG)-IgA. Data from a subset of the patients who had duodenal biopsies were analyzed to determine the risk gradient of CeD. Logistic regression models were used to evaluate the risk gradient and to calculate odds ratios (ORs) for being positive to CeD serology according to different HLA-DQ2 and DQ8 heterodimers. Of the 24,339 patients, 55% (n = 13,456) expressed HLA-DQ2 or DQ8 heterodimers. Compared with patients who had non-permissive HLA-DQ heterodimers, patients who had HLA-DQ2 homozygosity (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, or HLA-DQ2.2/DQ2.2) showed increased odds for tTG-IgA positivity (OR = 96.9; 95% CI, 58.3–147.9). Interestingly, the odds for patients who were compound heterozygous for HLA-DQ2.5 and HLA-DQ8 were similar to those for HLA-DQ2.5 heterozygotes. However, a single HLA-DQ2.2 haplotype (without HLA-DQ8, DQ2.2 heterozygous) was not associated with tTG-IgA positivity. These findings were confirmed in a subset of patients (n = 738) who had duodenal biopsies performed in addition to CeD serologic testing. This large national reference laboratory cohort study demonstrated that HLA-DQ2.2 heterozygous is not associated with positive tTG-IgA serology, suggesting the reclassification of this haplotype as non-permissive for CeD. [ABSTRACT FROM AUTHOR]

The U.S. Department of Agriculture (USDA) Forest Service, Forest Inventory and Analysis program recently inventoried trees on 257 sample plots in the urbanized areas of Oregon and Washington. Plots were located on the standard grid (≈1 plot/2428 ha) and installed with the 4-subplot footprint (≈.067 ha with 4 circular subplots). Using these data, we examined: 1) use of the land use classification data from the National Land Cover Database (NLCD) for post-stratification; 2) the resolution of the inventory data to make inferences about subdomains (specifically sub-regions) and subgroups (species and diameter classes); and 3) the i-Tree Eco software as a tool for data compilation, estimation, and reporting. [ABSTRACT FROM AUTHOR]

Summary Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti-neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition. [ABSTRACT FROM AUTHOR]

Research has shown there is a positive relationship between urban greenness and the well-being of city residents. But greenness is often unevenly distributed across a city, raising environmental justice issues. In 2011 and 2012 the USDA Forest Service, Forest Inventory and Analysis program installed ground plots in the urbanized areas of Oregon and Washington. We analyze these data for the urban areas west of the Cascade Mountains, linking it with demographic data from the U.S. Census to examine the relationship between greenness and socioeconomic status at a sub-regional scale. To explore some relations between urban forest measures and socioeconomic conditions and measures we developed four models: presence of tree canopy cover with a logistic mixed model, and on a subset of the data, percent tree canopy cover with a linear mixed model and tree count and tree species count with Poisson mixed models. We found that median household income, house value, land use, and years in the Tree City USA program contributed to explaining measures of greenness, such as canopy cover presence, percent canopy cover, tree counts, and tree species counts. This agrees with other studies, but does so at a broad scale covering the most densely populated areas in the Pacific Northwest. [ABSTRACT FROM AUTHOR]

Mcl-1, a pro-survival member of the Bcl-2 family located at the mitochondrial outer membrane, is subject to constitutive ubiquitylation by the Bcl-2 homology 3-only E3 ligase, Mule/ Lasui, resulting in rapid steady-state degradation via the proteasome, Insertion of newly synthesized Mcl-1 into the mitochondrial outer membrane is dependent on its C-terminal transmembrane segment, but once inserted, the N terminus of a portion of the Mcl-1 molecules can be subject to proteolytic processing. Remarkably, this processing requires an intact electrochemical potential across the inner membrane, Three lines of evidence directed at the endogenous protein, however, indicate that the resulting Mcl-1ΔN isoform resides in the outer membrane: (1) full-length Mcl-1 and Mcl-1ΔN resist extraction by alkali but are accessible to exogenous protease; (ii) almost the entire populations of Mcl-1 and Mcl-1ΔN are accessible to the membrane-impermeant Cys-reactive agent 4-acetamido-4' - [(iodoacetyl)amino]stilbene-2,2'-disuifonic acid; and (iii) Mcl-1 and Mcl-1ΔN exhibit equivalent chemical cross-linking to Bak in intact mitochondria, an Mcl-1 binding partner located in the outer membrane. In addition to the Mule Bcl-2 homology 3 domain, we show that interaction between Mcl-1 and Mule also requires the extreme N terminus of Mcl-1, which is lacking in Mcl-1ΔN. Thus, Mcl-lΔN does not interact with Mule, exhibits reduced steady-state ubiquitylation, evades the hyper-rapid steady-state degradation that is observed for full-length Mcl-1 in response to treatments that limit global protein synthesis, and confers resistance to UV stress-induced cell death. [ABSTRACT FROM AUTHOR]

Abstract: Background: The fast growing Middle Eastern (ME) population has rarely been studied in the U.S.. The purpose of this study was to compare the epidemiology of primary brain tumors in this ethnic population with the non-Hispanic, non-Middle Eastern White (NHNMW) in California. Methods: ME cases were identified by surname in the California cancer registry and ME population estimates were based on ancestry. Data for 683 cases of primary brain tumors (429 benign, 238 malignant, 16 uncertain) in the ME and 15,589 cases (8352 benign, 6812 malignant, 425 uncertain) in the NHNMW were available for this study. Results: ME patients were significantly (p <0.05) younger and their age-adjusted incidence rates per 100,000 for benign tumors of 10.0 in men and 17.6 in women were higher than similar rates of 7.3 and 10.6 in the NHNMW group (p <0.05). Rates for malignant tumors were similar. Meningioma was the main histology responsible for the observed increase in patients over 40 years of age. Also increased were benign tumors of the pituitary and pineal glands. The overall mortality in patients with benign tumors was significantly lower than malignant tumors. Conclusions: This study presents a significantly high incidence of benign meningioma in the ME population in California. This may be due to higher susceptibility or exposure of this ethnic group to the risk factor(s) for this neoplasm. Considering the reported causal association of benign meningioma with childhood radiation exposure from Israel, exposure to this risk factor in this ethnic group needs to be evaluated in future studies. [Copyright &y& Elsevier]

DHX9 is an ATP-dependent DEXH box helicase with a multitude of cellular functions. Its ability to unwind both DNA and RNA, as well as aberrant, noncanonical polynucleotide structures, has implicated it in transcriptional and translational regulation, DNA replication and repair, and maintenance of genome stability. We report that loss of DHX9 in primary human fibroblasts results in premature senescence, a state of irreversible growth arrest. This is accompanied by morphological defects, elevation of senescence-associated β-galactosidase levels, and changes in gene expression closely resembling those encountered during replicative (telomere-dependent) senescence. Activation of the p53 signaling pathway was found to be essential to this process. ChIP analysis and investigation of nascent DNA levels revealed that DHX9 is associated with origins of replication and that its suppression leads to a reduction of DNA replication. Our results demonstrate an essential role of DHX9 in DNA replication and normal cell cycle progression. [ABSTRACT FROM AUTHOR]