IAPs on the move : role of inhibitors of apoptosis proteins in cell migration

Inhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases. IAPs directly control Rho GTPases, thus regulating cell shape and migration. For instance, XIAP and cIAP1 function as the direct E3 ubiquitin ligases of Rac1 and target it for proteasomal degradation. IAPs are differentially expressed in tumor cells and have been targeted by several cancer therapeutic drugs that are currently in clinical trials. Here, we summarize the current knowledge on the role of IAPs in the regulation of cell migration and discuss the possible implications of these observations in regulating tumor cell metastases

A Software System to Collect Expert Relevance Ratings of Medical Record Items for Specific Clinical Tasks

Development of task-specific electronic medical record (EMR) searches and user interfaces has the potential to improve the efficiency and safety of health care while curbing rising costs. The development of such tools must be data-driven and guided by a strong understanding of practitioner information requirements with respect to specific clinical tasks or scenarios. To acquire this important data, this paper describes a model by which expert practitioners are leveraged to identify which components of the medical record are most relevant to a specific clinical task. We also describe the computer system that was created to efficiently implement this model of data gathering. The system extracts medical record data from the EMR of patients matching a given clinical scenario, de-identifies the data, breaks the data up into separate medical record items (eg, radiology reports, operative notes, laboratory results, etc), presents each individual medical record item to experts under the hypothetical of the given clinical scenario, and records the experts’ ratings regarding the relevance of each medical record item to that specific clinical scenario or task. After an iterative process of data collection, these expert relevance ratings can then be pooled and used to design point-of-care EMR searches and user interfaces tailored to the task-specific needs of practitioners

Freeze-thaw Resistance of an Alluvial Soil Stabilized with EcoSand and Asbestos-free Fiber Powder

Stabilization of poor soils subjected to large daily temperature variations requires careful selection of suitable stabilizer for improvement of such soils. This study investigated the freeze-thaw resistance of an alluvial soil stabilized with EcoSand and asbestos-free fiber powder (AFP). Physical and mechanical properties of the soil were determined. The soil sample was stabilized with 5 variants of equal mixtures of the EcoSand and AFP in proportions of 2, 4, 6, 8 and 10%, with 1% sodium silicate and 1% fly ash, by weight of the soil. UCS tests were conducted before and after three freeze-thaw cycles, while keeping the sample at 0ºC for 8 hours and later at 30ºC for 8 hours for each cycle. It was found that the 8% EcoSand + AFP with 1% sodium silicate and 1% fly ash content provided an optimized increase of the freeze-thaw resistance of the soil. The use of a mixture of EcoSand and AFP as a soil stabilizer for regions of the world experiencing large temperature variation has the potential to improve the resistance of sand to freezing and thawing

Diagnosis of second breast cancer events after initial diagnosis of early stage breast cancer

To examine whether there are any characteristics of women or their initial tumors that might be useful for tailoring surveillance recommendations to optimize outcomes. We followed 17,286 women for up to 5 years after an initial diagnosis of ductal carcinoma in situ (DCIS) or early stage (I/II) invasive breast cancer diagnosed between 1996 and 2006. We calculated rates per 1,000 women years of recurrences and second breast primaries relative to demographics, risk factors, and characteristics of initial diagnosis: stage, treatment, mode of initial diagnosis. Nearly 4% had a second breast cancer event (314 recurrences and 344 second breast primaries). Women who used adjuvant hormonal therapy or were ≥80 years had the lowest rates of second events. Factors associated with higher recurrence and second primary rates included: initial DCIS or stage IIB, estrogen/progesterone receptor-negative, younger women (<50 years). Women with a family history or greater breast density had higher second primary rates, and women who received breast conserving surgery without radiation had higher recurrence rates. Roughly one-third of recurrences (37.6%) and second primaries (36.3%) were not screen-detected. Initial mode of diagnosis was a predictor of second events after adjusting for age, stage, primary treatment, and breast density. A recent negative mammogram should not falsely reassure physicians or women with new breast symptoms or changes because one-third of second cancers were interval cancers. This study does not provide any evidence in support of changing surveillance intervals for different subgroups

Molecular mapping of genomic regions harbouring QTLs for root and yield traits in sorghum (Sorghum bicolor L. Moench)

Root system is a vital part of plants for absorbing soil moisture and nutrients and it influences the drought tolerance. Identification of the genomic regions harbouring quantitative trait loci (QTLs) for root and yield traits, and the linked markers can facilitate sorghum improvement through marker-assisted selection (MAS) besides the deeper understanding of the plant response to drought stress. A population of 184 recombinant inbred lines (RILs), derived from E36-1 × SPV570, along with parents were phenotyped for component traits of yield in field and root traits in an above ground rhizotron. High estimates of heritability and genetic advance for all the root traits and for most of the yield traits, presents high scope for improvement of these traits by simple selection. A linkage map constructed with 104 marker loci comprising 50 EST-SSRs, 34 non-genic nuclear SSRs and 20 SNPs, and QTL analysis was performed using composite interval mapping (CIM) approach. A total of eight and 20 QTLs were mapped for root and yield related traits respectively. The QTLs for root volume, root fresh weight and root dry weight were found co-localized on SBI-04, supported by a positive correlation among these traits. Hence, these traits can be improved using the same linked markers. The lack of overlap between the QTLs of component traits of root and yield suggested that these two sets of parameters are independent in their influence and the possibility of combining these two traits might enhance productivity of sorghum under receding moisture condition

Ubiquitin-dependent regulation of Cdc42 by XIAP

Rho GTPases control fundamental cellular processes and Cdc42 is a well-studied member of the family that controls filopodia formation and cell migration. Although the regulation of Cdc42 activity by nucleotide binding is well documented, the mechanisms driving its proteostasis are not clear. Here, we demonstrate that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42. XIAP binds to Cdc42 and directly conjugates poly ubiquitin chains to the Lysine 166 of Cdc42 targeting it for proteasomal degradation. Depletion of XIAP led to an increased protein stability and activity of Cdc42 in normal and tumor cells. Consistently, loss of XIAP enhances filopodia formation in a Cdc42-dependent manner and this phenomenon phenocopies EGF stimulation. Further, XIAP depletion promotes lung colonization of tumor cells in mice in a Cdc42-dependent manner. These observations shed molecular insights into ubiquitin-dependent regulation of Cdc42 and that of actin cytoskeleton

Table_1_Association of sarcopenia with survival in advanced NSCLC patients receiving concurrent immunotherapy and chemotherapy.pdf

BackgroundFrailty, sarcopenia and malnutrition are powerful predictors of clinical outcomes that are not routinely measured in patients with non-small cell lung cancer (NSCLC). The primary aim of this study was to investigate the association of sarcopenia, determined by the psoas muscle index (PMI) with overall survival (OS) in patients with advanced NSCLC treated with concurrent immune checkpoint inhibitor (ICI) and chemotherapy (CTX).MethodsWe retrospectively reviewed data from a cohort of patients with locally advanced or metastatic NSCLC who were treated between 2015 and 2021 at the University of Virginia Medical Center. The cross-sectional area of the psoas muscle was assessed on CT or PET/CT imaging prior to treatment initiation. Multivariate analysis was performed using Cox proportional hazards regression models.ResultsA total of 92 patients (median age: 64 years, range 36-89 years), 48 (52.2%) men and 44 (47.8%) women, were included in the study. The median follow-up was 29.6 months. The median OS was 17.8 months. Sarcopenia, defined by a PMI below the 25th percentile, was associated with significantly lower OS (9.1 months in sarcopenic patients vs. 22.3 months in non-sarcopenic patients, P = 0.002). Multivariate analysis revealed that sarcopenia (HR 2.12, P = 0.0209), ECOG ≥ 2 (HR 2.88, P = 0.0027), prognostic nutritional index (HR 3.02, P = 0.0034) and the absence of immune related adverse events (HR 2.04, P = 0.0185) were independently associated with inferior OS.ConclusionsSarcopenia is independently associated with poor OS in patients with advanced NSCLC undergoing concurrent ICI and CTX.</p