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AIM The purpose of this systematic review was to determine the effectiveness of self-management interventions for older adults with cancer and to determine the effective components of said interventions. METHODS We conducted a systematic review of self-management interventions for older adults (65+) with cancer guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. We conducted an exhaustive search of the following databases: Ageline, AMED, ASSIA, CINAHL, Cochrane, Embase, Medline, PsychINFO, and Sociological Abstracts. We assessed for quality using the Cochrane Risk of Bias tool and Down & Black for quasi-experimental studies, with data synthesized in a narrative and tabular format. RESULTS Sixteen thousand nine hundred and eight-five titles and abstracts were screened, subsequently 452 full-text papers were reviewed by two independent reviewers, of which 13 full-text papers were included in the final review. All self-management interventions included in this review measured Quality of Life; other outcomes included mood, self-care activity, supportive care needs, self-advocacy, pain intensity, and analgesic intake; only one intervention measured frailty. Effective interventions were delivered by a multidisciplinary teams (n = 4), nurses (n = 3), and mental health professionals (n = 1). Self-management core skills most commonly targeted included: problem solving; behavioural self-monitoring and tailoring; and settings goals and action planning. CONCLUSIONS Global calls to action argue for increased emphasize on self-management but presently, few interventions exist that explicitly target the self-management needs of older adults with cancer. Future work should focus on explicit pathways to support older adults and their caregivers to prepare for and engage in cancer self-management processes and behaviours.

Objectives Our objective was to explore and describe how older adults engage with technology to support cancer self-management behaviors, particularly as they live with multimorbidity. Data Sources We used a qualitative descriptive approach and semi-structured interviews with older adults with cancer who had at least one other chronic condition. Two authors analyzed the data using a descriptive thematic analysis approach using NVivo 12 software. Conclusion We found that older adults are interested in, if not already, engaging with technology and internet searching to manage their cancer diagnosis and treatment. Data were grouped into three themes: (1) Using technology to take control; (2) Confidence in technology supports competence in self-management; and (3) Desired features for future interventions. Participants felt they might need extra support learning how to craft a search, filter facts, and digest information from the internet to manage their cancer. Those who reported using technology to keep records about their health made more statements reflecting confidence in their technology usage. Implication for Nursing Practice Older adults are interested in engaging technology to support self-management. The specific implications that arise from this study are that (1) older adults’ interest in engaging with technology has a unique potential to support foundations for self-management behaviors and activities and (2) empowering self-management behaviors and attitudes through technology may result in better treatment outcomes, as evidenced by increased capabilities in the six core self-management skills.

Purpose To report on the perspectives of older adults (aged older than 65 years) with cancer and their caregivers who participated in patient-oriented research priority-setting activities called the Cancer and Aging Research Discussion Sessions. Participants & setting 35 older adults and caregivers participated in three public meetings and follow-up interviews. Methodologic approach Qualitative descriptive. Findings There was clear consensus from participants on research priorities related to two key areas. Implications for nursing Future research should focus on addressing age-related disparities in cancer care communication and support. By capitalizing on older adults' interest in research engagement, effective solutions can be cocreated to improve cancer experiences for older adults and their caregivers.

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wildtype PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies.

Background Cancer predominates in adults over age 65. Cancer treatments are known to create physical and psychosocial challenges, which may be amplified for older adults with cancer. Learning and applying self-management behaviours and skills during treatment with cancer can help to manage/recover health and improve quality of life. In many other chronic illnesses, self-management interventions are known to improve health outcomes and lower healthcare costs. The purpose of this systematic review is to determine the effectiveness of self-management interventions for older adults with cancer on physical, psychosocial, and health system-related outcomes. Methods We are conducting a systematic review of self-management interventions for older adults (65+) diagnosed with cancer (solid tumour or haematological) in the active treatment phase of cancer. This systematic review is guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Studies are limited to experimental or quasi-experimental methods published in English, French, German, or Dutch. A search strategy was designed with a Health Sciences librarian and performed using the following electronic databases: Ageline, AMED, ASSIA, Cinahl, Cochrane, Embase, Medline, PsychINFO, and Sociological Abstracts. Approximately 14,000 titles and abstracts are being electronically screened by a minimum of 2 reviewers, with relevant studies to be screened for full text. The final sample of included studies will be assessed for quality using the Cochrane Risk of Bias tool and Down and Black for quasi-experimental studies, with data synthesized in a narrative and tabular format. Discussion This systematic review will expand the knowledge base of interventions supporting self-management for older adults with cancer. This study will inform future intervention development by identifying gaps and strengths in effective self-management interventions targeting the needs of older adults receiving active treatment for cancer. Systematic review registration PROPERO registry ID# CRD42019134113

Purpose Older adults are most commonly diagnosed with cancer but needs related to managing multiple chronic conditions (multimorbidity) are often overlooked. Although self-management is a growing imperative in cancer care, the experiences of older adults managing multimorbidity alongside a cancer diagnosis have been less explored. In this study we interviewed older adults with cancer and multimorbidity to understand their experiences with cancer self-management while living with multimorbidity. Methods and Sample We used a descriptive qualitative approach and interviewed older adults (n = 14) about their experiences and had them complete the Multimorbidity Treatment Questionnaire; qualitative data were analyzed using thematic analysis. Results We identified three themes, including: Situating cancer and aging: personal, illness, and caregiving experiences; enacting and engaging in self-management; and challenges of living with cancer and navigating multimorbidity. Older adults demonstrated many strengths in engaging in self-management work but faced many challenges as they navigated the siloed healthcare system. Conclusion Oncology nurses play a critical role in supporting self-management for older adults with cancer. We propose that more in-depth research is needed to explore older adults’ experiences with cancer self-management to ensure that they are able to engage in the self-management that is required in our healthcare system.

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Identifying protein-protein interactions (PPIs) at an acceptable false discovery rate (FDR) is challenging. Previously we identified several hundred PPIs from affinity purification - mass spectrometry (AP-MS) data for the bacteria Escherichia coli and Desulfovibrio vulgaris. These two interactomes have lower FDRs than any of the nine interactomes proposed previously for bacteria and are more enriched in PPIs validated by other data than the nine earlier interactomes. To more thoroughly determine the accuracy of ours or other interactomes and to discover further PPIs de novo, here we present a quantitative tagless method that employs iTRAQ MS to measure the copurification of endogenous proteins through orthogonal chromatography steps. 5273 fractions from a four-step fractionation of a D. vulgaris protein extract were assayed, resulting in the detection of 1242 proteins. Protein partners from our D. vulgaris and E. coli AP-MS interactomes copurify as frequently as pairs belonging to three benchmark data sets of well-characterized PPIs. In contrast, the protein pairs from the nine other bacterial interactomes copurify two- to 20-fold less often. We also identify 200 high confidence D. vulgaris PPIs based on tagless copurification and colocalization in the genome. These PPIs are as strongly validated by other data as our AP-MS interactomes and overlap with our AP-MS interactome for D.vulgaris within 3% of expectation, once FDRs and false negative rates are taken into account. Finally, we reanalyzed data from two quantitative tagless screens of human cell extracts. We estimate that the novel PPIs reported in these studies have an FDR of at least 85% and find that less than 7% of the novel PPIs identified in each screen overlap. Our results establish that a quantitative tagless method can be used to validate and identify PPIs, but that such data must be analyzed carefully to minimize the FDR.

We present a strategy to discover recombinant monoclonal antibodies (mAbs) to specific cancers and demonstrate this approach using basal subtype breast cancers. A phage antibody library was depleted of antibodies to common cell surface molecules by incubation with luminal breast cancer cell lines, and then selected on a single basal-like breast cancer cell line (MDA-MB-231) for binding associated receptor-mediated endocytosis. Additional profiling against two luminal and four basal-like cell lines revealed 61 unique basal-specific mAbs from a pool of 1440 phage antibodies. The unique mAbs were further screened on nine basal and seven luminal cell lines to identify those with the greatest affinity, specificity, and internalizing capability for basal-like breast cancer cells. Among the internalizing basal-specific mAbs were those recognizing four transmembrane receptors (EphA2, CD44, CD73 and EGFR), identified by immunoprecipitation–mass spectrometry and yeast-displayed antigen screening. Basal-like breast cancer expression of these four receptors was confirmed using a bioinformatic approach, and expression microarray data on 683 intrinsically subtyped primary breast tumors. This overall approach, which sequentially employs phage display antibody library selection, antigen identification and bioinformatic confirmation of antigen expression by cancer subtypes, offers efficient production of high-affinity mAbs with diagnostic and therapeutic utility against specific cancer subtypes.

We used isobaric mass tagging (iTRAQ) and lectin affinity capture mass spectrometry (MS)-based workflows for global analyses of parotid saliva (PS) and whole saliva (WS) samples obtained from patients diagnosed with primary Sjögren's Syndrome (pSS) who were enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) as compared with two control groups. The iTRAQ analyses revealed up- and down-regulation of numerous proteins that could be involved in the disease process (e.g., histones) or attempts to mitigate the ensuing damage (e.g., bactericidal/permeability increasing fold containing family (BPIF) members). An immunoblot approach applied to independent sample sets confirmed the pSS associated up-regulation of β2-microglobulin (in PS) and down-regulation of carbonic anhydrase VI (in WS) and BPIFB2 (in PS). Beyond the proteome, we profiled the N-glycosites of pSS and control samples. They were enriched for glycopeptides using lectins Aleuria aurantia and wheat germ agglutinin, which recognize fucose and sialic acid/N-acetyl glucosamine, respectively. MS analyses showed that pSS is associated with increased N-glycosylation of numerous salivary glycoproteins in PS and WS. The observed alterations of the salivary proteome and N-glycome could be used as pSS biomarkers enabling easier and earlier detection of this syndrome while lending potential new insights into the disease process.

We are interested in the effects of dividend reduction decisions on the firms that make them. We compare financial ratios of distressed dividend-reducing firms to distressed firms that did not reduce dividends, of nondistressed dividend-reducing firms to nondistressed firms that did not reduce dividends, and ratios of distressed dividend- reducing firms to nondistressed dividend-reducing firms. Results indicate benefits of dividend reductions to both distressed and nondistressed firms. We find a cost to nondistressed firms, i.e., a drop in the market value of the firm in the year following the dividend reduction.

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Numerous affinity purification-mass spectrometry (APMS) and yeast two-hybrid screens have each defined thousands of pairwise protein-protein interactions (PPIs), most of which are between functionally unrelated proteins. The accuracy of these networks, however, is under debate. Here, we present an AP-MS survey of the bacterium Desulfovibrio vulgaris together with a critical reanalysis of nine published bacterial yeast two-hybrid and AP-MS screens. We have identified 459 high confidence PPIs from D. vulgaris and 391 from Escherichia coli. Compared with the nine published interactomes, our two networks are smaller, are much less highly connected, and have significantly lower false discovery rates. In addition, our interactomes are much more enriched in protein pairs that are encoded in the same operon, have similar functions, and are reproducibly detected in other physical interaction assays than the pairs reported in prior studies. Our work establishes more stringent benchmarks for the properties of protein interactomes and suggests that bona fide PPIs much more frequently involve protein partners that are annotated with similar functions or that can be validated in independent assays than earlier studies suggested.

We used a lectin chromatography/MS-based approach to screen conditioned medium from a panel of luminal (less aggressive) and triple negative (more aggressive) breast cancer cell lines (n = 5/subtype). The samples were fractionated using the lectins Aleuria aurantia (AAL) and Sambucus nigra agglutinin (SNA), which recognize fucose and sialic acid, respectively. The bound fractions were enzymatically N-deglycosylated and analyzed by LC-MS/MS. In total, we identified 533 glycoproteins, ~90% of which were components of the cell surface or extracellular matrix. We observed 1011 glycosites, 100 of which were solely detected in ≥3 triple negative lines. Statistical analyses suggested that a number of these glycosites were triple negative-specific and thus potential biomarkers for this tumor subtype. An analysis of RNAseq data revealed that approximately half of the mRNAs encoding the protein scaffolds that carried potential biomarker glycosites were upregulated in triple negative vs. luminal cell lines, and that a number of genes encoding fucosyl- or sialyltransferases were differentially expressed between the two subtypes, suggesting that alterations in glycosylation may also drive candidate identification. Notably, the glycoproteins from which these putative biomarker candidates were derived are involved in cancer-related processes. Thus, they may represent novel therapeutic targets for this aggressive tumor subtype.

Background The carbohydrate portions of salivary glycoproteins play important roles, including mediating bacterial and leukocyte adhesion. Salivary glycosylation is complex. Many of its glycoproteins present ABO and Lewis blood group determinants. An individual’s genetic complement and secretor status govern the expression of blood group antigens. We queried the extent to which salivary glycosylation varies according to blood group and secretor status. First, we screened submandibular/sublingual and parotid salivas collected as ductal secretions for reactivity with a panel of 16 lectins. We selected three lectins that reacted with the largest number of glycoproteins and one that recognized uncommon lactosamine-containing structures. Ductal salivas representing a secretor with complex blood group expression and a nonsecretor with a simple pattern were separated by SDS-PAGE. Gel slices were trypsin digested and the glycopeptides were individually separated on each of the four lectins. The bound fractions were de-N-glycosylated. LC–MS/MS identified the original glycosylation sites, the peptide sequences, and the parent proteins. Results The results revealed novel salivary N-glycosites and glycoproteins not previously reported. As compared to the secretor, nonsecretor saliva had higher levels of N-glycosylation albeit with simpler structures. Conclusions Together, the results suggested a molecular basis for inter-individual variations in salivary protein glycosylation with functional implications for oral health. Electronic supplementary material The online version of this article (doi:10.1186/s12014-015-9100-y) contains supplementary material, which is available to authorized users.

Summary Objectives: To assess the clinical efficacy of the self-pressurized air-Q ILA� (ILA-SP). Aim: The purpose of this prospective audit was to evaluate the feasibility of the ILA-SP in clinical practice and generate data for future comparison trials. Background: The ILA-SP is a new first-generation supraglottic airway for children with a self-adjusting cuff and lack of a pilot balloon. Methods: Over a 4-month period, 352 children with an ASA physical status of I–III, newborn to 18 years of age, undergoing various procedures were studied. Data points assessed included insertion success rates, airway leak pressures, quality of ventilation, and perioperative complications associated with the use of this device. Results: In 349 of the 352 patients in this study, the ILA-SP was used successfully as a primary supraglottic airway device in a variety of patients. Three patients required conversion to a standard laryngeal mask airway or a tracheal tube. The mean initial airway leak pressure for all patients was 17.8 ± 5.4 cm H2O, and 20.4 ± 5.5 cm H2O when re-checked at 10 min, which was statistically significant (P < 0.001). Complications were limited to 14 patients and related to reflex activation of the airway (coughing, laryngospasm, and bronchospasm) (n = 10), sore throat (n = 3), and blood staining on removal of the device (n = 1). There were no episodes of regurgitation, aspiration, or hoarseness. Conclusions: Acceptable clinical performance was demonstrated with the ILA-SP for a variety of procedures in infants and children with spontaneous and positive pressure ventilation. Future studies comparing this device to other supraglottic airways may provide useful information regarding the safety of the ILA-SP in pediatric clinical practice.

Glycans are cell-type-specific, posttranslational protein modifications that are modulated during developmental and disease processes. As such, glycoproteins are attractive biomarker candidates. Here, we describe a mass spectrometry-based workflow that incorporates lectin affinity chromatography to enrich for proteins that carry specific glycan structures. As increases in sialylation and fucosylation are prominent among cancer-associated modifications, we focused on Sambucus nigra agglutinin (SNA) and Aleuria aurantia lectin (AAL), lectins which bind sialic acid- and fucose-containing structures, respectively. Fucosylated and sialylated glycopeptides from human lactoferrin served as positive controls, and high-mannose structures from yeast invertase served as negative controls. The standards were spiked into Multiple Affinity Removal System (MARS) 14-depleted, trypsin-digested human plasma from healthy donors. Samples were loaded onto lectin columns, separated by HPLC into flow-through and bound fractions, and treated with peptide: N-glycosidase F to remove N-linked glycans. The deglycosylated peptide fractions were interrogated by ESI HPLC-MS/MS. We identified a total of 122 human plasma glycoproteins containing 247 unique glycosites. Importantly, several of the observed glycoproteins (e.g., cadherin 5 and neutrophil gelatinase-associated lipocalin) typically circulate in plasma at low nanogram per milliliter levels. Together, these results provide mass spectrometry-based evidence of the utility of incorporating lectin-separation platforms into cancer biomarker discovery pipelines.

Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low mug/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma.

Existing data indicate that sleep-wakefulness is an essential behavior. The biological function(s) of sleep, however, remains unknown, due, in part, to the lack of information available at the intracellular level. Preliminary microarray analyses show that changes in behavioral state influence regional mRNA profiles; however, the impact of sleep on protein signatures is virtually unexplored. In these studies, cortical protein profiles were examined after timed bouts of spontaneous sleep-wakefulness. Within minutes of each behavioral state examined, a small number of spots showing unique expression were detected. Mass spectroscopy analyses of sleep- and wake-related spots identified proteins associated with multiple functional categories. Two sleep-associated proteins were further validated using a sleep deprivation paradigm. We found preliminary evidence for two different post-transcriptional mechanisms-one (GAPDH) in which the amount of protein was increased in the recovery sleep following prolonged waking, while the other (actin) suggested that post-translational modifications may underlie sleep. The similarities between the effects of sleep on both protein and mRNA profiles indicate that dynamic intracellular changes underlie sleep-wake states and are consistent with roles for sleep in multiple biological functions.

Endogenous proteinases in biological fluids such as human saliva produce a rich peptide repertoire that reflects a unique combination of enzymes, substrates, and inhibitors/activators. Accordingly, this subproteome is an interesting source of biomarkers for disease processes that either directly or indirectly involve proteolysis. However, the relevant proteinases, typically very low abundance molecules, are difficult to classify and identify. We hypothesized that a sensitive technique for monitoring accumulated peptide products in an unbiased, global manner would be very useful for detecting and profiling proteolytic activities in complex biological samples. Building on the longstanding use of 18O isotope-based approaches for the classification of proteolytic and other enzymatic processes we devised a new method for evaluating endogenous proteinases. Specifically, we showed that upon ex vivo incubation endogenous proteinases in human parotid saliva introduced 18O from isotopically enriched water into the C-terminal carboxylic groups of their peptide products. Subsequent peptide sequence determination and inhibitor profiling enabled the detection of discrete subsets of proteolytic products that were generated by different enzymes. As a proof-of-principle we used one of these fingerprints to identify the relevant activity as tissue kallikrein. We termed this technique PALeO. Our results suggest that PALeO is a rapid and highly sensitive method for globally assessing proteinase activities in complex biological samples.

Executive Overview Corporate governance research emphasizes the influence of institutional owners on company outcomes such as strategic decisions, organizational structures, and executive compensation. However, little is known about the process companies use to gain support for management-sponsored compensation plan resolutions. This article reviews prior literature linking institutional ownership and compensation practices and investigates the little-studied process of how management tries to work with owners to secure shareholder approval of compensation plans. In addition, it provides brief cases of two Fortune 300 companies (General Mills and PepsiCo) that received positive votes on their compensation plans. The article ends with several recommendations for managers trying to gain institutional owners' approval of future compensation plans.

Purpose: The heat shock protein 90 (Hsp90) chaperone plays an important role in transformation by regulating the conformational maturation and stability of oncogenic kinases and transcription factors. Ansamycins, such as 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), inhibit Hsp90 function; induce the degradation of Hsp90 client proteins such as HER2, and have shown activity in early clinical trials. However, the utility of these drugs has been limited by their hepatotoxicity, poor solubility, and poorly tolerated formulations. Experimental Design: We determined the pharmacodynamic and antitumor properties of a novel, synthetic Hsp90 inhibitor, SNX-2112, in cell culture and xenograft models of HER kinase–dependent cancers. Results: We show in a panel of tumor cell lines that SNX-2112 and its prodrug SNX-5542 are Hsp90 inhibitors with properties and potency similar to that of 17-AAG, including: degradation of HER2, mutant epidermal growth factor receptor, and other client proteins, inhibition of extracellular signal-regulated kinase and Akt activation, and induction of a Rb-dependent G1 arrest with subsequent apoptosis. SNX-5542 can be administered to mice orally on a daily schedule. Following oral administration, SNX-5542 is rapidly converted to SNX-2112, which accumulates in tumors relative to normal tissues. A single dose of SNX-5542 causes HER2 degradation and inhibits its downstream signaling for up to 24 h, and daily dosing results in regression of HER2-dependent xenografts. SNX-5542 also shows greater activity than 17-AAG in a non–small cell lung cancer xenograft model expressing mutant EGFR. Conclusions: These results suggest that Hsp90 inhibition with SNX-2112 (delivered as a prodrug) may represent a promising therapeutic strategy for tumors whose growth and survival is dependent on Hsp90 clients.

Apolipoprotein E (apoE) is a major protein component of cholesterol-transporting lipoprotein particles in the central nervous system and in plasma. Polymorphisms of apoE are associated with cardiovascular disease and with a predisposition to Alzheimer's disease and other forms of neurodegeneration. For full biological activity, apoE must be bound to a lipoprotein particle. Complexes of apoE and phospholipid mimic many of these activities. In contrast to a widely accepted discoidal model of apoA-I bound to dimyristoylphosphatidylcholine, which is based on solution studies, an X-ray diffraction study of apoE bound to dipalmitoylphosphatidylcholine (DPPC) indicated that apoE*DPPC particles are quasi-spheroidal and that the packing of the phospholipid core is similar to a micelle. Using small-angle X-ray scattering, we show that apoE*DPPC particles in solution are ellipsoidal and that the shape of the phospholipid core is compatible with a twisted-bilayer model. The proposed model is consistent with the results of mass spectrometric analysis of products of limited proteolysis. These revealed that the nonlipid-bound regions of apoE in the particle are consistent with an alpha-helical hairpin.

Bartonella quintana is a fastidious, gram-negative, rod-shaped bacterium that causes prolonged bacteremia in immunocompetent humans and severe infections in immunocompromised individuals. We sought to define the outer membrane subproteome of B. quintana in order to obtain insight into the biology and pathogenesis of this emerging pathogen and to identify the predominant B. quintana antigens targeted by the human immune system during infection. We isolated the total membrane proteins of B. quintana and identified 60 proteins by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and peptide mass fingerprinting. Using the newly constructed proteome map, we then utilized two-dimensional immunoblotting with sera from 21 B. quintana -infected patients to identify 24 consistently recognized, immunoreactive B. quintana antigens that have potential relevance for pathogenesis and diagnosis. Among the outer membrane proteins, the v ariably expressed o uter m embrane p rotein adhesins (VompA and VompB), peptidyl-prolyl cis-trans -isomerase (PpI), and h emin- b inding p rotein E (HbpE) were recognized most frequently by sera from patients, which is consistent with surface expression of these virulence factors during human infection.

APOBEC3G (A3G) and related deoxycytidine deaminases are potent intrinsic antiretroviral factors. A3G is expressed either as an enzymatically active low-molecular-mass (LMM) form or as an enzymatically inactive high-molecular-mass (HMM) ribonucleoprotein complex. Resting CD4 T cells exclusively express LMM A3G, where it functions as a powerful postentry restriction factor for HIV-1. Activation of CD4 T cells promotes the recruitment of LMM A3G into 5- to 15-MDa HMM complexes whose function is unknown. Using tandem affinity purification techniques coupled with MS, we identified Staufen-containing RNA-transporting granules and Ro ribonucleoprotein complexes as specific components of HMM A3G complexes. Analysis of RNAs in these complexes revealed Alu and small Y RNAs, two of the most prominent nonautonomous mobile genetic elements in human cells. These retroelement RNAs are recruited into Staufen-containing RNA-transporting granules in the presence of A3G. Retrotransposition of Alu and hY RNAs depends on the reverse transcriptase machinery provided by long interspersed nucleotide elements 1 (L1). We now show that A3G greatly inhibits L1-dependent retrotransposition of marked Alu retroelements not by inhibiting L1 function but by sequestering Alu RNAs in cytoplasmic HMM A3G complexes away from the nuclear L1 enzymatic machinery. These findings identify nonautonomous Alu and hY retroelements as natural cellular targets of A3G and highlight how different forms of A3G uniquely protect cells from the threats posed by exogenous retroviruses (LMM A3G) and endogenous retroelements (HMM A3G).

There is an increasing need in biology and clinical medicine to robustly and reliably measure tens to hundreds of peptides and proteins in clinical and biological samples with high sensitivity, specificity, reproducibility, and repeatability. Previously, we demonstrated that LC-MRM-MS with isotope dilution has suitable performance for quantitative measurements of small numbers of relatively abundant proteins in human plasma and that the resulting assays can be transferred across laboratories while maintaining high reproducibility and quantitative precision. Here, we significantly extend that earlier work, demonstrating that 11 laboratories using 14 LC-MS systems can develop, determine analytical figures of merit, and apply highly multiplexed MRM-MS assays targeting 125 peptides derived from 27 cancer-relevant proteins and seven control proteins to precisely and reproducibly measure the analytes in human plasma. To ensure consistent generation of high quality data, we incorporated a system suitability protocol (SSP) into our experimental design. The SSP enabled real-time monitoring of LC-MRM-MS performance during assay development and implementation, facilitating early detection and correction of chromatographic and instrumental problems. Low to subnanogram/ml sensitivity for proteins in plasma was achieved by one-step immunoaffinity depletion of 14 abundant plasma proteins prior to analysis. Median intra- and interlaboratory reproducibility was

Saliva plays many biological roles, from lubrication and digestion to regulating bacterial and leukocyte adhesion. To understand the functions of individual components and families of molecules, it is important to identify as many salivary proteins as possible. Toward this goal, we used a proteomic approach as the first step in a global analysis of this important body fluid. We collected parotid saliva as the ductal secretion from three human donors and separated the protein components by two-dimensional SDS-polyacrylamide gel electrophoresis (2D SDS-PAGE). Proteins in gel spots were identified by peptide mass fingerprinting, and the results were confirmed by tandem mass spectrometry of selected peptides. Complementing this approach we used ultrafiltration to prepare a low-molecular-weight fraction of parotid saliva, which was analyzed directly or after reversed phase high-performance liquid chromatography separation by using mass spectrometric approaches. MS analyses of 2D SDS-PAGE spots revealed known components of saliva, including cystatins, histatins, lysozyme, and isoforms and/or fragments of alpha-amylase, albumin, and proline-rich proteins. We also discovered novel proteins, such as several isoforms of Zn-alpha-2-glycoprotein and secretory actin-binding protein. MS analyses of the ultrafiltrate showed that the low-molecular-weight fraction of parotid saliva was peptide-rich, with novel fragments of proline-rich proteins and histatins in abundance. Experiments using Candida albicans as the test organism showed that at least one of the novel peptides had antifungal activity. Our results show that saliva is a rich source of proteins and peptides that are potential diagnostic and therapeutic targets.

Prior research provides evidence that firms make accounting choices to avoid violation of debt covenant provisions and the resulting costs of technical default. We extend this research by asking why some firms refrain from making accounting policy changes when faced with costs of technical default. We considered two possible explanations. First, we hypothesise that these defaulting firms may lack the flexibility to make accounting changes. Second, we hypothesise that these defaulting firms may lack incentive to change accounting methods. Results confirm prior research and indicate that defaulting firms make more accounting changes than non‐defaulting firms. The decision by defaulting firms to change or not change accounting methods during the three years ending in the year of a technical default of debt covenants can be explained in part by the ability of the firm and by the incentives of the firm to make a change.

We have analyzed the proteome of several strains of Haemophilus ducreyi by two-dimensional gel electrophoresis (2-DE) and mass spectrometry. Over 100 spots were analyzed from the soluble and insoluble protein fractions from the prototype strain 35000HP and 122 distinct proteins were identified. Functions of approximately 80% of the 122 proteins were deduced by identification with close homologues of Haemophilus influenzae. Four additional wild type and three mutant strains were also analyzed that vary in their virulence and/or outer-membrane lipooligosaccharide structures. Overall, the 2-DE gel maps of the wild type and mutant strains were similar to strain 35000HP, suggesting little proteome diversity in relation to carbohydrate expression and/or virulence. An exception was the Kenyan strain 33921 which contained significant differences in its proteome 2-DE map and also synthesizes an unusual LOS with a trisaccharide branch structure. This African strain may represent a prototype of a second clonal group of H. ducreyi.

This paper provides another test of the litigation hypothesis proposed by Hall and Stammerjohan (1997) and provides evidence that subtle differences in the underlying business environment may be very important in predicting the accounting reaction of management to major events. The litigation hypothesis predicts that firms that are defendants in litigation with potentially large damage awards (major litigation) will attempt to reduce the size of those damage awards by making income-decreasing accounting choices. The oil firms in the Hall and Stammerjohan study appeared to systematically reduce reported earnings during the litigation periods by under-reporting new reserves. The fourteen chemical and pharmaceutical firms, involved in fifteen litigation events, examined by this study produce a very different result. The chemical and pharmaceutical firms faced a different business environment during their litigation periods and appear to have made income-increasing accounting choices. These firms appear to have been able to perpetuate earnings growth without corresponding sales revenue growth during the litigation periods through unexpected reversals in deferred income tax expense.

The process for discovery and development of biomarkers of solid tumors presents exceptional challenges. The major technical obstacle is the disconnection between the site of their generation (tissue, proximal fluid) and the source of detection (body fluids, predominantly serum and plasma). This single factor limits, in practical terms, the potential pool of biomarkers to those that are secreted, shed, or leaked from the cell surface. On reaching the circulation, a biomarker undergoes “dilution” into a mixture of thousands of proteins that are present at concentrations spanning at least 10 orders of magnitude. Furthermore, the integrity of a circulating biomarker may be compromised by proteolytic degradation or distortion of its posttranslational modifications. Other levels of complexity involve the inherent variability of biological systems (intraindividual and across a population) and ambiguities in defining disease phenotypes. Finally, fundamental and technological difficulties involved in biomarker studies are exacerbated by preanalytical variables associated with sample collection, handling, and storage (1, 2). An ideal cancer biomarker would be detectable in body fluids at an early stage of disease in a highly specific and selective fashion and be measurable for an inexpensive price. Development of such a biomarker is not a trivial endeavor. To promote efficiency and rigor in cancer biomarker research, Pepe et al. (3) introduced guidelines for a generally appropriate process that could be applied to many other diseases and classes of biomarker (e.g., a protein or a metabolite). These guidelines propose specific aims and measures of success for each of the 5 phases of a biomarker discovery pipeline in the context of progress being made in the field and relevant published studies. It is now evident that the majority of proteomics and genomics studies published to date do not progress far beyond the discovery stage (phase 1), because the development of clinical …

This study evaluates and ranks 80 US doctoral granting institutions based on the placement of their graduates at top-tier universities, productive accounting research departments, AACSB-accredited institutions, and US doctoral granting institutions. We employ two measurement scales that facilitate our evaluations and rankings. Our first scale uses US News and World Report: America's Best Colleges (1997) information to measure the placement of each degree granting institution's graduates along a continuum that ranges from top-tier national universities to tier-four regional universities. Our second scale uses research productivity information reported by Hasselback and Reinstein [ Hasselback, J. R., & Reinstein, A. (1995a). A proposal for measuring scholarly productivity of accounting faculty. Issues in Accounting Education, 10, 269–306. ] to measure the placement of each degree granting institution's graduates along a continuum that ranges from placements in the most productive accounting research departments to placements in the least productive research departments. The primary purpose of our study is to provide potential doctoral students and those advising potential doctoral students with a resource to assist them in the assessment of the placement abilities of US doctoral programs. Consistent with this purpose, we: (1) examine the population of active US degree granting institutions; (2) employ measures of placement ability that are based on the attributes of the initial-placement institutions; and (3) employ measures that are allowed to vary over the entire range of doctoral granting and non-doctoral granting initial-placement institutions.

Protein identification can be accomplished with an enzymatic digestion of the protein followed by mass spectrometric analysis of the peptide mass fingerprint followed by database searching. However, if a protein is not in a database, sequence information must be obtained to characterize and identify it. This can be done either by classical Edman sequencing or/and by tandem mass spectrometry. To determine the sequence of an unknown protein from Bacillus pumilus PH-01, which adsorbs environmental pollutants such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs), both sequencing and de novo peptide sequencing by tandem MS/MS of the peptide fragments were performed. Edman sequencing of the reduced and alkylated protein revealed the majority of the sequence; however, all information on disulfide bonding was lost. Therefore, a tryptic digest of the native protein was performed to obtain both complete sequence information and the connectivity of the disulfide bonds. We performed the de novo sequencing using a hybrid quadrupole-time-of-flight mass spectrometer (Q-TOF MS) instrument. The high mass accuracy and sensitivity of the hybrid Q-TOF MS made low-level sequencing of this novel naturally isolated protein possible.

Anesthesiologists have been widely viewed as the experts on malignant hyperthermia syndrome since the first description of the syndrome by Denborough in 1960. 10 Because this condition most commonly is diagnosed in the perioperative period, all anesthesiologists should be familiar with the basic concepts of diagnosis and treatment and the salient features of the syndrome that serve as a basis for consultation with patients, families, and other physicians. This role is unique for anesthesiologists because other physicians, such as internists, pediatricians, and geneticists, often serve as the primary experts on a syndrome and are consulted by anesthesiologists for advice. In this role as expert, anesthesiologists should be aware of the current clinical understanding of malignant hyperthermia syndrome and its proper evaluation and treatment. This article describes commonly important issues in the clinical setting.

Background Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. Methods Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. Results All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. Conclusions A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.

The effect of solvent on the rate of leuprolide degradation and on the structure of the degradation products was explored. Leuprolide solutions (370 mg/mL) were prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROS osmotic implants. Both solvent systems demonstrated better than 90% stability after 1 year at 37 degrees C, where the DMSO formulation afforded better stability than the aqueous formulation and was used in subsequent clinical trials. The rate of leuprolide degradation in DMSO was also observed to accelerate with increasing moisture content, indicating that the aprotic solvent minimized chemical degradation. Interestingly, leuprolide degradation products varied with formulation vehicle. The proportions of leuprolide degradation products observed to form in water and DMSO at 37 degrees C were hydrolysis > aggregation > isomerization > oxidation and aggregation > oxidation > hydrolysis > isomerization, respectively. Specifically, more N-terminal hydrolysis and acetylation were observed under aqueous conditions, and increased Trp oxidation and Ser beta-elimination were seen under non-aqueous conditions. Furthermore, the major chemical degradation pathway changed with temperature in the DMSO formulation (decreasing oxidation with increasing temperature), but not in the aqueous formulation.

UNLABELLED We compared the efficacy of an adult circle system versus a Bain system to deliver minute ventilation (V(E)) to an infant test lung model using pressure-limited ventilation. To simulate a wide variety of potential infant clinical states, V(E) was measured with two compliances: at peak inspiratory pressures (PIP) of 20, 30, 40, and 50 cm H2O and at respiratory rates (RR) of 20, 30, 40, and 50 breaths/min. Each measurement was made three times, and their average was used for analysis. Data were analyzed using the multiple regression technique. In both normal and low-compliance lung models, V(E) was nearly identical between adult circle and Bain systems (P = 0.67 for normal compliance model, P = 0.89 for low-compliance model). V(E) positively correlated with RR (P < 0.001), PIP (P < 0.001), and lung compliance (P < 0.001). Very high PIP or RR were required to deliver V(E) to the low-compliance lung model. The adult circle system is equivalent to the Bain system in its ability to ventilate an infant test lung over a wide range of RR, PIP, and two compliances during pressure-limited ventilation. V(E) is dependent of PIP, RR, and lung compliance. With low-compliance lungs, both systems require a high PIP. We conclude that both anesthetic systems deliver ventilation over a wide range of respiratory variables during pressure-limited ventilation in infants. IMPLICATIONS We obtained results from this infant test lung study that indicate that either an adult circle breathing system or the Bain system can reliably deliver ventilation over a wide range of respiratory variables during pressure-limited ventilation in infants.

This in vitro study examined the effect of circuit compliance on delivered ventilation (VE) using a time-cycled, volume controlled circle system in an infant lung model. A Bio-Tek ventilator tester set to simulate normal and abnormal lung compliance measured VE delivered by the Narkomed 2B system. Circle circuits of varied compliance (2.75, 1.22 and 0.73 microliters.cm H2O-1) were tested. Tidal volume was adjusted to peak inflation pressures (PIP) of 20, 30, 40, and 50 cm H2O with three circuits, two lung compliances, and four different size tracheal tubes (TT) (2.5, 3.5, 4, 4.5 mm ID). Data were analysed using the multiple regression technique. Delivered VE was directly related to PIP and lung compliance. Delivered VE was not affected by the choice of circuit. TT size had minimal effects on VE when lung compliance was low; TT size was a more important factor when test lung compliance was normal. Extrapolating this data to the clinical setting, adequate ventilation of infants can be achieved with an adult circle system if an appropriate PIP is chosen, regardless of the compliance of the circuit used. Infants with poor lung compliance may require very high PIP for adequate ventilation.

Matrix-assisted laser desorption ionization (MALDI) is one of the most sensitive ionization methods currently available for the mass spectrometric investigation of a wide range of structural problems involving macromolecules of biomedical significance. This laboratory has recently reported the use of MALDI with tandem mass spectrometry and high energy collision induced dissociation for the unambiguous de novo sequence analysis of peptides from an unknown P450 protein [K.F. Medzihradszky, G.W. Adams, R.H. Bateman, M.R. Green and A.L. Burlingame, J. Am. Soc. Mass Spectrom., 7 (1996) 1]. This report describes the characteristics and the advantages now available using high energy collisional activation of MALDI-generated pseudomolecular ions for sequence and structural characterization of proteins and covalently modified proteins that are not accessible under low energy conditions for many types of structures.

Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM-MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LC-SID-MRM-MS platforms for routine use, with pass/fail criteria for system suitability performance measures defined as peak area coefficient of variation

This paper reviews earnings management literature from the perspective of the financial statement analyst. The analyst will want to know if the company being analyzed is likely to have manipulated or managed the financial statement numbers, which numbers in the financial statements are most likely to have been managed, and the magnitude of the management. For several decades researchers have been documenting the manipulation or management of financial statement numbers. They have documented various management devices and a host of contexts that provide incentive to manage. Yet, this review reveals that an individual analyst, working to understand a single company, has little to guide him or her in assessing the probability that the firm under consideration has managed financial statement numbers, which numbers may have been managed, and to what extent they may have been managed. While much work has been done and many papers published, the hard work of making the research useful to the financial statement user remains to be done.

Children will probably always need to be sedated for some radiologic procedures, and controlling the state of consciousness of a child involves more than selecting an agent. The safe and effective sedation process emanates from a carefully designed sedation program. This program begins even before it is determined that sedation is necessary to properly perform a radiologic examination or procedure. Although several issues, controversies, and choices are involved, the context and dialogue of sedation must originate from the principle of protecting the health and safety of children.

Anesthesiologists have a history of being pioneers in health care. They have been in the forefront of exploring the properties of new medications and their uses. It has been anesthesiologists who have defined the parameters of use of not only anesthetics, such as the volatile agents, but also drugs, such as the synthetic narcotics, that have use outside the realm of operating room anesthesia. Anesthesiologists have also pioneered the use of drugs in new ways, such as nasal midazolam and transmucosal fentanyl. They have been eager and quick to explore the extended range of use of tools available to them. Anesthesiologists have in the last 30 years identified several opportunities to use their expertise to provide service outside the traditional operating room environment. In each instance, the service had two things in common. First, the knowledge and skills of the anesthesia community provided a new level of expertise. Second, at the time anesthesiologists became involved, there was a dearth of other practitioners serving the needs of patients. Anesthesiologists were among the first involved in critical care units , bringing their expertise in hemodynamic and respiratory management to an area that lacked a unified focus in the approach to acutely ill patients. As anesthesiologists increasingly provided support and care in this dynamic area, the potential for careers in critical care became obvious. In later years, anesthesiologists pioneered the principles and practice of acute and chronic pain management . Again, the potential for careers in this dynamic and overlooked area became noticeable. In both these forays outside the operating room, anesthesiologists brought a new level of patient care and service to the medical community. As these practitioners had success, however, other nonanesthesiologists became interested in these areas. Anesthesiologists began to find surgeons, internists, and pediatricians competing with them to provide service for these populations. Anesthesiologists increasingly found stiff competition to maintain their roles in areas where they had pioneered the principles of care. In many cases, anesthesiologists have been content to abandon their new areas and return to the operating room environment. Now, anesthesiologists have been asked to fill a new niche—advisor and provider of services outside the traditional operating room environment. The interest in our involvement has come for several reasons. There is an increase in diagnostic and invasive procedures performed by nonsurgeons outside the operating room. Radiologists, cardiologists, and gastroenterologists, among others, have expanded their practices by noninvasively performing evaluations and treating conditions that they previously had not done. Also, there is an increase in the number of pediatric patients undergoing procedures that require sedation or anesthesia, such as MR imaging. 15 Often the reason for sedation or general anesthesia being needed is that the child is frightened by factors such as a claustrophobic setting, the need for immobility, and the loud noise or discomfort that accompanies these studies. Another important factor is the increased appreciation by radiologists and others that there are benefits to providing sedation and proper analgesia for procedures that are either frightening or painful. Traditionally, the pediatric patient has been undertreated compared with adults in terms of both analgesia and sedation because of the fear of overdose or adverse reactions when administering medication to children. Practitioners of all types have now appreciated that the proper care of children involves provision of adequate sedation and analgesia as well as age and condition-appropriate monitoring and evaluation. Because of uncertainty about how to provide this care, many practitioners have increasingly looked to anesthesiologists to either provide this care or guide the practitioners' efforts to provide it themselves. Anesthesiologists are asked to assist with care outside the operating room in a variety of ways. In the most straightforward situation, the anesthesiologist is asked to provide general anesthesia in a manner similar to that provided in the operating room setting. In other cases, the anesthesiologist is asked to provide monitored anesthesia care (MAC) services for diagnostic and therapeutic procedures. In adults, this often has been associated with administering sedation in addition to monitoring the patient. In children, the usefulness of sedation is tempered by the need to sedate a child that is terrified versus the ease of providing general anesthesia. The anesthesia department of an institution may also be requested to assist with advice about care and development of institution-wide sedation practices that will be provided by nonanesthesiologists. This involvement has the disadvantage of removing the anesthesia service from providing clinical care under their own control (with a consequent loss of revenue). It does provide an opportunity to influence and improve pediatric care within the institution. This change in the type and level of care provided children can precipitate a major growth in sophisticated and humane management of children.

Cell membranes represent the "front line" of cellular defense and the interface between a cell and its environment. To determine the range of proteins and protein complexes that are present in the cell membranes of a target organism, we have utilized a "tagless" process for the system-wide isolation and identification of native membrane protein complexes. As an initial subject for study, we have chosen the Gram- negative sulfate-reducing bacterium Desulfovibrio vulgaris. With this tagless methodology, we have identified about two-thirds of the outer membrane- associated proteins anticipated. Approximately three-fourths of these appear to form homomeric complexes. Statistical and machine-learning methods used to analyze data compiled over multiple experiments revealed networks of additional protein−protein interactions providing insight into heteromeric contacts made between proteins across this region of the cell. Taken together, these results establish a D. vulgaris outer membrane protein data set that will be essential for the detection and characterization of environment-driven changes in the outer membrane proteome and in the modeling of stress response pathways. The workflow utilized here should be effective for the global characterization of membrane protein complexes in a wide range of organisms.