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Background: Statins are among the most commonly prescribed medications, and improve patient outcomes by lowering cholesterol levels, but also have side effects. Variations in statin response can be attributed to a handful of factors that include pharmacogenetics. Methods: While not a true review article, this work was written using various search engines and terms and previous and newly published Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statins to provide a historical perspective in addition to the current status of statin-related pharmacogenetics and future perspectives. Results: This article provides historical background on statins and associated adverse effects, reviews pharmacogenetic implications, applies clinical decision support, incorporates the latest CPIC guidelines and addresses future implications. Conclusion: Statins are a beneficial medication, but not without risk. Pharmacogenomics can help mitigate some risk factors. Clinical decision support, implementation, research and guidelines will continue to influence statin prescribing.

Genomic sequencing of healthy newborns to screen for medically important genetic information has long been anticipated but data around downstream medical consequences are lacking. Among 159 infants randomized to the sequencing arm in the BabySeq Project, an unanticipated monogenic disease risk (uMDR) was discovered in 18 (11.3%). We assessed uMDR actionability by visualizing scores from a modified ClinGen Actionability SemiQuantitative Metric and tracked medical outcomes in these infants for 3-5 years. All uMDRs scored as highly actionable (mean 9, range: 7-11 on a 0-12 scale) and had readily available clinical interventions. In 4 cases, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 cases provided risk stratification for future surveillance. In 8 cases, uMDRs prompted screening for multiple at-risk family members. These results suggest that actionable uMDRs are more common than previously thought and support ongoing efforts to evaluate population-based newborn genomic screening.

Reverse-phase protein array (RPPA) is a high-throughput antibody-based targeted proteomics platform that can quantify hundreds of proteins in thousands of samples derived from tissue or cell lysates, serum, plasma, or other body fluids. Protein samples are robotically arrayed as microspots on nitrocellulose-coated glass slides. Each slide is probed with a specific antibody that can detect levels of total protein expression or post-translational modifications, such as phosphorylation as a measure of protein activity. Here we describe workflow protocols and software tools that we have developed and optimized for RPPA in a core facility setting that includes sample preparation, microarray mapping and printing of protein samples, antibody labeling, slide scanning, image analysis, data normalization and quality control, data reporting, statistical analysis, and management of data. Our RPPA platform currently analyzes ∼240 validated antibodies that primarily detect proteins in signaling pathways and cellular processes that are important in cancer biology. This is a robust technology that has proven to be of value for both validation and discovery proteomic research and integration with other omics data sets.

Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays, however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes.

Background Somatostatin receptor type 5 (SSTR5) P335L is a hypofunctional, single nucleotide polymorphism of SSTR5 with implications in the diagnostics and therapy of pancreatic neuroendocrine neoplasms. The purpose of this study is to determine whether a SSTR5 P335L–specific monoclonal antibody could sufficiently differentiate pancreatic neuroendocrine neoplasms (PNENs) with different SSTR5 genotypes. Methods Cellular proliferation rate, SSTR5 mRNA level, and SSTR5 protein level were measured by performing MTS assay, a quantitative reverse transcription polymerase chain reaction study, Western blot analysis, and immunohistochemistry, respectively. SSTR5 genotype was determined with the TaqMan SNP Genotyping assay (Applied Biosystems, Foster City, CA). Results We found that the SSTR5 analogue RPL-1980 inhibited cellular proliferation of CAPAN-1 cells more than that of PANC-1 cells. Only PANC-1 (TT) cells, but not CAPAN-1 (CC) cells expressed SSTR5 P335L. In 29 white patients with PNENs, 38% had a TT genotype for SSTR5 P335L, 24% had a CC genotype for WT SSTR5, and 38% hada CT genotype for both SSTR5 P335L and WT SSTR5. Immunohistochemistry using SSTR5 P335L monoclonal antibody detected immunostaining signals only from the neuroendocrine specimens with TT and CT genotypes, but not those with CC genotypes. Conclusion A SSTR5 P335L monoclonal antibody that specifically recognizes SSTR5 P335L but not WT SSTR5 could differentiate PNENs with different SSTR5 genotypes, thereby providing a potential tool for the clinical diagnosis of PNEN.

The utility of a new instrument for rapid virus quantitation, the Virus Counter, was evaluated in a blind study conducted at three sites. This instrument is a substantially improved version of the original academic research instrument described previously by Stoffel et al. (2005a). The addition of hydrodynamic focusing, a self-contained fluidics system and customized software for system control and data analysis has resulted in a commercially viable and available design. Baculovirus samples were provided by Protein Sciences Corporation and blinded to InDevR and Baylor College of Medicine. Protein Sciences Corporation and Baylor College of Medicine analyzed the samples by plaque assay and InDevR analyzed the samples using the Virus Counter. Serial dilution of stock viruses into growth media and buffer allowed for comparison of measured versus intended concentrations. Direct log-scale comparison between pooled Virus Counter results and pooled plaque assay results indicated a linear relationship (slope = 1.1 ± 0.2, R2 = 0.86) with statistically significant Pearson correlation (r = 0.93, p < 0.001).

PurposeIn the author's experience, even veteran executives often make statements about competitive advantage that reflect either genuine misunderstanding or casual misuse of the term. This paper aims to offer a clear explanation of what constitutes competitive advantage so as to facilitate identification, assessment and strategizing.Design/methodology/approachThe paper proposes a definition of competitive advantage that differs from that proposed by many textbooks. It is based on the idea that competitive advantage can only be defined in terms of customer value.FindingsA number of cases are examined in the light of the customer value approach to identifying competitive advantage.Practical implicationsCompany executives learn to periodically engage in systematic information gathering regarding customer‐perceived competitive advantages.Originality/valueOrganizations that adopt this customer‐perceived approach to competitive advantage can make better assessments of where to expend their efforts and resources to outmaneuver their rivals and improve profitability.

Objective Erythropoietin (Epo) bioactivity is significantly reduced by modification of lysine residues with amine-reactive reagents, which are the most commonly used reagents for attaching polyethylene glycols (PEGs) to proteins to improve protein half-life in vivo. The aims of this study were to determine whether Epo bioactivity can be preserved by targeting attachment of maleimide-PEGs to engineered cysteine analogs of Epo, and to determine whether the pegylated Epo cysteine analogs have improved pharmacokinetic properties in vivo. Materials and Methods Thirty-four Epo cysteine analogs were constructed by site-directed mutagenesis and expressed as secreted proteins in baculovirus-infected insect cells. Following purification, monopegylated derivatives of 12 cysteine analogs were prepared using 20-kDa maleimide-PEGs. In vitro biological activities of the proteins were measured in an Epo-dependent cell proliferation assay. Plasma levels of insect cell–expressed wild-type Epo (BV Epo) and a pegylated Epo cysteine analog were quantitated by ELISA following intravenous administration to rats. Results Biological activities of 17 purified Epo cysteine analogs and 10 purified pegylated Epo cysteine analogs were comparable to that of BV Epo in the in vitro bioassay. The only pegylated cysteine analogs that displayed consistently reduced in vitro bioactivities were substitutions for lysine residues, PEG-K45C and PEG-K154C. The pegylated Epo cysteine analog had a slower initial distribution phase and a longer terminal half-life than BV Epo in rats, but the majority of both proteins were cleared rapidly from the circulation. Conclusions Targeted attachment of maleimide-PEGs to engineered Epo cysteine analogs permits rational design of monopegylated Epo analogs with minimal loss of in vitro biological activity. Insect cell–expressed Epo proteins are cleared rapidly from the circulation in rats, possibly due to improper glycosylation. Site-specific pegylation appears to improve the pharmacokinetic properties of Epo.

Monoclonal antibodies directed against human estrogen receptor (ER) and progesterone receptor (PR) have been used extensively for biochemical and immunohistochemical detection of receptors independent of hormone-binding assays. These antibodies have been valuable both for experimental work and for detection of receptors in clinical breast cancer specimens. The purpose of this study was to characterize the sensitivity and specificity of different antibodies for detection of PR by immunohistochemistry (IHC) of formalin-fixed paraffin breast carcinoma sections. The panel of twelve antibodies included two new ones (PgR636 and PgR1294) produced prospectively to be resistant to formalin fixation and paraffin embedding. Fifty-nine breast carcinomas, having known PR levels by biochemical ligand-binding assay, were used to prepare multitumor paraffin-embedded tissue blocks for characterization of the PR antibodies. Of all the antibodies tested, both PgR636 and PgR1294 stained the highest percentage of breast carcinomas known to be positive by the biochemical assay (95-98%) and they exhibited the highest concordance with the biochemical assay (88-90%). The PgR636 and PgR1294 antibodies, along with one other, PR 88, also gave the highest intensity of nuclear staining, while PgR636 and PgR1294 stained the highest mean percentage of tumor cell nuclei. Antigen retrieval was not necessary for PR immunostaining by PgR636 and PgR1294 in most tumors and other tissues examined, but did slightly increase the staining intensity. The majority of the other antibodies tested were highly dependent on antigen retrieval; only PR 88 and KD 68 antibodies approached the performance of PgR636 and PgR1294 without antigen retrieval. These results indicate that PgR636 and PgR1294 are optimal antibodies for IHC detection of PR in routine paraffin tissue blocks.

A detailed chemical kinetic model for oxidation of CS2 has been developed, on the basis of ab initio calculations for key reactions, including CS2 + O2 and CS + O2, and data from literature. The mechanism has been evaluated against experimental results from static reactors, flow reactors, and shock tubes. The CS2 + O2 reaction forms OCS + SO, with the lowest energy path involving crossing from the triplet to the singlet surface. For CS + O2, which yields OCS + O, we found a high barrier to reaction, causing this step to be important only at elevated temperatures. The model predicts low temperature ignition delays and explosion limits accurately, whereas at higher temperatures it appears to overpredict both the induction time for CS2 oxidation and the formation rate of [O] upon ignition. The predictive capability of the model depends on the accuracy of the rate constant for the initiation step CS2 + O2, which is difficult to calculate due to the intersystem crossing, and the branching fraction for CS2 + O, which is measured only at low temperatures. The governing reaction mechanisms are outlined on the basis of calculations with the kinetic model.

This article posits a framework that shows how market-based assets and capabilities are leveraged via market-facing or core business processes to deliver superior customer value and competitive advantages. These value elements and competitive advantages can be leveraged to result in superior corporate performance and shareholder value and reinvested to nurture market-based assets and capabilities in the future. The article also illustrates how resource-based view (RBV) and marketing considerations in the context of generating and sustaining customer value can refine and extend each other’s traditional frames of analysis. Finally, the article posits a set of research directions designed to enable scholars to further advance the integration of RBV and marketing from both theory-driven practice management as well as a problem-driven theory development perspectives.

BACKGROUND: Hepatorenal syndrome is a potentially reversible renal failure associated with severe liver disease. The disease is relatively common among people with decompensated cirrhosis. Terlipressin is a drug that increases the blood flow to the kidneys by constricting blood vessels. The previous version of this systematic review found a potential beneficial effect of terlipressin on mortality and renal function in people with cirrhosis and hepatorenal syndrome. OBJECTIVES: To assess the beneficial and harmful effects of terlipressin versus placebo/no intervention for people with cirrhosis and hepatorenal syndrome. SEARCH METHODS: We identified eligible trials through searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Science Citation Index Expanded, and manual searches until 21 November 2016. SELECTION CRITERIA: Randomised clinical trials (RCTs) involving participants with cirrhosis and type 1 or type 2 hepatorenal syndrome allocated to terlipressin versus placebo or no intervention. We allowed co‐administration with albumin administered to both comparison groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from trial reports and undertook correspondence with the authors. Primary outcomes were mortality, hepatorenal syndrome, and serious adverse events. We conducted sensitivity analyses of RCTs in which participants received albumin, subgroup analyses of participants with type 1 or type 2 hepatorenal syndrome, and Trial Sequential Analyses to control random errors. We reported random‐effects meta‐analyses with risk ratios (RR) and 95% confidence intervals (CI). We assessed the risk of bias based on the Cochrane Hepato‐Biliary Group domains. We graded the quality of the evidence using GRADE. MAIN RESULTS: We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non‐mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low‐quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low‐quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low‐quality evidence). Non‐serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low‐quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low‐quality evidence). We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1. Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies. AUTHORS' CONCLUSIONS: This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.

Lipolysis in adipocytes is regulated by phosphorylation of lipid droplet-associated proteins, including perilipin 1A and hormone-sensitive lipase (HSL). Perilipin 1A is potentially phosphorylated by cAMP(adenosine 3′,5′-cyclic monophosphate)-dependent protein kinase (PKA) on several sites, including conserved C-terminal residues, serine 497 (PKA-site 5) and serine 522 (PKA-site 6). To characterize perilipin 1A phosphorylation, novel monoclonal antibodies were developed, which selectively recognize perilipin 1A phosphorylation at PKA-site 5 and PKA-site 6. Utilizing these novel antibodies, as well as antibodies selectively recognizing HSL phosphorylation at serine 563 or serine 660, we used high content analysis to examine the phosphorylation of perilipin 1A and HSL in adipocytes exposed to lipolytic agents. We found that perilipin PKA-site 5 and HSL-serine 660 were phosphorylated to a similar extent in response to forskolin (FSK) and L-γ-melanocyte stimulating hormone (L-γ-MSH). In contrast, perilipin PKA-site 6 and HSL-serine 563 were phosphorylated more slowly and L-γ-MSH was a stronger agonist for these sites compared to FSK. When a panel of lipolytic agents was tested, including multiple concentrations of isoproterenol, FSK, and L-γ-MSH, the pattern of results was virtually identical for perilipin PKA-site 5 and HSL-serine 660, whereas a distinct pattern was observed for perilipin PKA-site 6 and HSL-serine 563. Notably, perilipin PKA-site 5 and HSL-serine 660 feature two arginine residues upstream from the phospho-acceptor site, which confers high affinity for PKA, whereas perilipin PKA-site 6 and HSL-serine 563 feature only a single arginine. Thus, we suggest perilipin 1A and HSL are differentially phosphorylated in a similar manner at the initiation of lipolysis and arginine residues near the target serines may influence this process.

Vasoconstrictor drugs may improve renal function in hepatorenal syndrome (HRS), but the effect on mortality has not been established. We therefore performed a systematic review of randomized trials on vasoconstrictor drugs for type 1 or type 2 HRS. Mortality was the primary outcome measure. Eligible trials were identified through electronic and manual searches. Intention-to-treat random effects meta-analyses were performed. Ten randomized trials on terlipressin alone or with albumin, octreotide plus albumin, and noradrenalin plus albumin were included. The total number of patients was 376. Overall, vasoconstrictor drugs used alone or with albumin reduced mortality compared with no intervention or albumin (relative risk [RR], 0.82; 95% confidence interval [CI], 0.70–0.96). In subgroup analyses, the effect on mortality was seen at 15 days (RR, 0.60; 95% CI, 0.37–0.97) but not at 30 days (RR, 0.74; 95% CI, 0.40–1.39), 90 days (RR, 0.89; 95% CI, 0.66–1.22), or 180 days (RR, 0.83; 95% CI, 0.65–1.05). Subgroup analyses stratified by the treatments assessed showed that terlipressin plus albumin reduced mortality compared with albumin (RR, 0.81; 95% CI, 0.68–0.97). The effect was seen in subgroup analyses of type 1 but not type 2 HRS. The remaining trials were small and found no beneficial or harmful effects of the treatments assessed. Conclusion: Terlipressin plus albumin may prolong short-term survival in type 1 HRS. The duration of the response should be considered when making treatment decisions and in the timing of potential liver transplantations. Considering the small number of patients included, the evidence does not allow for treatment recommendations regarding type 2 HRS or any of the remaining treatment comparisons assessed. (HEPATOLOGY 2009.)

Human progesterone receptors (PR) were overexpressed in Spodoptera frugiperda (Sf9) insect cells using a recombinant baculovirus system. Recombinant viruses were constructed that produced either full-length A (94K) or B (120K) forms of human PR, and each was expressed as a functional protein. Steroid and DNA binding activities were found to be indistinguishable from that of endogenous human PR in T47D breast cancer cells. Moreover, as analyzed by gel-mobility shift, recombinant PR-A and PR-B each bound to specific progesterone response elements in a strictly hormone-dependent manner. Native receptors expressed in Sf9 cells also exhibited structural properties similar to that of endogenous PR. Cytosolic PR (PR-A or PR-B), prepared in low salt buffer, sedimented on density gradients as an 8S oligomeric complex that was converted largely to 4S by treatment with 0.4 M NaCl. Immune isolation of the 8S cytosol PR complex and analysis of protein composition revealed the presence of two specific copurifying proteins of approximately 90K and 70K. The 90-K component was identified immunologically as heat shock protein 90. The 70-K component was not identified but is likely to be the insect equivalent of heat shock protein 70. Immune isolation of PR from Sf9 cells metabolically labeled with [32Pi], revealed that expressed PR was capable of being phosphorylated in insect cells. Hormone addition to Sf9 cells, however, did not stimulate the same increase in PR phosphorylation or upshift in mobility on sodium dodecyl sulfate gels that occurs with endogenous receptors in T47D cells. Thus some, but not all, phosphorylations occur with human PR expressed in Sf9 cells. These phosphorylation data, together with the fact that expressed PR required hormone for DNA binding, indicate that the hormone-dependent phosphorylation step responsible for PR upshifts on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is not required for receptor binding to DNA. The baculovirus expression system, therefore, may prove valuable in dissecting the functional role(s) for both hormone-dependent and hormone-independent PR phosphorylation.

SUMMARY This paper incorporates both diversification strategy and market structure variables in a study of corporate economic performance. A subsample of 128 firms from Rumelt's 1974 study was updated and utilized to investigate the possibility that market structure variables might modelrate or confound the diversification/performance relationship he reported. Study results indicate that performance differences could be demonstrated for some of Rumelt's categories, but, across the range of categories, a hypothesis of performance differences was rejected. As expected, categories associated with distinctly high or distinctly low economic performance were also associated with significant differences in a series of market structure variables. Researchers from several disciplines have sought to identify factors which influence corporate economic performance. Strategic management researchers have sought to relate corporate economic performance to the major direction-setting decisions made by the firm. For a new and growing firm, these decisions frequently relate to the degree and manner in which its product line and served market should be extended. For an older firm which wishes to continue to grow, the key decisions generally relate to the degree and manner in which it should diversify into different businesses (Chandler, 1962; Scott, 1971). Starting from a very different perspective, researchers in industrial organization economics have been guided by a conceptual framework which examines possible relationships among (1) the structure of the industry (or industries) in which the firm operates, (2) the conduct of the firms within that industry, and (3) the level of economic performance both of the individual firms and of their associated industries. This effort has yielded an extensive literature, much of which supports the proposition that firm profits are strongly influenced by the structure of the market or markets in which the firm operates (Scherer, 1970). These two streams of research have developed in large measure independently of each other. It is the purpose of the present research to incorporate both diversification strategy and market structure variables in a study of corporate economic performance.

This article defines the domain of strategy content research as embracing decisions about the goals, scope, and/or competitive strategies of a corporation or one of its business units. It reviews and evaluates several important streams of strategy content research (goals, diversification, strategic groups, market share, competitive strategy taxonomies, and stages of market evolution) in terms of the relationships among environmental conditions, strategic decisions, and performance results. It also makes recommendations for future research.

Care should be employed in applying BCG's prescriptions to "dog" businesses, particularly where the assumptions of the model are not met or where capability to implement the prescriptions is limite...