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Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This manuscript discusses the complexities of novel biomarker discovery, validation and international regulatory qualifications intended for clinical trial applications and shares specific examples from Pfizer Research and Development. As safety biomarkers become widely accepted and qualified by the regulatory agencies, they will increasingly be implemented in early clinical trials, play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development.
The pharmaceutical industry continues to face challenges in terms of declining productivity. The overall cost of drug development and time for most drugs to reach market has been increasing over the past several decades. From 1975 to 2015, the total expenditures per year for drug discovery and development rose approximately 5-fold while the number of United States Food and Drug Administration (FDA) new drug registrations per year remained relatively flat (Boyer et al., 2016). Substantial resources are being invested in research and development (R&D) across the industry into compounds that eventually fail. The current pharmaceutical R&D process results in only ~10% of the molecules entering phase 1 clinical trials reaching full approval by the FDA (Hay et al., 2014). This high rate of attrition is a key driver in reducing productivity and a significant challenge to the industry. There are a number of explanations for the decrease in productivity including a focus of the industry in areas of unmet medical need and novel biological mechanisms with high risk of failure, a higher entry bar for new drugs due to a competition with enhanced standard of care, higher regulatory hurdles, commercial and financial portfolio decisions and an increase in the complexity and cost of clinical trials (Roberts et al., 2014; Hay et al., 2014); however when a root-cause analysis was completed on 359 phase 3 and 95 new molecular entities and biologic license applications, safety and efficacy were shown to be the two primary causes for compound suspension (Hay et al., 2014).
The standard preclinical testing paradigm has markedly improved drug safety over the past 30 years. In 2000, the results from a multinational pharmaceutical survey and the outcome of an International Life Sciences Institute (ILSI) Workshop were reported and showed that 70% of human toxicity observed during clinical trials is predicted by preclinical studies (Olson et al., 2000). In addition, a 2013 study in Japan reported that 48% of adverse drug reactions observed in clinical trials were predicted by a comprehensive preclinical safety assessment (Ahuja and Sharma, 2014); and in 2017, the IQ Consortium created and utilized an industry-wide nonclinical to clinical translational database to report that animal studies not only have value in predicting human toxicities but also that an absence of toxicity in nonclinical studies predicts a similar outcome in the clinic (Monticello et al., 2017). However, the inability to predict failures before or early in clinical trials remains a main cause of attrition (Ahuja and Sharma, 2014) as failures in clinical safety not predicted in preclinical studies continue to be a major cause of compound termination (Clark and Steger-Hartmann, 2018). In addition, clinical failures due to toxicity are not limited to the early clinical portfolio but are also evident in late stage development and post-marketing surveillance (Waring et al., 2015). Thus while preclinical data has had a significant impact on improving clinical drug safety, failures due to toxicity remain a key challenge facing the industry.
The high rate of attrition and cost of drug development has prompted a surge in research in the area of biomarkers. According to the FDA/National Institute of Health (NIH)’s BEST (Biomarkers, Endpoints, and other Tools Resource) guide, a biomarker is a ‘defined characteristic that is measured as an indicator of normal biologic processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions (FDA, 2016a).’ Biomarkers are invaluable drug development tools utilized to better understand the translatability of preclinical findings into human adverse events and to better assess and monitor these findings in the clinic especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist. Several precompetitive consortia (e.g., PSTC, IMI) are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be implemented in preclinical studies and clinical trials to accelerate drug development. This paper discusses the complexities of discovering, validating and qualifying novel biomarkers to understand organ toxicities and to accelerate drug development decisions. Specific biomarker case examples are highlighted to describe their implementation in preclinical and early clinical development to characterize safety issues, understand mechanisms and monitor clinical safety. As safety biomarker assays are validated and qualified by the regulatory agencies, they will increasingly play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development. This, however, is not a trivial endeavor and the path to success may best be achieved through a collaborative effort among industry, academia and regulatory partners.
In 2004, the FDA’s Critical Path Initiative emphasized the need for innovation in drug development and suggested the use of biomarkers to evaluate and predict safety and effectiveness, provide informative links between mechanism of action and clinical utility, understand the translatability between preclinical species and humans, and serve as surrogate endpoints. With a focus on generating and implementing translatable biomarkers early in the drug development process, the goal was for the pharmaceutical industry to improve the high attrition rates and process inefficiencies in terms of cost and time observed across the industry (Haim, 2011; Woodcock and Woosley, 2008). In drug development, biomarkers categorized as target biomarkers assess the ability of the drug to reach and engage the target while mechanism biomarkers test the ability of the drug to induce the expected measurable molecular or cellular pharmacodynamics response. Finally, the linkage of the mechanism to the clinical response or efficacy is assessed by disease biomarkers or clinical activity scores. Ideally, safety biomarkers inform the presence or extent of toxicity and thus increase confidence in safety and the ability to predict, detect and monitor the progression of drug-induced toxicity. The ability of safety biomarkers to detect early toxicity, monitor onset and reversibility, and manage adverse effects observed in the clinic will determine its overall utility and impact in preclinical and clinical drug development. With the emergence of innovative technologies and a diverse set of in vitro and in vivo models, the development of novel safety biomarkers has evolved to include not only the singular measurement of circulating proteins but also expression profile signatures in blood/tissue, noninvasive imaging and genetic variations in DNA (Currid and Gallagher, 2008). Assays for these biomarkers range from exploratory fit for purpose to fully validated and qualified by the regulators for a specific context of use and the process of assay validation should be regarded as being continuous and evolving over-time. Pfizer has a strong commitment to developing and implementing translatable biomarker strategies within drug development including applying protein biomarkers for drug-induced toxicity in the stomach, kidney, skeletal muscle and liver and small molecules/metabolites as biomarkers for drug-induced toxicity to the liver and heart. Several biomarker case examples from Pfizer R&D efforts are included in this review. All procedures performed on animals used in Pfizer examples were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee.
A number of emerging urinary kidney markers including kidney injury molecule 1 (KIM-1), clusterin, microalbumin, trefoil factor 3, α-glutathione S-transferase, N-acetyl-β- D-glucosaminidase (NAG), neutrophil gelatinase-associated protein (NGAL) and osteopontin are currently being evaluated across the industry. Published studies of emerging markers show promising results in terms of increased sensitivity and specificity in comparison to the standard serum markers, serum creatinine (sCr) and blood urea nitrogen (BUN) (Chen et al., 2017; Dieterle et al., 2010a; Fuchs and Hewitt, 2011; Ozer et al., 2010; Koyner et al., 2010). Although sCr and BUN continue to be utilized as primary renal markers in clinical practice, they are considered poor indicators of early renal dysfunction due to limited sensitivity, remaining relatively unchanged until significant renal damage occurs. Consequently, further evaluation of novel urinary biomarkers of acute kidney injury (AKI) is warranted both in preclinical species and in humans. In order to better understand the performance of KIM-1, NGAL, and NAG in the rat and to provide foundational information for potential clinical studies, a rat study was conducted to compare the performance of these urinary biomarkers to the standard serum markers of AKI for the detection of nephrotoxicity (Burt et al., 2014). These 3 markers were selected after a prescreening of a larger panel based on performance after administration of polymyxin B, a polypeptide antibiotic used for the treatment of life-threatening Gram-negative bacterial infections. Use of these antibiotics in the clinic has been drastically limited due to drug-induced AKI and thus the further development of more-sensitive renal markers has the potential to not only impact drug development but also patient care in the clinic. In this study, rats (5/group) were dosed with 0.1, 0.4, 1, 4 or 10 mg/kg polymyxin B for 2 or 14 days and then necropsied. The highest tolerated dose was 4 mg/kg. Histopathological examination of kidneys from the treated rats showed minimal chronic progressive nephropathy (CPN) in a single rat at the 3 lowest doses, minimal to moderate tubular degeneration/regeneration in 4 animals dosed at 4 mg/kg/day and minimal tubular necrosis in a single rat at 10/mg/kg/day, indicative of drug-induced kidney injury. Of the biomarkers tested, only NGAL and KIM-1 produced dose-dependent statistically significant elevations, 13-fold and 3-fold respectively, as early as 48 hr post-dose. In comparison, sCr was not affected by polymyxin treatment and increases in BUN were small (1.3-fold) and were not dose-dependent. Urinary NGAL, however, was the most sensitive biomarker of AKI in this rat model, responding to the early onset of kidney injury observed with polymyxin. Since urinary NGAL levels reached a maximum increase at 48 hr post-dose (Fig. 1) that correlated with kidney histopathology, a 2-day study design was implemented for screening and rank ordering potential drug candidates utilizing NGAL as the biomarker for AKI. This design provided an important tool for selecting novel polymyxin B analogs with an improved kidney safety profile, affording an efficient, cost-effective drug development biomarker-driven strategy. This work also provided a basis for potential clinical studies to further evaluate the diagnostic utility of these urinary kidney biomarkers in patients (Burt et al., 2014).
NGAL response in rats to polymyxin B treatment. Urine was collected at intervals throughout the study with dosing on Day 0. Group mean values from the treated group were compared with the mean of the saline control group (* p < 0.05; ** p < 0.01).
Spontaneous histologic changes in laboratory animal species including rabbits can hamper accurate toxicologic interpretation in preclinical safety studies, especially if detailed study procedures are included. As early as 1924, publications described inflammatory heart findings with multifocal myocardial infiltrates of lymphocytes and/or macrophages in otherwise healthy rabbits (Sellers et al., 2017). In order to better characterize these myocardial findings and further understand the impact of study-related procedures on these findings, a large study was designed in New Zealand White female rabbits with either an increase (Group 1) or decrease (Group 2) in the number of study-related procedures and animal handling. Blood was collected for coagulation, hematology and clinical chemistry analysis including stress-associated serum biomarkers (epinephrine, norepinephrine, cortisol, and corticosterone) at various time points throughout the study for Group 1 and only at baseline and necropsy for Group 2 to minimize handling and procedures (Sellers et al., 2017). Group 1 animals with the increased procedures had a higher incidence of inflammation with degeneration/necrosis in cardiac myocytes than the animals from the minimal procedure group (Group 2). Serum stress markers including cortisol and norepinephrine showed the greatest response in Group 1 animals with peak values usually occurring 4 hr and 48 hr post-dose respectively (Fig. 2). This study provided further evidence that increased procedures and handling during study conduct exacerbates the frequency and severity of myocardial inflammatory findings and may be mediated by a stress response. Based on these findings, it was proposed that stress hormones, in particular norepinephrine and cortisol, could be utilized to assess the risk of the myocardial findings observed in rabbit toxicology studies (Sellers et al., 2017).
Norepinephrine and Cortisol levels in rabbits following dosing with saline on Days 29, 43 and 57 with blood collections pre-dose (vertical lines) and at 4, 24 and 48 hr post-dose. Data represents group means ± SEM.
Hyaluronic Acid (HA) is a polysaccharide located in the extracellular matrix. It is synthesized by mesenchymal cells and cleared almost exclusively by liver sinusoidal endothelial cells (SECs). Circulating HA levels have been shown to be elevated with structural and/or functional damage to the liver SEC and have shown promise in the clinic when studied for the noninvasive detection of sinusoidal obstruction syndrome (SOS). Currently the diagnosis of SOS in the clinic relies on nonspecific clinical and laboratory measures and/or events occurring late in the development of the disease including jaundice, painful hepatomegaly, weight gain and ascites. SOS has been reported in patients treated with antibody-calicheamicin conjugates including gemtuzumab ozogamicin and inotuzumab developed for acute myeloid leukemia and acute lymphoblastic leukemia, respectively (Guffroy et al., 2017). Liver toxicity based on elevated aspartate aminotransferases (AST) and bilirubin levels was observed with occasional hepatic SOS following treatment with these antibody-drug conjugates (ADCs). While these two ADCs have different monoclonal antibodies, they are composed of the same linker and calicheamicin payload. To further evaluate the mechanism of the adverse event and to identify potential safety biomarker to detect the damage throughout the disease course, an experiment was initiated to characterize the liver injury observed with the ADCs. Cynomologous monkeys were dosed with an antibody-calicheamicin conjugate containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab. Monkeys were dosed with up to 3 intravenous bolus injections 3 weeks apart and were necropsied 48 hr following the first dose on day 3 and 3 weeks after the third administration on day 63. Liver histopathology showed midzonal degeneration and loss of SECs on day 3 and variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Minimal increases in AST levels (up to 3.1x) were observed on day 4 and remained elevated over the duration of the study. HA levels (up to 8.5x) were elevated on day 3 and were sustained thru day 63 in all treated monkeys (Fig. 3) demonstrating the ability of this marker to detect early structural damage (day 3) and later functional impairment (day 63) of SECs. HA also showed good correlation to AST levels and microscopic liver findings throughout the study. Since HA, unlike AST, is linked mechanistically to SOS, it was proposed as a sensitive exploratory diagnostic marker of liver microvascular injury capable of non-invasive detection of SOS in the clinic (Guffroy et al., 2017).
Hyaluronic Acid (HA) and Aspartate Aminotransferase (AST) levels in monkeys following dosing (vertical lines) with an antibody-calicheamicin conjugate and linker. Data represents group means. Statistically significant changes were observed for both HA and AST when compared to vehicle controls at all time points following dosing.
Gastrin is secreted from the stomach and plays a key role in the regulation of gastric acid secretion. Gastrin is synthesized in special endocrine cells (G cells) primarily in the antral region of the gastric mucosa and binds receptors found predominantly on parietal cells stimulating gastric juice secretion, the best-known of which is hydrochloric acid (HCl) (Henderson, 2001). The capacity of the stomach to secrete HCl normally is directly proportional to the parietal cell number. High levels of circulating gastrin can occur when the pH of the stomach is high while gastrin secretion by antral G cells is inhibited by the direct action of acid on the G cells. When the stomach lining is damaged and unable to produce and release acid, gastrin continues to be secreted from the fundus and circulating levels rise. Changes in serum gastrin have been shown to be predictive of the functional status of the antral mucosa, making it attractive as a potential biomarker of drug-induced stomach toxicity (Graham et al., 2006; Nicolaou et al., 2014). To further evaluate gastrin as a potential marker of stomach toxicity, a 28-day dog study was conducted with a compound associated with gastric effects. Minimal to moderate atrophy and minimal degeneration of the fundic mucosa were seen at histologic examinations. Mean serum gastrin levels in the treated animals were 23x higher than concurrent controls (Fig. 4) and were attributed to the lack of acid production by the damaged parietal cells, indicating a failure of the feedback mechanism that controls the acid output in the stomach. In individual dogs, serum gastrin levels were elevated (up to 52x) compared to concurrent controls and these levels correlated with the severity of the adverse microscopic stomach findings. Based on these data, serum gastrin was proposed as a non-invasive stomach-specific biomarker to monitor for stomach toxicity in the clinic.
Gastrin concentrations in a 28 Day Dog Study following treatment with vehicle or a compound associated with gastric effects. Data represents group means ± SD.
Many of the safety biomarkers currently considered conventional and measured routinely in both preclinical and clinical drug development as well as in clinical practice were established prior to the implementation of a formal regulatory qualification process. They were accepted based on scientific community consensus, i.e. review of datasets published in peer reviewed journals, experience in clinical practice, and recommendations from professional medical associations. For example, cardiac troponin (cTn) was recognized as a clinical biomarker of acute myocardial infarction by the American College of Cardiology and the European Society of Cardiology in 2000 (Jaffe, 2001) just thirteen years after the development of the first troponin assay (Danese and Montagnana, 2016). Diagnostic criteria were recommended based on published literature and clinical experience with an acknowledgement that the criteria should continue to evolve as additional knowledge was gained (Jaffe, 2001). Subsequent to clinical acceptance, cTn was evaluated as a preclinical marker by the Health and Environmental Sciences Institute (HESI) Cardiac Troponins Biomarker Working Group (Reagan, 2010) and received full qualification from the FDA in 2012 based solely on evidence from peer reviewed scientific literature (FDA, 2012).
Another pathway to biomarker approval is through biomarker evaluation for a drug-specific application. In this case, the biomarker may only be used in a single drug development program and the data required to support the use of the biomarker in the program is determined by the sponsor communicating directly with the regulatory reviewing division accountable for the program (Mattes and Goodsaid, 2018). Utilization of this pathway limits the knowledge of the biomarker’s performance and intended use for the specified program but may enable time saving and efficient progression of a promising compound into clinical development.
In order for a biomarker to be approved for multiple drug development programs, it must pass the rigor of the full regulatory qualification process. Qualification is defined by the FDA as ‘a conclusion that within the stated context of use, the results of assessment with a drug development tool (biomarker) can be relied upon to have a specific interpretation and application in drug development and regulatory review (FDA, 2014).’ Biomarkers reaching this milestone can support regulatory decisions in drug development programs for the approved context of use (COU) in clinical trials. According to the FDA, the COU is ‘a comprehensive and clear statement that describes the manner of use, interpretation, and purpose of use of the biomarker in drug development (FDA, 2016b).’ With the enactment of the 21st Century Cures Act in December 2016, an updated multi-stage biomarker qualification process was established which included three submission stages: the Letter of Intent, the Qualification Plan and the Full Qualification Package. The Biomarker Qualification Program is one of the Drug Development Tools created by the Center of Drug Evaluation and Research to provide a framework for development and regulatory acceptance of biomarkers for use in drug development programs. Similar programs outlining processes for the submission and review of data supporting the approval of new biomarkers are also in place at the European Medicines Agency (EMA) and the Japanese Pharmaceutical and Medical Devices Agency (PDMA). While the agencies work closely on qualification efforts, a fully harmonized approach has yet to be established. However, these regulatory pathways provide a process to review, evaluate and adopt new tools into regulatory decision making in drug development and facilitate consensus science and acceptance of the biomarker’s proposed COU in drug development (Dennis et al., 2013).
To better understand the elements of biomarker qualification, a framework for evidentiary standards for biomarker qualification was recently proposed under the auspices of the Foundation for the National Institute of Health (FNIH) Biomarkers Consortium with representatives from FDA, NIH, industry, patient groups and academia. Five components were incorporated into the framework and included: 1) defining a statement of need (knowledge gap or drug development need) that the biomarker intends to address; 2) defining the COU; 3) assessing the benefits in light of the COU; 4) assessing the risks with regards to the COU and 5) defining the evidentiary criteria required to support the COU (Leptak et al., 2017). The COU determines the level of evidence needed both for the validation of analytical technology employed and for the qualification of the biomarker. The greater the risk to human health of an incorrect decision based on the use of the biomarker, the greater the level of evidence required for the qualifying the biomarker for that COU (Dennis et al., 2013). The assessment of the evidentiary criteria is intended to be utilized as a ‘communication tool for gaining alignment between submitters and FDA reviewers at several key milestones for a biomarker development plan: (i) initial discussions to align expectations; (ii) purposeful interim progress updates to ensure that evidence expectations have been met before proceeding further; and (iii) review evaluation to support the qualification outcome (Leptak et al., 2017).’ The ultimate goal of this effort was to improve the quality of submissions to the FDA, facilitate a level of predictability in the qualification process, and provide clarity as to the type and level of evidence needed to support a biomarker’s COU (Leptak et al., 2017).
Due to the complexity of the qualification process and considerable resources required to reach full qualification of a biomarker, efforts are primarily focused in consortia such the HESI, the PSTC, the IMI Safer and Faster Evidence-based Translation (SAFE-T) consortium and more recently the IMI Translational Safety Biomarker Pipeline (TransBioLine) consortium. To date, 4 safety biomarker submissions have been successful. This included 2 preclinical qualifications for a number of emerging urinary nephrotoxicity biomarkers and one nonclinical qualification of circulating cardiac troponins as indicators of cardiotoxicity. Earlier this year, the first clinical safety biomarker submission reached approval for a panel of urinary biomarkers to aid in the detection of kidney tubular injury in phase 1 trials in healthy volunteers (FDA, 2018b).
GLDH has been shown to be a sensitive measure of hepatotoxicity in preclinical species and in humans (Giffen et al., 2003; Schomaker et al., 2013) and is currently going through the regulatory qualification process sponsored by the PSTC and the Duchenne Regulatory Science Consortia (D-RSC). The gold standard biomarker for the diagnosis of liver injury is alanine aminotransferase (ALT). However since ALT is also present in myocytes, serum ALT activities can increase with muscle injury; thus, the development of more specific biomarkers for drug-induced liver injury (DILI) is needed. For this qualification, the proposed COU for GLDH is that ‘elevated serum GLDH activity is a measure of hepatocellular injury, and can be used in healthy subjects and patients as an adjunct to ALT, the current standard biomarker used to assess hepatocellular injury, in all stages of drug development. In a clinical situation when ALT increases are observed, GLDH can lend weight of evidence to confirm or rule out hepatocellular injury (EMA, 2017).’ The qualification submission will include a full technical validation of the assay and an evaluation of the clinical relevance of the biomarker, e.g., added value relative to aminotransferase activity, correlation to histopathology in a preclinical species and exploratory and confirmatory analyses in clinical subjects with regulatory guidance. The evaluation of clinical relevance includes establishing reference ranges for healthy subjects and evaluating the influence of gender and age, confirming GLDH as a sensitive biomarker of liver injury and establishing medically relevant cutoffs for DILI, and establishing GLDH as a specific biomarker of hepatocellular injury in comparison to ALT. In March of 2017, a joint FDA and EMA biomarker qualification consultation meeting was held for GLDH. This meeting provided regulatory support for using organ injury induced by diseases with a wide range of etiologies as approximation of chemical-induced organ injury for evaluation of performance of novel biomarkers. This was a paradigm shift in the development of safety biomarkers, since it eliminates the need for lengthy clinical trials and improves feasibility and efficiency of biomarker research. The EMA issued a Letter of Support (LoS) in November 2017 demonstrating the Agency’s support of the qualification and provided additional feedback regarding data needed for achieving full qualification of GDLH as a “Drug Development Tool”. This LoS not only recognized the potential value of GLDH as a liver specific biomarker of hepatocellular injury to address important unmet medical need but also endorsed data interpretation including medically relevant levels of GLDH (2.5x and 5x above upper limit of normal) that were established as part of the qualification effort (EMA, 2017). This qualification effort, initiated in 2015 supported by Pfizer internal exploratory data, is expected to reach fruition in 2019 with the submission of the full qualification package. The formal qualification of GLDH as a liver specific biomarker of hepatocellular injury will not only allow for the broad application of GLDH across programs, but will also enable the diagnosis of the onset of liver disease in subjects with underlying muscle impairments, which is an important unmet medical need widely recognized by the medical community. To this end, Pfizer has partnered with the PSTC, the Duchenne Regulatory Science Consortium (D-RSC), Roche, the maker of the research grade GLDH assay, and FDA to validate the GLDH assay as an in vitro diagnostic (IVD) which would allow the assay to be utilized in clinical practice and lead to an improved standard of care for patients living with muscle disease.
Serum AST and creatine kinase (CK) have been used for decades as the primary biomarkers for skeletal muscle (SKM) injury as a measure of myocyte degeneration/necrosis. However, these markers lack tissue specificity for SKM and sensitivity for SKM degeneration/necrosis in both rats and humans. In 2010, the PSTC’s Skeletal Muscle Working Group was formed with a goal to identify and qualify novel safety biomarkers of drug-induced SKM injury that would add value to the current markers, CK and AST, for monitoring SKM injury. The muscle injury panel (MIP) selected for evaluation included skeletal troponin I, myosin light chain, fatty acid-binding protein and creatine kinase measured by a mass assay. These markers were assessed in 34 rat studies and were shown to outperform AST and CK (enzymatic assay) individually and as a panel in terms of sensitivity and specificity and/or added value for the diagnosis of drug-induced SKM injury defined as myocyte degeneration/necrosis (Burch et al., 2016). Based on this data, the FDA and EMA issued Letters of Support (EMA, 2015; FDA, 2015) for the use of these markers in preclinical development and encouraged their use in early clinical trials in an exploratory context. This endorsement encouraged Burch et al. (Burch et al., 2015) to evaluate the translatability of these markers in patients with DMD and other muscular diseases and their ability to monitor disease progression and the response to treatment. In this study, the MIP biomarker responses was compared to current clinical assessments including CK activity, ambulatory status and cardiac function and were shown to not only better reflect the patients’ disease state compared to CK activity but also correlate with clinical endpoints in patients with DMD and other muscular diseases. These preclinical and clinical evaluations provided support for a qualification submission which is currently in progress. This qualification, sponsored by the PSTC, will evaluate the marker’s ability to monitor SKM degeneration/necrosis in conjunction with AST and CK enzymatic activity in early clinical trials and encourage the utilization of the MIP markers throughout drug development to improve patient safety in clinical trials (Burch et al., 2016). In support of the qualification effort, Pfizer has included the MIP markers on a number of clinical trials as exploratory biomarkers; however, the utility of the markers as SKM safety or efficacy end points to these therapeutic interventions has yet to be determined (Goldstein, 2017).
In 2008 the first formal qualification of preclinical safety biomarkers was granted by the FDA (FDA, 2008) and EMA (EMA, 2008a) followed by PMDA in 2010 (PMDA, 2010) for seven urinary safety biomarkers submitted by the PSTC. In 2010, a qualification was rendered by the FDA for the two preclinical urinary biomarkers, clusterin, renal papillary antigen-1 (RPA-1), submitted by HESI and in 2018 the FDA qualified the first clinical safety biomarkers, a set of six urinary markers interpreted as a Composite Measure (CM) (FDA, 2018a) submitted by PSTC. In all cases, the biomarkers are to be used in conjunction with the traditional measures, serum creatinine (sCr) and blood nitrogen urea (BUN), for the evaluation of nephrotoxicity. sCr and BUN are both insensitive and nonspecific, changing only after significant injury and with a time delay relative to the onset of injury (Vaidya et al., 2008) limiting their ability to accurately estimate injury onset and the severity of the dysfunction following injury (Ferguson et al., 2008).
The seven biomarkers included in the PSTC preclinical submission included KIM-1, clusterin (CLU), albumin, total protein, β2-microglobulin, cystatin C and trefoil factor 3 (TFF3) in urine. The submission contained data and data interpretation from a number of rat studies, a review of the scientific literature in humans (KIM-1, albumin, total protein, cystatin C, and β2-microglobulin), COUs for each biomarker (Dieterle et al., 2010b) and key conclusions. The PSTC put forth three specific biomarker claims in the submission. First, urinary KIM-1, CLU, and albumin can individually outperform and add information to BUN and sCr assays as early diagnostic biomarkers of drug-induced kidney tubular alterations in rat toxicology studies. Second, urinary TFF3 can add information to BUN and sCr assays in rat toxicology studies as an early diagnostic biomarker of drug-induced acute kidney injury tubular alterations. Third, total urinary protein, cystatin C, and β2-microglobulin can individually outperform sCr assays and add information to BUN and sCr assays as early diagnostic biomarkers in rat toxicology studies of acute drug-induced glomerular alterations or damage resulting in impairment of kidney tubular reabsorption (Dieterle et al., 2010b). In addition, the PSTC claimed that this rat data taken together with the published peer-reviewed clinical data supported the voluntary use of KIM-1, albumin, total protein, cystatin C, and β2-microglobulin as bridging markers for early clinical trials on a case-by-case basis when concerns are generated in GLP animal toxicology studies. During the qualification effort, the FDA and EMA provided feedback regarding submission gaps, statistical considerations and preliminary conclusion statements (EMA, 2008b) which culminated in letters of acceptance for the preclinical qualifications from both agencies. In 2008, the FDA and EMA concluded that the urinary kidney biomarkers KIM-1, CLU, albumin, total protein, β2-microglobulin, cystatin C and TFF3 were acceptable for the detection of acute drug-induced kidney injury in rats to be included along with traditional clinical chemistry markers and histopathology in toxicology studies. The EMA also stated that while it was worthwhile exploring their utility in early clinical trials as clinical biomarkers, until additional data was available “to correlate the biomarkers with the evolution of the nephrotoxic alternations, and their reversibility, their general use for monitoring nephrotoxicity in clinical setting cannot be recommended (EMA, 2008b).” Based on this data, in 2010 the PDMA announced the first biomarker qualification decision under the new consultation process on pharmacogenomics/biomarkers use in Japan. These recommendations, consistent with the concept of a progressive biomarker qualification, prompted the generation and submission of additional preclinical and clinical data to expand the COU.
In an expanded effort, the SAFE-T and PSTC consortia continued the work on urinary kidney injury biomarkers by evaluating the performance of KIM-1, CLU, NGAL, albumin, total protein, cystatin C, α -glutatione S-transferase and urinary osteopontin in clinical trials. The trials included a study in healthy volunteers, an exploratory study with cisplatin-treated cancer patients, and a study in patients undergoing coronary angiography. The markers selected are localized in different regions of the nephron thus the panel was expected to respond to a variety of nephrotoxicants. Based on the readout from these studies, both the FDA and EMA issued Letters of Support in 2016 encouraging the exploratory use of these markers as biomarkers of renal tubular injury in early clinical trials to be used in conjunction with traditional biomarkers and clinical and nonclinical findings (FDA, 2016c; EMA, 2016).
Also in 2016, the FNIH Biomarker Consortium and the PSTC submitted a qualification submission for a kidney injury biomarker panel to be interpreted as a Composite Measure (the geometric mean of the fold change from baseline of the six urine biomarkers normalized to urine creatinine) of the following six biomarkers: KIM-1, CLU, cystatin C, NAG, NGAL and urinary osteopontin. According to the COU, “the safety composite biomarker panel is to be used in conjunction with traditional measures to aid in the detection of kidney tubular injury in phase 1 trials in healthy volunteers when there is an a priori concern that a drug may cause renal tubular injury in humans (FDA, 2018a).” The qualification strategy included a nonclinical phase, a clinical exploratory phase and a clinical confirmatory phase with a cisplatin study in cancer patients and an aminoglycoside study in cystic fibrosis patients. Based on this data, this panel, interpreted as a CM, was the first clinical safety biomarker to be qualified by the FDA. Following on the success of this qualification, the FNIH and PSTC have continued their partnership and have submitted a letter of intent to FDA, EMA and PDMA to further qualify the panel of biomarkers based on the individual biomarker response thus expanding on the qualified CM COU.
Significant progress has been made towards implementing translational safety biomarker strategies into the drug development portfolio. Several pharmaceutical companies have been adopting exploratory biomarkers in their preclinical and clinical drug development programs and contributing to consortia led qualification efforts. While much progress has been made towards the qualification of biomarkers for some organ injures including liver, kidney, and muscle, significant gaps remain for other target organs such as biomarkers of vascular injury in humans, sensitive biomarkers of pancreatic injury, circulating biomarkers of testicular toxicity, and biomarkers of injury to the central nervous system. Because the process of biomarker development is complex and requires considerable resources (Gerlach et al., 2018), these efforts will best be pursued by consortia such as PSTC and IMI. Prior to widespread acceptance, each biomarker must undergo a rigorous assay validation; demonstrate relevance to humans and an association with clinical endpoints reproducibly in multiple studies and gain consensus regarding the level of evidence needed to support a qualification for the stated COU. Due to the complexity and feasibility challenges of prospective randomized drug intervention clinical trials, alternative sample collection strategies like the prospective collection of samples of organ damage etiologies from patients undergoing hospital visits employed in the GLDH qualification effort, need to be considered. These disease patient populations, once identified, can serve as surrogates for drug-induced organ injury to evaluate biomarker performance as long as common molecular and mechanistic pathways are shared between the disease and organ toxicity of interest. The prospective collection and storage of samples from clinical trials conducted for drug development is also an option (Aubrecht et al., 2013). As safety biomarkers become accepted and qualified by the regulatory agencies, they will increasingly play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development, leading to the realization of our most critical goal: delivering the right dose of the right medicines to the right patients at the right time (Gerlach et al., 2018).
Safety and tolerability of newly approved drug candidates still remains a key concern in drug development leading to black box warnings and withdrawals of promising therapeutics. A major hurdle is the lack of validated and qualified safety biomarkers that accurately diagnose, predict and inform mechanism of organ toxicities. Regulatory qualification of a safety biomarker is critical for routine application in clinical development. To address this hurdle and the complexities in biomarker development, considerable resources and partnerships across industry, academia, and regulators is needed. Although tremendous progress has been made towards identifying and implementing translational safety biomarkers for organ toxicities such as kidney and liver, significant gaps still exist to monitor toxicities for other common target organs such as pancreas, central nervous system, testis, and skeletal muscle. With the enactment of 21st Century Cures Act, the FDA biomarker qualification process has become more streamlined. In addition to developing a clear frame work for regulatory qualification, there is optimism towards expediting the qualification process so that promising therapeutics can be safely tested in the clinic and ultimately provide patients access to new medicines.
Ahuja, V. and Sharma, S. (2014): Drug safety testing paradigm, current progress and future challenges: an overview. J. Appl. Toxicol., 34, 576-594.
Aubrecht, J., Schomaker, S.J. and Amacher, D.E. (2013): Emerging hepatotoxicity biomarkers and their potential to improve understanding and management of drug-induced liver injury. Genome Med., 5, 85-87.
Boyer, S., Brealey, C. and Davis, A. (2016): Attrition in Drug Discovery and Development. John Wiley and Sons Inc.
Burch, P.M., Greg Hall, D., Walker, E.G., Bracken, W., Giovanelli, R., Goldstein, R., Higgs, R.E., King, N.M., Lane, P., Sauer, J.M., Michna, L., Muniappa, N., Pritt, M.L., Vlasakova, K., Watson, D.E., Wescott, D., Zabka, T.S. and Glaab, W.E. (2016): Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats. Toxicol. Sci., 150, 247-256.
Burch, P.M., Pogoryelova, O., Goldstein, R., Bennett, D., Guglieri, M., Straub, V., Bushby, K., Lochmüller, H. and Morris, C. (2015): Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy. J. Neuromuscul. Dis., 2, 241-255.
Burt, D., Crowell, S.J., Ackley, D.C., Magee, T.V. and Aubrecht, J. (2014): Application of emerging biomarkers of acute kidney injury in development of kidney-sparing polypeptide-based antibiotics. Drug Chem. Toxicol., 37, 204-212.
Chen, Y., Dale Thurman, J., Kinter, L.B., Bialecki, R. and Eric McDuffie, J. (2017): Perspectives on using a multiplex human kidney safety biomarker panel to detect cisplatin-induced tubular toxicity in male and female Cynomolgus monkeys. Toxicol. Appl. Pharmacol., 336, 66-74.
Clark, M. and Steger-Hartmann, T. (2018): A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans. Regul. Toxicol. Pharmacol., 96, 94-105.
Currid, C.A. and Gallagher, W.M. (2008): Selected highlights of the Third Annual Biomarkers Congress: from discovery to validation in the drug development arena. Expert Opin. Med. Diagn., 2, 1091-1094.
Danese, E. and Montagnana, M. (2016): An historical approach to the diagnostic biomarkers of acute coronary syndrome. Ann. Transl. Med., 4, 194.
Dennis, E.H., Walker, E.G., Baker, A.F. and Miller, R.T. (2013): Opportunities and challenges of safety biomarker qualification: perspectives from the predictive safety testing consortium. Drug Dev. Res., 74, 112-126.
Dieterle, F., Perentes, E., Cordier, A., Roth, D.R., Verdes, P., Grenet, O., Pantano, S., Moulin, P., Wahl, D., Mahl, A., End, P., Staedtler, F., Legay, F., Carl, K., Laurie, D., Chibout, S.D., Vonderscher, J. and Maurer, G. (2010a): Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat. Biotechnol., 28, 463-469.
Dieterle, F., Sistare, F., Goodsaid, F., Papaluca, M., Ozer, J.S., et al. (2010b): Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat. Biotechnol., 28, 455-462.
EMA (2008a): Final Report on the pilot Joint EMEA/FDA VXDS experience on Qualification of Nephrotoxicity biomarkers.
EMA (2008b): Final Report on the Pilot Joint EMEA/FDA VXDS Experience on Qualification of Nephrotoxivity Biomarkers.
EMA (2015): Letter of Support for Skeletal Muscle Injury Biomarkers.
EMA (2016): Letter of support for drug-induced renal tubular injury. Biomarkers.
EMA (2017): Letter of Support for Glutamate Dehydrogenase, a biomarker of hepatocellular liver injury.
FDA (2008): Qualification Letter for Seven Biomarkers of Drug-Induced Nephrotoxicity in Rats.
FDA (2012): Biomarker Qualificaton Decision for the Use of Circulating Cardiac Troponins in NonClinical Drug Development in Rats, Dogs and Monkeys.
FDA (2014): Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools.
FDA (2015): FDA Letter of Support for Serum and Plasma Biomarkers: Myosin Light Chain 3 (Myl3), Skeletal Muscle Troponin I (sTNI), Fatty Acid Binding Protein 3 (FABP3), Creatine Kinase, Muscle Type (CK-M, the Homodimer CK-MM).
FDA (2016a): BEST (Biomarkers, EndpointS, and other Tools) Resource.), Silver Spring (MD): Food and Drug Administration (US); Bethesda (MD): National Institutes of Health (US).
FDA (2016b): FDA Case Study: A Collaborative Effort to Qualify a Novel Biomarker.
FDA (2016c): Safer and Faster Evidence-based Translation (SAFE-T) Consortium Letter of Support for Drug-induced Renal Tubular Injury Biomarkers.
FDA (2018a): Biomarker Qualification Determination Letter for Renal Biomarkers.
FDA (2018b): Biomarker Qualification Program: List of Qualified Biomarkers.
Ferguson, M.A., Vaidya, V.S. and Bonventre, J.V. (2008): Biomarkers of nephrotoxic acute kidney injury. Toxicology, 245, 182-193.
Fuchs, T.C. and Hewitt, P. (2011): Preclinical perspective of urinary biomarkers for the detection of nephrotoxicity: what we know and what we need to know. Biomarkers Med., 5, 763-779.
Gerlach, C.V., Derzi, M., Ramaiah, S.K. and Vaidya, V.S. (2018): Industry Perspective on Biomarker Development and Qualification. Clin. Pharmacol. Ther., 103, 27-31.
Giffen, P.S., Turton, J., Andrews, C.M., Barrett, P., Clarke, C.J., Fung, K.W., Munday, M.R., Roman, I.F., Smyth, R., Walshe, K. and York, M.J. (2003): Markers of experimental acute inflammation in the Wistar Han rat with particular reference to haptoglobin and C-reactive protein. Arch. Toxicol., 77, 392-402.
Goldstein, R.A. (2017): Skeletal Muscle Injury Biomarkers: Assay Qualification Efforts and Translation to the Clinic. Toxicol. Pathol., 45, 943-951.
Graham, D.Y., Nurgalieva, Z.Z., El-Zimaity, H.M., Opekun, A.R., Campos, A., Guerrero, L., Chavez, A. and Cardenas, V. (2006): Noninvasive versus histologic detection of gastric atrophy in a Hispanic population in North America. Clin. Gastroenterol. Hepatol., 4, 306-314.
Guffroy, M., Falahatpisheh, H., Biddle, K., Kreeger, J., Obert, L., Walters, K., Goldstein, R., Boucher, G., Coskran, T., Reagan, W., Sullivan, D., Huang, C., Sokolowski, S., Giovanelli, R., Gerber, H.P., Finkelstein, M. and Khan, N. (2017): Liver Microvascular Injury and Thrombocytopenia of Antibody-Calicheamicin Conjugates in Cynomolgus Monkeys-Mechanism and Monitoring. Clin. Cancer Res., 23, 1760-1770.
Haim, A. (2011): Biomarkers in Drug development: A Useful Tool but Discrepant results may have a major Impact. In: Intech.
Hay, M., Thomas, D.W., Craighead, J.L., Economides, C. and Rosenthal, J. (2014): Clinical development success rates for investigational drugs. Nat. Biotechnol., 32, 40-51.
Henderson, A.R. (2001): Gastric, Pancreatic, and Intestinal Function. In: Tietz Fundamentals of Clincial Chemistry (Burtis, C.a.A., Edward, ed.), pp. 774-776, Saunders, Philadelphia Pennsylvania.
Jaffe, A.S.; World Health Organization; European Society of Cardiology; American College of Cardiology. (2001): New standard for the diagnosis of acute myocardial infarction. Cardiol. Rev., 9, 318-322.
Koyner, J.L., Vaidya, V.S., Bennett, M.R., Ma, Q., Worcester, E., Akhter, S.A., Raman, J., Jeevanandam, V., O’Connor, M.F., Devarajan, P., Bonventre, J.V. and Murray, P.T. (2010): Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin. J. Am. Soc. Nephrol., 5, 2154-2165.
Leptak, C., Menetski, J.P., Wagner, J.A., Aubrecht, J., Brady, L., Brumfield, M., Chin, W.W., Hoffmann, S., Kelloff, G., Lavezzari, G., Ranganathan, R., Sauer, J.M., Sistare, F.D., Zabka, T. and Wholley, D. (2017): What evidence do we need for biomarker qualification? Sci. Transl. Med., 9, 417.
Mattes, W.B. and Goodsaid, F. (2018): Regulatory landscapes for biomarkers and diagnostic tests: Qualification, approval, and role in clinical practice. Exp. Biol. Med. (Maywood), 243, 256-261.
Monticello, T.M., Jones, T.W., Dambach, D.M., Potter, D.M., Bolt, M.W., Liu, M., Keller, D.A., Hart, T.K. and Kadambi, V.J. (2017): Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: the IQ consortium nonclinical to clinical translational database. Toxicol. Appl. Pharmacol., 334, 100-109.
Nicolaou, A., Thomas, D., Alexandraki, K.I., Sougioultzis, S., Tsolakis, A.V. and Kaltsas, G. (2014): Predictive value of gastrin levels for the diagnosis of gastric enterochromaffin-like cell hyperplasia in patients with Hashimoto’s thyroiditis. Neuroendocrinology, 99, 118-122.
Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., Lilly, P., Sanders, J., Sipes, G., Bracken, W., Dorato, M., Van Deun, K., Smith, P., Berger, B. and Heller, A. (2000): Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol., 32, 56-67.
Ozer, J.S., Dieterle, F., Troth, S., Perentes, E., Cordier, A., Verdes, P., Staedtler, F., Mahl, A., Grenet, O., Roth, D.R., Wahl, D., Legay, F., Holder, D., Erdos, Z., Vlasakova, K., Jin, H., Yu, Y., Muniappa, N., Forest, T., Clouse, H.K., Reynolds, S., Bailey, W.J., Thudium, D.T., Topper, M.J., Skopek, T.R., Sina, J.F., Glaab, W.E., Vonderscher, J., Maurer, G., Chibout, S.D., Sistare, F.D. and Gerhold, D.L. (2010): A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nat. Biotechnol., 28, 486-494.
PMDA (2010): PDMA Qual Letter for Rat Kidney Biomarkers.
Reagan, W.J. (2010): Troponin as a biomarker of cardiac toxicity: past, present, and future. Toxicol. Pathol., 38, 1134-1137.
Roberts, R.A., Kavanagh, S.L., Mellor, H.R., Pollard, C.E., Robinson, S. and Platz, S.J. (2014): Reducing attrition in drug development: smart loading preclinical safety assessment. Drug Discov. Today, 19, 341-347.
Schomaker, S., Warner, R., Bock, J., Johnson, K., Potter, D., Van Winkle, J. and Aubrecht, J. (2013): Assessment of emerging biomarkers of liver injury in human subjects. Toxicol. Sci., 132, 276-283.
Sellers, R.S., Pardo, I., Hu, G., Khan, K.N., Perry, R., Markiewicz, V., Rohde, C., Colangelo, J., Reagan, W. and Clarke, D. (2017): Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies. Toxicol. Pathol., 45, 416-426.
Vaidya, V.S., Ferguson, M.A. and Bonventre, J.V. (2008): Biomarkers of acute kidney injury. Annu. Rev. Pharmacol. Toxicol., 48, 463-493.
Waring, M.J., Arrowsmith, J., Leach, A.R., Leeson, P.D., Mandrell, S., Owen, R.M., Pairaudeau, G., Pennie, W.D., Pickett, S.D., Wang, J., Wallace, O. and Weir, A. (2015): An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug Discov., 14, 475-486.
Woodcock, J. and Woosley, R. (2008): The FDA critical path initiative and its influence on new drug development. Annu. Rev. Med., 59, 1-12.

industry_corpus2: Biopharmaceuticals


text: The Jewish Studies Program also offers what here at Penn State we call “Embedded Courses”; these are short, intensive educational trips, run in conjunction with a standard class, often over Spring Break or Thanksgiving or shortly after the conclusion of the semester, that students can take for an extra credit. Professor Ann Killebrew offers one of these to Israel in conjunction with some of her courses, and Professors Tobias Brinkmann and Eliyana Adler are developing an embedded course to Poland and Germany to be run in conjunction with our Holocaust courses. More embedded courses are in the planning stages. Embedded courses will be advertised as they are run, and the Jewish Studies Program can often offer interested students financial support.

industry_corpus2: Subject Education


text:
The Wanted Girls is a series of stories about young Black mothers struggling to survive poverty and an oppressive system of intrusion into their lives with special rules that create a second society within America, an unconstitutional bastion of policies and practices held over from the days of slavery. Is America post-racial? It isn't even post-racist. It isn't even post-slavery!
These are all projected, in progress works. Also, look for the audio book of Hook Up coming soon - with original music!
Begun in 2002, this series of stories chronicling the trials and troubles of young women in Cleveland has only intensified in recent months. Is there no hope?
For good reason there is awareness now of new policies of separation of families of illegal immigrants at the border, but there is a long history of intereference in the families of minority Americans. The practise is hardly new. Find out more in The Wanted Girls.

industry_corpus2: Film & Entertainment


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This highly successful organisation are looking for a Consultant/Business Analyst to join an established software development team with technical understanding of application development and knowledge of the software development life cycle. Relevant operational experience within the UK Energy or Utilities sector is required with a strong understanding of Energy billing.
• Support existing and potential customers through delivery of knowledge transfer and product support to the CRM and billing systems.
• To perform a lead role to prospects, customers and the project team members on the optimal approach to implementing a solution to the customers’ business need.
• Proven experience as a Consultant or BA with relevant operational experience within Energy or Utilities sector.

industry_corpus2: Power & Energy


text:
At A Clean Sweep, cleanliness is our business. Working in the Mukilteo area for many years, we’ve built our skills and team so that we can provide you with the best of the best. When it comes to getting a house sparkling, we’re the ones to call.
Offering competitive rates, we never cut corners—that’s right, that little space between the fridge and the counter is going to be cleaner than you’ve ever seen it!
Our specialty is finding spots that you didn’t even think were dirty and get them to be so flawless you’ll have never seen your home look quite so great.
Professionalism is important in any industry, but residential cleaning services require a guarantee. It’s no secret that letting a cleaning agency into your home can come with trust issues. At A Clean Sweep, we’re not embarrassed to talk about it, because we’ve got nothing to hide.
Every member of our detail-oriented team are fully licensed, bonded, and insured, and have completed the training required to treat you and your home with the respect you deserve.
There’s no room in your home or apartment we can’t get clean! Not only that, but you’ll find we’re one of the most affordable cleaning services around. From studio suites, to bungalows, to mansions, our housekeeping services have taken us to everywhere you can imagine in Mukilteo.
We can tackle all these rooms and more. Mud room? Laundry room? Guest house? Not a problem. At our initial meeting, we’ll discuss the housekeeping services you require and get the job done whenever you need us.
We have the equipment to clean appliances, countertop surfaces, tables, chairs, perform vacuuming and floor washing tasks, get to those tough spots like mouldings, window borders, and ventilation gaps, as well as dust and disinfect to your heart’s content!
Most of our Mukilteo clients set up regular home cleaning visits during which we accomplish regular cleaning tasks. But a few times a year there are going to be additional requirements that we are pros at handling!
If you need us to clean walls and ceilings, windows, or carpets, it’s not a problem. We have the equipment to steam clean or clean with a high-pressure water gun.
Did you just finish a renovation? No need to hire a reno-specific company, we’re able to provide the professional cleaning services we know you signed up for. Debris and sawdust are nothing for us to handle!
Since we first opened our doors in Mukilteo, we’ve been going the extra mile for our clients.
Before we enter your home to provide cleaning services, we’ll meet with you on site and determine all of your needs. If you have pets, we’ll get to know them a little so they’re not scared when we stop by!
We build lasting relationships with our clients built on trust, transparency, and of course, some amazingly clean houses.
All information provided is provided for information purposes only and does not constitute a legal contract between A Clean Sweep Cleaning Service and any person or entity unless otherwise specified. Information is subject to change without prior notice. Although every reasonable effort is made to present current and accurate information, LinkNow™ Media makes no guarantees of any kind.

industry_corpus2: Hospitality & Catering


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Walk through the doors of the One 2 One Studio and experience complete, undivided attention from our skilled professionals. Enjoy the unique, contemporary atmosphere of the One 2 One Hair Salon and relax in the serenity of the One 2 One Spa. Bring the Beautiful Experience home with you and enjoy some of the world’s top products and treasures from our One 2 One Boutique.
One 2 One Studio combines intimacy and elegance with industry-leading techniques and superior products to enhance your Beautiful Experience. When you enter the door to One 2 One Studio, in the heart of Forest Hill, Toronto, our courteous and professional reservationists will welcome you and offer a selection of coffee and tea to warm you on chilly days, and sparkling and lemon water to keep you hydrated. This is only the beginning of the Beautiful Experience that awaits you at One 2 One Studio.
Located at 506 Eglinton Avenue West, in picturesque Forest Hill, Toronto – One 2 One Studio has set the standard for beauty, relaxation and rejuvenation in our state of the art facility. Welcome to our Studio where you may indulge in luxury and style. Take the first step, elevate beauty, and body renewal to a superior level. Using only superior products from Biologique Recherche, Valmont, Goldwell, Kerastase, Aqua del’Elba and more, One 2 One Studio is Toronto’s first class hair salon and spa experience.
Welcome to a world where the focus is you. Led by Kiril Mumdjiev and Davide Palmieri, you have finally arrived at your Beautiful Experience.
Offering both women’s and men’s haircuts – our commitment to our clients sets us apart. One 2 One Studio’s superior hair salon employs the most knowledgeable, talented stylists in the industry– passionate, fun and professional personalities who deliver the best haircut. One 2 One Studio is the best hair salon Toronto has to offer. In addition to Women’s haircuts and men’s haircuts, One 2 One Studio’s hair salon offers the best hair colour services –as well as updos, hair extensions and hair treatments, which will perfectly match your new hairstyle to your signature look. Once your hair is perfect, using the most modern, involved techniques, One 2 One Studio's makeup specialists can finish your look with a makeup application. We offer detailed lessons, on make-up application for the specific contours and intricacies of your face, helping your inner-beauty shine. Come to One 2 One Studio for hair extensions and the best womens hair cuts and mens hair cuts in Toronto!
Renew your spirit. Ignite your soul. Rejuvenate your body as One 2 One Spa – elevates personal beauty to a new level. Unlike any other spa in the Toronto area, this moment is yours. Lay back and unwind with a relaxing Facial. Get bikini-ready with our state of the art Cutura Laser Hair Removal System, or try our waxing and threading services. Focus your attention to details with incredible Manicures and Pedicures in the nail salon. Release the tension in your muscles with Massage Therapy. Add some glamour to your look with new Eye Lashes. Feel revitalized and confident with a customized facial therapy or microdermabrasion treatment. Like no other spa or hair salon Toronto can offer, we invite you to One 2 One Spa where you can enjoy a Beautiful Experience. Book your facial therapy or microdermabrasion today!
The beautiful experience of One 2 One Studio does not have to end when you leave. Extend your experience by visiting our boutique and take home some of the best beauty products from around the globe, including; Biologique Recherché, Valmont, Goldwell, Kerastase, and Aqua dell’ Elba. To maintain your incredible new look, pick up these products from One 2 One Boutique to look your best until your next visit.
Offering both women’s and men’s haircuts – our commitment to our clients sets us apart. One 2 One Studio’s superior hair salon employs the most knowledgeable, talented stylists in the industry– passionate, fun and professional personalities who deliver the best haircut. One 2 One Studio is the best hair salon Toronto has to offer. In addition to Women’s haircuts and men’s haircuts, One 2 One Studio’s hair salon offers the best hair colour services – as well as updos, hair extensions and hair treatments, which will perfectly match your new hairstyle to your signature look. Once your hair is perfect, using the most modern, involved techniques, One 2 One Studio's makeup specialists can finish your look with a makeup application. We offer detailed lessons, on make-up application for the specific contours and intricacies of your face, helping your inner-beauty shine. Come to One 2 One Studio for hair extensions and the best womens hair cuts and mens hair cuts in Toronto!


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Botanically, custard is a “multiple-fruit” wherein the fruit is developed from the merger of several individual flowers (ovaries) into a large fruit mass (infructescence).
The custard apple plant is a large shrub belonging to the Annonaceae family. It is native to the tropical rainforests of Central America and naturalized in many parts of the world, spreading along the tropical stretches, from South America to Africa and Asia.
Custard apple is a globular, round to heart-shaped fruit with polygonal indentations on its surface. Many cultivars exist, and depending upon the variety there can be green, brown, yellow, maroon fruits.
Custard apple features tough, outer skin. Inside, individual arils consist of cream-white sheath enveloping single, glossy, deep brown color seeds. The flesh just underneath its surface has a granular texture. Skin and seeds are inedible and discarded. Its flavor described as a reminiscence of mangosteen, sweet and pleasantly tangy, melts inside the mouth.
Custard apple is smaller in size than cherimoya (A. cherimola), Pond apple (A. glabra) and soursop (A. muricata) but a bit larger than sugar apple (A. squamosa). Oftentimes, Sugar apple is termed interchangeably to custard apple.
Custard apple has relatively more calories than cherimoya. 100 g of the fruit carries 101 calories against 56 calories of cherimoya. The major portion of the calorie comes from simple carbohydrates. It, however, contain no saturated fats or cholesterol.
As in other Annona family fruits, custards also contain several polyphenolic antioxidants. Among them, the most prominent are Annonaceous acetogenins. Acetogenin compounds such as asimicin and annonacin are potent cytotoxins. These compounds have been found to have anti-cancer, anti-malarial and de-worming properties.
Custards compose of more vitamin-C (19.2 mg/100 g) than that of in cherimoya. Sugar-apples, however, carry the highest (36.3 mg/100 g) amount of this vitamin among all the Annona fruits. Vitamin-C is a powerful natural antioxidant. Consumption of fruits rich in vitamin-C helps the human body develop resistance against infectious agents and scavenge harmful, pro-inflammatory free radicals from the body.
Custard apple is a modest source of B-complex vitamins, especially vitamin B-6 (pyridoxine, 17% per 100 g)). Pyridoxine helps keep up GABA neurochemical in the brain. High GABA levels in the blood help calm down nervous irritability, tension, and headache ailments.
Custards contain minerals such as calcium, copper, magnesium, iron (9% of RDI per 100 g) and manganese. Additionally, they compose more potassium (382 mg per 100 g) than cherimoya (287 mg per 100 g).
Fresh Annonaceae genus fruits can be readily available in the US all- round the seasons. Custard apples arrive in the markets from July to November in the Southern and Central states. While buying, look for fresh, light yellow, compact, completely mature fruits with an intact thick stem. Completely grown fruits continue to ripen at home at room temperature. If you want to buy ripe fruits, look for those featuring soft, sweet and musky aroma that can be appreciated from a distance. Avoid very soft, mushy, broken, crack or split skin fruits as they may carry risk.
At home, store unripe fruits in a fruit basket where they continue to ripen and stay well for another 4-5 days. Ripe fruits, however, should be used early. Custards, like other Annona fruits, cannot be stored in the refrigerator for an extended period as they sustain chilling injury. However, juiced or pureed, the fruit may be kept inside the freezer for several weeks.
Simply wash the fruits to remove surface dirt. Mop them dry using a soft towel. Fresh ripe fruits can be eaten on their own without any additions and seasoning. Gently pull apart the fruit to expose cream white arils inside. You can use a spoon to scoop edible flesh. Spit out seeds as they are inedible.
The fruit is better enjoyed out of hand on its own, without any additions or seasonings.
Pulp pureed and mixed with other fruits in salads or can be used for ice-cream toppings.
Custard apple milkshake is refreshing drink in India.
Tart flavored guanabana or soursop can be mixed with honey, sugar, milk, lemon, and ice; and serve chilled as sorbet or with other fruit cocktails and milkshakes.
Custard apple seeds and leaf parts contain toxic alkaloids, and therefore, should not be consumed. Do not chew seeds inside the mouth as this releases toxins. If consumed accidentally, the whole seed would not pose any threat as it comes out of the gastrointestinal tract undigested.

industry_corpus2: Agriculture & Fisheries


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Details of the divorce of Nas and Kelis have been revealed, and include information about her income and expenses.
Kelis Rogers filed for divorce in May after almost five years of marriage to rapper Nas, and is seeking $20,000 for baby expenses such as cribs and strollers.
She is also asking for money to pay for a baby nurse and other staff.
According to media reports, singer Kelis listed her expenses as $80,831 per month, but only made an average of $21,616 per month in the past year.
Included in her expenses is $15,000 per month on entertaining, gifts and vacations.
Kelis is due to have her baby next month.


text:
Our client Boojum is due to open in Cork this week…and the excitement is Cork is well and truly building.
Late last month the Boojum team came to town and caused a major buzz as they travelled around in their branded cars filled with Boojum goodies.
While I knew Boojum was popular I didn’t quite realise how popular it was and how much people wanted it to open in Cork!
I can’t believe the buzz and anticipation in Cork City for the award winning Mexican restaurant to open its doors. With stores already in Belfast, Dublin and Galway, Cork will be the first new city for Boojum in 4 years, and their 3rd new store to open in the past 12 months.
Boojum addict t-shirts have become a highly coveted item belonging only to the most loyal of customers and Boojum Cork have commissioned special edition t-shirts especially for the Cork customers designed (and modelled!! See below) by our very own Paul Wade in our Fuzion design department.
Since they were revealed we have been inundated with calls from people looking to get their hands on one.
The t-shirts will be available exclusively from Boojum Cork so keep an eye on the Boojum Cork Facebook and Twitter accounts where they may just give away a t-short or two!
The new store, which will be located on 7 Winthrop Street, is approximately 2700 sq ft over 2 floors, seating 50 people.
Will one of these be you?!!
We can’t let the South Mall go south!!
When I was in college in Cork in the early ‘80’s I used love to walk down South Mall and take in the atmosphere of this bustling busy business street and I vowed I’d someday work there – that is of course, after I travelled and conquered the world!!!
I always knew that Cork would be my home and after a long and winding road now it is. I can’t believe that I am lucky enough to not only work on the South Mall, but that I own a business on this historic business precinct.
We have an equally good location in Dublin on Fitzwilliam Street and even though we continue to grow in Dublin, Cork will always be my base and the South Mall will always be where I am drawn to work – and often play thanks to great places like Electric, right across the road from us!
I know though at the moment I am seeing the Mall with tinted glasses.
Because it’s home to me the glare of all the “To Let” and “For Sale” signs fade into the façades of the buildings. But what must people think when they look at the South Mall now, when viewing the area as a location to set up a business?
With all the vacant signs, it’s probably the last place people new to the city would consider setting up a business. I bet sometimes some people think all that is missing is the tumble-weed – although there are weeds growing off many of the empty buildings!!!
Reports and studies are great but are they getting us anywhere? Is anyone taking the advice, recommendations on board? Where are the incentives to encourage people to move into the South Mall? Are the Estate Agents doing their jobs properly? Is there something more the business community could be doing? Is there more that the landlords should be doing to make their properties more attractive to businesses?
It just breaks my heart sometimes when I see another business leave, just as strongly as it leaps for joy when I see a business opening. Thankfully there have been a few in the last six months.
Perhaps the business community on the South Mall should join together?
Now I know we have an excellent Chamber of Commerce and there is the Cork Business Association – but should we mount an organic PR campaign for the South Mall; where businesses pro-actively talk up this great business precinct and support the businesses on the Mall.
This could not only help keep businesses on our main business centre but also encourage more businesses to make the South Mall their home. We could make sure new businesses on the Mall are welcomed by neighbours, through social media, through one to one well wishes and the ultimate support, by doing the best to do business with neighbouring businesses.
The South Mall could once again become a real thriving business community, supporting each other and encouraging new neighbours.
Fuzion are delighted to be working on two great initiatives that have been introduced by the Government and are being operated by the Local Enterprise Boards.
The first of these is Ireland’s Best Young Entrepreneur, which was recently launched by the Taoiseach and the Minister for Jobs, Enterprise and Innovation.
It is a new competition to find Ireland’s Best Young Entrepreneur, with a total fund of €2 million available to invest in winning businesses and entrepreneurs in every county in the country.
The competition is being run by the new Local Enterprise Offices, and the winners at county level will be eligible for an investment in their business of up to €25,000, while the winners at national level can receive an additional investment of up to €50,000. Investments in the winning businesses will be determined according to business prospects and investment needs.
This is really encouraging to see as it recognises the importance and encourages entrepreneurship in Ireland. The competition is applicable to anyone aged 30 and under with an outstanding idea/commercial venture for a start-up or existing business.
Almost any young person with a business idea can enter the IBYE competition.
It doesn’t matter what their background is and it encourages anyone who has researched a business idea, anyone who is itching to be their own boss, or an existing young entrepreneur, who has an idea to improve their existing business.
It also includes anyone who wants to return home and set up their own business in Ireland. Getting some of Ireland’s best talent to return and set up a new business would be fabulous for our economy.
The competition falls into three categories including Best New Idea, Best Start Up and Best Idea by an Established business.
If you know anyone who fits this bill then please encourage them to enter the competition, which has some great prizes including financial and other supports.
Young entrepreneurs can apply via the IBYE website.
Any initiative that encourages, supports and celebrates young entrepreneurs must be applauded – well done!
Check out the other terrific initiative, Online Trading Vouchers which is designed to encourage and assist Irish businesses with eCommerce potential to get trading online and not miss the opportunity to expand their business. Vouchers of up to €2,500 are available to qualifying businesses.
A few months ago I found myself having a coffee in town on a Saturday morning chatting with an old school buddy who I hadn’t see in thirty years. We had connected on LinkedIn and it was as if those thirty years had disappeared in a flash.
I always thought he was “sound”, one of the good guys and in truth not a whole pile had changed – both of us had done a lot of living in between but we were essentially the same two school mates – we had a good laugh recalling stories about our teachers and football matches we had played in. I had a photo of our “winning” team in some school tournament and there we were the two of us in our red kit!
Both of us have done well in our varied careers and he was in the early stages of a new online project – by the end of the conversation he asked if I wanted to come on board with the project utilising our expertise on some type of a shareholding arrangement. In a few years the plan was to sell the business and we would all make good money. Hmmm ….sounded good.
After this me met a few times and got down to business and delved into the nitty gritty of his project and our involvement in it.
While his project was really interesting to my surprise I found myself not being as enthusiastic as he was about it. Why was this I was asking myself?
Like every great “driver” he was pushing me for our plans and input. I did this of course but I discovered his project wasn’t my No.1 priority. My clients and our own projects motivate me and this project just wasn’t having the impact that I was expecting.
It wasn’t a client and it wasn’t “my” project.
My buddy needs more than 1,000% from me and everyone else involved in the project for it to be a success. I realise this more than anyone.
Before we damaged our friendship we gracefully concluded our arrangement and that was cool with both of us. We’ll meet again for coffee soon – probably in about another 30 years!
It’s important that we spend our time chasing our own dreams.
Sometimes are you better off not saying the right thing?
Must be a great shop !
At this stage between the initial briefing meeting and the time spent researching and working on the plan we have spent well over a day’s work before we meet with the prospect and present our Marketing\PR plan for his business.
This is always a tricky stage for us – if you want to have a chance of winning the new account you have to punch in the time, put in the research, brainstorm and put all your best ideas and thinking into the plan.
We don’t get paid for this but we do obviously hope that the client likes what we are proposing and then engages us to execute the plan for them – Put your best foot forward if you are serious about winning the business.
We are two hours into our presentation and the prospect seems to be embracing the plan and it is all looking very positive. Our plans are always quite comprehensive and cover everything from being found on-line, a review of marketing collateral and website, a PR plan including ideas that should generate the right media coverage and a social media plan to accelerate all of these efforts.
At the end of the presentation, while everything seems to be going well there is one huge, risky issue that we wish to discuss.
“We feel your business name isn’t right” we gently explain to the prospect. This could be as delicate as telling someone you don’t like their child’s name!
“But what about my website, my branding, the money I’ve invested to date in advertising, pushing the name out there?” he asks.
“It is saying the wrong thing about your business, it is giving the wrong impression of what you are about” … he seems to be digesting and contemplating what we are saying , so we continue “we feel strongly that we would be doing a huge disservice to you if we drove on with a plan without first addressing the issue of your business name“.
After a few minutes he admitted that he always had some concerns about the name “fit” and we were the only (maybe foolish?) ones he met that had raised the issue.
We presented him with some alternative names that we felt more accurately captured the essence of the business offering and he seemed genuinely interested in them.
In truth we could have made life easier for ourselves and probably for him by just ignoring the business name issue and presenting a plan that was in keeping exactly to the brief.
In 1960, the relatively unknown Senator John F Kennedy debated against Vice President Nixon in a US first television live debate in a presidential election campaign.
It’s widely acknowledged that without that debate, Kennedy would never have been president. Nixon, pale and underweight from a recent hospitalisation, appeared sickly and under pressure, also famously refusing makeup, while Kennedy appeared calm and confident, tanned, robust and healthy, wearing full make up.
Those who listened to the debate on the radio thought Nixon had won. Those who watched it on television, thought Kennedy had been victorious. While Nixon went on to perform much better in subsequent debates (and to look better, due to weight gain), 20 million people watched that first one, and the damage had been done.
For the first time ever in the US, viewers judged presidential candidates on not just content, but style, stage presence, appearance. For the first time, it demonstrated that how you present yourself, counts.
In our working lives we make presentations, give interviews and conduct meetings, leaving first impressions every day. We don’t want to be all style and no substance, but how you present yourself, matters. How you dress, how you shake hands, how you speak at that first meeting, may be the only shot you have, so you have to make it count.
Sometimes we are casual in our approach with business associates, with prospective clients, with colleagues, and we conspiratorially confess that business hasn’t been great, that we couldn’t wait to leave the office to go home and watch the Olympics, assuming we are making friends, but this is not the climate for over sharing- this economic climate requires your game face!
People like to think they’re doing business with a focused, capable, confident person, and that first impression will do at least half the convincing, that you’re the right person for the job.
Nixon himself insisted on campaigning right up to an hour before that famous debate, not having fully recovered from a hospital visit either, but he never got a chance to explain that in the live debate- the public presumed him exhausted, weaker than his opponent. Not fair, not true, but the rest is history.
Of course we all do our best to look smart going to work, and make a greater effort for important meetings, but we should probably assume that how we present ourselves says more about us than we realise. Bear it mind as you’re getting dressed tomorrow morning- time to get your game face on!
Jill Collins is an account director at Fuzion.
Jill Collins conducts presentation skills training and media training in both Cork and Dublin.
“Guess who is selling his bar and buying a 5 star restaurant” Tommy, my Sales Manager said to me. I was the General Manager of Deasy & Co at the time, a subsidiary of Guinness.
One of our loyal customers who was running a good solid suburban bar had done a decent job with the place and he was made an offer to sell up. The offer was “too good to be true” and our customer was going to make a clear profit from the deal.
His plan was to buy and run this very successful five star, fine dining restaurant whose reputation had been built around a well known chef. He reckoned he could manage the purchase with the windfall from the pub sale and even be in a position to upgrade the restaurant premises with some support from the bank.
The problem as we all saw it was that our guy wasn’t exactly Mr.Sophistication and in truth he was the last person that we could imagine operating this 5 star restaurant. He always did well in the pub but that was with a very different, country type crowd.
My buddy Tommy was really close to him – should he have a strong word with him and advise him against his dream?
Our customer was determined, full of enthusiasm so maybe we were the ones that were wrong – who were we to say anything? If Tommy said something to him it could backfire and damage the professional friendship they had.
Shortly after the restaurant opened under the new owner we went there for a meal to support him. Our worst fears were realised as we had a poor meal and you could see that our customer, who was a really nice guy just wasn’t able for this level of fine dining. Maybe he was on a learning curve and it would get better?
Unfortunately within a year the place was shut, the “fine dining” reputation in tatters, he had lost huge money and the building was handed back to the bank and our customer had lost everything.
The crazy thing was that we all saw it coming ….
Would you have said something ?
My son Brendan Canty has just qualified from CIT, having completed a multi media course. He wants to work in film in some way and he is also really passionate about music.
How unusual – a 22 year old being passionate about music!
Like every other parent you worry about what your children will do – you want them to find a job, earn a living and in this climate it has never been quite so tough.
“You need to find a god solid job” I hear myself saying..
Well – he has set up his own website operating under the name Feel Good Lost and he has been busy producing videos for bands from all over the world – with the web and modern technology this is all quite easy, apparently!
His last music video was for a “secret” American solo artist who goes under the name Slow Magic and the track he produced was for a song called Corvette Cassette. There is a video producers peer website called Vimeo (this is like a worldwide YouTube for video and film producers), which has just featured this song as a staff pic – at the time of writing the video has been viewed 63,000 times across the world.
While Brendan does some excellent corporate video work for Fuzion and his own clients he excels when he combines his love of music and his film profession. On Friday nights he DJ’s in The Pavilion in Cork combining music and visuals as part of his unique set operating under the Feel Good Lost name.
Slow Magic // Corvette Cassette from Feel Good Lost on Vimeo.
He is following his dream and his passion and it had me thinking about career choices and Three Circles..
The basic principle is that if companies concentrate their efforts on activities that meet all three of these criteria then they will inevitably be very successful – this is one of the factors that Jim Collins attributes to the success of what he calls “Great” companies.
If you are looking for a new job or a new challenge how about using the Three Circle Criteria for deciding which path you choose?
Are you Making a Sale or Changing a Customers Routine?
Do you change your routine easily?
I admit it … I’m boring!
Every Sunday morning myself and Dee go for a walk with our four legged creature, Bing to the local park with our good friends Tommy and Joan and their four legged creature, Tammy.
This routine was so predictable – walk to Ballincollig Park, lap of the first field, walk alongside the river to the lower fields, cut up through the Gunpowder mills and the GAA fields, into the village, stop for coffee and scones at Nosh and Coffee, chat, walk through the village and home. This as I mentioned is what we do pretty much every Sunday.
A few months ago a very cute little mobile coffee kiosk moved into the car park at the start of the park serving coffee and buns and they even have a few very neat tables and chairs outside their unit complete with flowers in vases. Now, this didn’t really suit our break “routine” as the location of the kiosk was at the start of our walk and not in the middle so even though it was a really nice set up it wasn’t quite right for us (its a big deal changing people’s habits!).
Recently we did our usual walk but some of the “crew members” were a little hungover so having completed stage one of our walk we double backed, cut the walk short and went back to the little kiosk, “Cafe Chico” (the owner called the kiosk after her dog, who she brings with her for company each day) for some very welcome refreshments.
The woman working in the kiosk was really friendly, the coffee and home made scones were perfect and to top it all she offered us biscuits from a tin especially for the four legged creatures – Wow! this woman knew and understood her customers really well.
Officially we have changed our routine! Now the first leg of our walk is the same as it was before but now we do a few laps of the lower fields, double back along the river to lap the first field again and then return to the beginning to enjoy our coffee, scones and chat at Cafe Chico!
Why? She runs a great little friendly business, she understands her customer and she goes a little further than you would expect but fully appreciate.
Are you making a sale or are you changing a customers routine – which is worth more?
While we can look after your PR needs, your reputation starts with what you do yourself.
Broken Man – We need him now more than ever ..
n he bounded about two years ago full of energy, enthusiasm and little bit of arrogance but full of confidence.
His plan was to launch a brand new product in a sector that he reckoned was totally under serviced but one that was growing in interest and importance. He was fully convinced about the viability of this project and needed our help to design and launch it in the marketplace. We were swept along by this guys enthusiasm and everyone in the team got behind the new project – it was really exciting.
The new product did come out, probably at the worst possible time – in the middle of 2009 when no one was taking a chance on anything new. Despite his enthusiasm and powers of persuasion the revenue targets were badly missed.
The product sold well in outlets where it was given a chance on the shelves but in most others it was returned within the week! That often happens with new products that battle for space on the retailers shelves. Product feedback was really superb by the few who actually managed to get their hands on it.
Fast forward to 2011 ..
We did manage to get a few quid off what was owed to Fuzion but there was still a really large sum outstanding. I guessed the phone call would be a waste of time but in any case it had to be made..
..no answer, he’s probably not up to the conversation – can’t be easy. Two minutes later I get a call back and we have a really good chat.
His other business ventures had also ceased (construction sector), he didn’t have money for me just now but promised to pay when fortunes improved. His mortgage payments have slipped by a few months and he was now job hunting. There is nothing here for him he reckoned .. his preferred destination is Australia but he wouldn’t get a work visa so he guessed he would end up in Abu Dhabi. This would be difficult as he has two young kids.
He is a broken man, his world is in tatters – he is not the only one I have met recently.
The truth is this broken man is an entrepreneur, someone who is willing to take a chance, someone who will make things happen. Sometimes things go wrong but often they go right and they end up employing people and service providers in the process.
In Ireland we need the broken man now more than ever – if you meet him give him a break and encourage him to get on his feet again.


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Home What's on Tancredi by Rossini.
Until 10 Nov 2004. Conducted by Gianluigi Gelmetti, directed by Pier Luigi Pizzi, with Daniela Barcellona, Mariella Devia, Raul Gimenez, Giacinta Nicotra.
Venices great theatre, La Fenice, has finally come back to life. After its official opening last December, followed by a years closure for final checks and controls, the first season of the new Fenice is finally under way, with a more interesting programme than ever before. The first opera to be staged is Verdis La Traviata (12-20 Nov). Names to note include Lorin Maazel and Robert Carsen. The former is a fine conductor with excellent technical preparation who seldom appears in Italy. The latter, no less famous, is an ingenious director who is very active in Italy; remember his production last year of Handels Orlando in Reggio Emilia and Poulencs Dialogues des Carmlites in Milan, both great successes. The protagonist of La Traviata is Patrizia Ciofi, a soprano who stunned everyone in Pesaro in August with her beautiful interpretation of Amenaide in Rossinis Tancredi. For information tel. 041786575, www.teatrofenice.it.
This same production of Rossinis Tancredi will be in Rome (2-10 Nov), with staging and costumes by Pier Luigi Pizzi. The conductor is Gianluigi Gelmetti who has often performed this opera and has a special feeling for its neo-classical atmosphere. The protagonists are Daniela Barcellona (Tancredi) and Mariella Devia (Amenaide), who, like Gelmetti, know the opera very well. Both of them are expert Rossini singers and also expert singers of this opera. Tel. 0648160255-064817003, fax 064881755, www.operaroma.it.


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What can you do to equip your employees with competitive communication and leadership skills?
As an executive speech coach and creator of Fripp Virtual Training my clients include corporate leaders, celebrity speakers, well-known sports and media personalities, and even political candidates. Mastery of public speaking is a essential for public office. If you feel the call to leadership, but you’re intimidated by public speaking, remember that with help and practice anyone can learn how to speak in public with confidence. My friend, Sims Wyeth, author of The Essentials of Persuasive Public Speaking, notes, “Churchill fainted at his first speech in Parliament. As Secretary of The Navy, FDR bored people to tears. Bill Clinton was booed at the 1988 Democratic Convention for his long-windedness. Yet all three are now known as brilliant communicators.” As we reflect on our Nation’s recent midterm elections, I share this from Toastmasters on the role of public speaking in politics, public office, and leadership itself.


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industry_corpus2: Automobiles


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A pyramidal, dense growing habit of this large shrub makes it ideal for screening. The pale green leaves with creamy white variegation will add colour and interest to the garden. Quick to establish and easy to grow this ideal screening plant can also be trimmed for hedging.
Prefers an open sunny sposition with mosit but well drained soil. Plant 1 per meter. Trim to maintain height and form. Benefits from summer watering.


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nice article Nik. but as someone born in Auckland in he mid-60s and who grew up there in the 70s and 80s, i feel your view is somewhat Christchurch-centric, unsurprisingly. the Asian influence definitely built up momentum starting in the early 80s when local Chinese with ties to Hong Kong began opening more restaurants and doing very well based on the huge popularity of their takeaway businesses which really did huge turnover from the mid-70s onward. by the time i started university in 1985, there was already a fast-expanding choice of Chinese and other Asian restaurants in Auckland, and they seemed to do pretty well. you need to remember that in the lead-up to the handover of HK in 1997, there was reasonably substantial immigration into Auckland (enough to prompt the nickname "Chowick" in reference to the Chinese community in Howick).
well, having lived in Japan for twenty-something years, tori sashimi is not passing my lips anytime soon. neither is basashi (horse-meat sashimi), which is a local delicacy in Nagano prefecture, where i live.
and as for teriyaki chicken sushi... totally a western adaptation (California/NYC/Honolulu, i would guess). there are some non-seafood ingredients used in traditional sushi, but these are mostly vegetable-based. although in Takayama (Gifu), which is famous for Hida-gyu (beef) i had some pretty amazing beef nigiri-zushi (beef cooked rare).
Since 2005 I have advocated for the threshold to be halved to 2.5% (one-fortieth of the party vote instead of one-twentieth). With a five percent threshold that means a party has to win the nominal equivalent of six seats, whereas the nominal equivalent of three seats seems much more realistic, fair and democratic. I think there are valid arguments for retaining a threshold in excess of one seat. Anyway, the convenience of 2.5% is that if it is reached the party is guaranteed at least three seats, which has practical advantages within the way parliament works.
And the coat-tails provision should definitely be scrapped if the threshold were to be halved.
In this election, TOP wouldn't have made it on the face of the result, but I think that if the threshold were 2.5% they would have attracted a lot more votes from people who did not want to waste their party vote on a party unlikely to make the threshold. So there is a strong chance that they would have made it.
The current version of MMP is not functioning as well as it could if it was fine-tuned to make it fairer and more transparent.
It's mind boggling that it took more than five years before any media organisations began to investigate the background of this MP. Dr. Jian Yang has never mentioned his education or career in China in any of his CVs. That's a 16-year blank (1978-1994) in his background, ffs. And after six years as a NZ MP, we now have some questions being asked. Well, it certainly puts into perspective who the National Party are actually working for.
But there’s no rule that says Labour needs two partners.
Obviously there is no rule, but a cursory look at the numbers suggests strongly that they will need both the Greens and NZ First to form a government. I mean, are Labour likely to get the largest share of the party vote? Seems pretty unlikely. Will Labour plus Winston have enough to overtake National and whoever they can scrape up as potential coalition partners? That also looks like a very long shot to me. Hence the three-party coalition looks to be the most realistic hope of getting rid of National.
This latest poll seems pretty bizarre though. Greens going from 15% to 4% in one go? Even allowing for all the negative publicity around Metiria's resignation it still seems too much of a drop. I really would be shocked if they go under 8% in the election.
If the Greens really do fail to meet the threshold, then a change of government is pretty much impossible. Labour needs two substantial coalition partners to form a government. So, abandoning the Greens because you think there is a danger that they might not reach 5% and thus waste your vote is potentially very counterproductive, IMHO.
i'm really struggling with the idea that the content of that Andrea Vance article is not satire.