Lessons Learned from EPA\u27s Climate Leaders Program: An Evaluation to Fortify Voluntary Environmental Initiatives

A voluntary environmental program (VEP) called Climate Leaders was recently cancelled by the U.S. Environmental Protection Agency (EPA). To find out why and gather lessons learned, the program was examined using a three-pronged approach: 1) a meta-analysis of program evaluation theory literature, 2) a review of guides and external reports on Climate Leaders, and 3) interviews with former program participants and implementers. Findings reveal that environmental protection is best achieved by combining regulation with voluntary methods as they complement and buttress each other. Recommendations were compiled to help future VEPs minimize wasted resources and improve environmental conditions. These recommendations were vetted by industry, and ultimately contribute to a comprehensive “guiding framework” for the design, implementation, and evaluation of VEPs. Existing VEP models and evaluative tools still lack the perspective of several key disciplines, so additional program evaluations are necessary to capture all of the primary characteristics correlated with program success and complete the guiding framework

Future supply chains enabled by continuous processing - opportunities and challenges : May 20–21, 2014 continuous manufacturing symposium

This paper examines the opportunities and challenges facing the pharmaceutical industry in moving to a primarily “continuous processing”-based supply chain. The current predominantly “large batch” and centralized manufacturing system designed for the “blockbuster” drug has driven a slow-paced, inventory heavy operating model that is increasingly regarded as inflexible and unsustainable. Indeed, new markets and the rapidly evolving technology landscape will drive more product variety, shorter product life-cycles, and smaller drug volumes, which will exacerbate an already unsustainable economic model. Future supply chains will be required to enhance affordability and availability for patients and healthcare providers alike despite the increased product complexity. In this more challenging supply scenario, we examine the potential for a more pull driven, near real-time demand-based supply chain, utilizing continuous processing where appropriate as a key element of a more “flow-through” operating model. In this discussion paper on future supply chain models underpinned by developments in the continuous manufacture of pharmaceuticals, we have set out; •The significant opportunities to moving to a supply chain flow-through operating model, with substantial opportunities in inventory reduction, lead-time to patient, and radically different product assurance/stability regimes. •Scenarios for decentralized production models producing a greater variety of products with enhanced volume flexibility. •Production, supply, and value chain footprints that are radically different from today's monolithic and centralized batch manufacturing operations. •Clinical trial and drug product development cost savings that support more rapid scale-up and market entry models with early involvement of SC designers within New Product Development. •The major supply chain and industrial transformational challenges that need to be addressed. The paper recognizes that although current batch operational performance in pharma is far from optimal and not necessarily an appropriate end-state benchmark for batch technology, the adoption of continuous supply chain operating models underpinned by continuous production processing, as full or hybrid solutions in selected product supply chains, can support industry transformations to deliver right-first-time quality at substantially lower inventory profiles

THE SYNTHSEQ APPROACH TO PERSONAL GENOTYPING

Inspired by the Archon X Prize for Genomics, our research project involves implementing a novel strategy for sequencing the human genome. This prize worth $10 million will be awarded to the first company to sequence 100 human genomes with 99.999$10,000 each. However, the possibility of winning the X Prize is secondary to the prospect of revolutionizing medical diagnostics. Currently, the genomic state of‐the‐art involves identifying SNPs (single nucleotide polymorphisms) that are correlated to certain diseases. Compared to such existing diagnostics, the genome‐wide, sequence‐based biomarkers that will be made possible by fast and affordable human genome sequencing are staggering. After six months of thorough investigation and development, we are pleased to present SynthSeq, a cutting‐edge, whole‐genome sequencing venture based on the novel sequencing‐bysynthesis technology. In contrast to high‐priced competitors, our inexpensive and comparatively error‐free whole genome sequencing solution will prove to be an invaluable diagnostic resource, and it will only become more valuable as advances are made in the field of molecular diagnostics. At our intended retail price of $5,000, series A investors can expect a worst‐case MIRR of 22$700 thousand. We are confident that our innovative SynthSeq technology will deliver high‐fidelity, low‐cost whole genome sequencing to as many as 3,000 customers per year as currently envisioned, with the potential for scale‐up to millions

Future Supply Chains Enabled by Continuous Processing-Opportunities Challenges May 20-21 2014 Continuous Manufacturing Symposium.

This paper examines the opportunities and challenges facing the pharmaceutical industry in moving to a primarily "continuous processing"-based supply chain. The current predominantly "large batch" and centralized manufacturing system designed for the "blockbuster" drug has driven a slow-paced, inventory heavy operating model that is increasingly regarded as inflexible and unsustainable. Indeed, new markets and the rapidly evolving technology landscape will drive more product variety, shorter product life-cycles, and smaller drug volumes, which will exacerbate an already unsustainable economic model. Future supply chains will be required to enhance affordability and availability for patients and healthcare providers alike despite the increased product complexity. In this more challenging supply scenario, we examine the potential for a more pull driven, near real-time demand-based supply chain, utilizing continuous processing where appropriate as a key element of a more "flow-through" operating model. In this discussion paper on future supply chain models underpinned by developments in the continuous manufacture of pharmaceuticals, we have set out; The paper recognizes that although current batch operational performance in pharma is far from optimal and not necessarily an appropriate end-state benchmark for batch technology, the adoption of continuous supply chain operating models underpinned by continuous production processing, as full or hybrid solutions in selected product supply chains, can support industry transformations to deliver right-first-time quality at substantially lower inventory profiles. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association.The authors would like to acknowledge the following for valuable comments and inputs during the preparation of this white paper; Professor Lee Cronin (Glasgow University, UK), Patricia Hurter (Vertex), Mark Buswell (GSK), and Chris Price (GSK). We would also like to acknowledge the support and funding from the UK's Engineering and Physical Sciences Research Council's (EPSRC) Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC), and the UK's Department of Business Innovation and Skill's (BIS) Advanced Manufacturing Supply Chain Initiative (AMSCI) funded Project Remedies.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/jps.2434

Examination of oral cancer biomarkers by tissue microarray analysis.

OBJECTIVE: To validate the DNA microarray results on a subset of genes that could potentially serve as biomarkers of oral squamous cell carcinoma (OSCC) by examining their expression with an alternate quantitative method and by assessing their protein levels. DESIGN: Based on DNA microarray data from our laboratory and data reported in the literature, we identified 6 potential biomarkers of OSCC to investigate further. We used quantitative real-time polymerase chain reaction to examine expression changes of CDH11, MMP3, SPARC, POSTN, TNC, and TGM3 in OSCC and histologically normal control tissues. We further examined validated markers at the protein level by immunohistochemical analysis of OSCC tissue microarray sections. RESULTS: Quantitative real-time polymerase chain reaction analysis revealed upregulation of CDH11, SPARC, POSTN, and TNC gene expression and decreased TGM3 expression in OSCC tissue compared with control tissue; MMP3 was not found to be differentially expressed. In tissue microarray immunohistochemical analyses, SPARC (secreted protein, acidic, rich in cysteine), periostin, and tenascin C exhibited increased protein expression in tumor tissue compared with control tissue, and their expression was primarily localized within tumor-associated stroma rather than tumor epithelium. Conversely, transglutaminase 3 protein expression was found only within keratinocytes in control tissue and was significantly downregulated in cancer cells. CONCLUSIONS: Of 6 potential gene markers of OSCC, initially identified by DNA microarray analyses, differential expression of CDH11, SPARC, POSTN, TNC, and TGM3 were validated by quantitative real-time polymerase chain reaction. Differential expression and localization of proteins encoded by SPARC, POSTN, TNC, and TGM3 were clearly shown by tissue microarray immunohistochemical analysis

Genomewide gene expression profiles of HPV-positive and HPV-negative oropharyngeal cancer: potential implications for treatment choices.

OBJECTIVE: To study the difference in gene expression between human papillomavirus (HPV)-positive and HPV-negative oral cavity and oropharyngeal squamous cell carcinoma (OSCC). DESIGN: We used Affymetrix U133 plus 2.0 arrays to examine gene expression profiles of OSCC and normal oral tissue. The HPV DNA was detected using polymerase chain reaction followed by the Roche LINEAR ARRAY HPV Genotyping Test, and the differentially expressed genes were analyzed to examine their potential biological roles using the Ingenuity Pathway Analysis Software, version 5.0. SETTING: Three medical centers affiliated with the University of Washington. PATIENTS: A total of 119 patients with primary OSCC and 35 patients without cancer, all of whom were treated at the setting institutions, provided tissues samples for the study. RESULTS: Human papillomavirus DNA was found in 41 of 119 tumors (34.5%) and 2 of 35 normal tissue samples (5.7%); 39 of the 43 HPV specimens were HPV-16. A higher prevalence of HPV DNA was found in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88). We found no significant difference in gene expression between HPV-positive and HPV-negative oral cavity cancer but found 446 probe sets (347 known genes) differentially expressed in HPV-positive oropharyngeal cancer than in HPV-negative oropharyngeal cancer. The most prominent functions of these genes are DNA replication, DNA repair, and cell cycling. Some genes differentially expressed between HPV-positive and HPV-negative oropharyngeal cancer (eg, TYMS, STMN1, CCND1, and RBBP4) are involved in chemotherapy or radiation sensitivity. CONCLUSION: These results suggest that differences in the biology of HPV-positive and HPV-negative oropharyngeal cancer may have implications for the management of patients with these different tumors

Gene expression profiling identifies genes predictive of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is associated with substantial mortality and morbidity. To identify potential biomarkers for early detection of invasive OSCC, we compared gene expression of incident primary OSCC, oral dysplasia, and clinically normal oral tissue from surgical patients without head and neck cancer or pre-neoplastic oral lesions (controls), using Affymetrix U133 2.0 Plus arrays. We identified 131 differentially expressed probe sets using a training set of 119 OSCC patients and 35 controls. Forward and stepwise logistic regression analyses identified 10 successive combinations of genes which expression differentiated OSCC from controls. The best model included LAMC2, encoding laminin gamma 2 chain, and COL4A1, encoding collagen, type IV, alpha 1 chain. Subsequent modeling without these two markers showed that COL1A1, encoding collagen, type I, alpha 1 chain, and PADI1, encoding peptidyl arginine deiminase, type 1, also can distinguish OSCC from controls. We validated these two models using an internal independent testing set of 48 invasive OSCC and 10 controls and an external testing set of 42 head and neck squamous cell carcinoma (HNSCC) cases and 14 controls (GEO GSE6791), with sensitivity and specificity above 95%. These two models were also able to distinguish dysplasia (n=17) from control (n=35) tissue. Differential expression of these four genes was confirmed by qRT-PCR. If confirmed in larger studies, the proposed models may hold promise for monitoring local recurrence at surgical margins and the development of second primary oral cancer in OSCC patients

Direct pulse oximetry within the esophagus, on the surface of abdominal viscera, and on free flaps

Pulse oximetry is a noninvasive photometric technique that provides information about arterial blood oxygen saturation (SpO2) and heart rate and has widespread clinical applications. This is accomplished via peripheral pulse oximetry probes mainly attached to the finger, toe, or earlobe. The direct application of pulse oximetry to an organ, such as the esophagus, liver, bowel, stomach or free flap, might provide an indication of how well perfused an organ or a free flap is. Also, the placement of a pulse oximetry probe at a more central site, such as the esophagus, might be more reliable at a time when conventional peripheral pulse oximetry fails

Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival

<p>Abstract</p> <p>Background</p> <p>Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.</p> <p>Results</p> <p>We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with <it>p </it>= 0.044 or 0.011, respectively).</p> <p>Conclusions</p> <p>Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.</p