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The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors
The development of immune checkpoint inhibitors has changed the treatment paradigm for advanced cancers across many tumor types. Despite encouraging and sometimes durable responses in a subset of patients, most patients do not respond. Tumors have adopted the PD-1/PD-L1 axis for immune escape to facilitate tumor growth, which can be leveraged as a potential target for immune checkpoint inhibitors. On this basis, PD-L1 protein expression on tumor or immune cells emerged as the first potential predictive biomarker for sensitivity to immune checkpoint blockade. The goal of our study was to evaluate PD-L1 as a predictive biomarker based on all US Food and Drug Administration (FDA) drug approvals of immune checkpoint inhibitors. We evaluated the primary studies associated with 45 FDA drug approvals from 2011 until April 2019. In total, there were approvals across 15 tumor types. Across all approvals, PD-L1 was predictive in only 28.9% of cases, and was either not predictive (53.3%) or not tested (17.8%) in the remaining cases. There were 9 FDA approvals linked to a specific PD-L1 threshold and companion diagnostic: bladder cancer (N = 3), non-small cell lung cancer (N = 3), triple-negative breast cancer (N = 1), cervical cancer (N = 1), and gastric/gastroesophageal junction cancer (N = 1) with 8 of 9 (88.9%) with immune checkpoint inhibitor monotherapy. The PD-L1 thresholds were variable both within and across tumor types using several different assays, including approvals at the following PD-L1 thresholds: 1, 5, and 50%. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both. In conclusion, our findings indicate that PD-L1 expression as a predictive biomarker has limitations and that the decision to pursue testing must be carefully implemented for clinical decision-making.
Journal Article
Demand-driven inventory optimization and replenishment : creating a more efficient supply chain
\"Remove built-in supply chain weak points to more effectively balance supply and demand Demand-Driven Inventory Optimization and Replenishment shows how companies can support supply chain metrics and business initiatives by removing the weak points built into their inventory systems. Beginning with a thorough examination of Just in Time, Efficient Consumer Response, and Collaborative Forecasting, Planning, and Replenishment, this book walks you through the mathematical shortcuts set up in your management system that prevent you from attaining supply chain excellence. This expanded second edition includes new coverage of inventory performance, business verticals, business initiatives, and metrics, alongside case studies that illustrate how optimized inventory and replenishment delivers results across retail, high-tech, men's clothing, and food sectors. Inventory optimization allows you to avoid out-of-stock situations without impacting the bottom line with excessive inventory maintenance. By keeping just the right amount of inventory on hand, your company is better able to meet demand without sacrificing the cost-effectiveness of other supply chain strategies. The trick, however, is determining "just the right amount"--and this book provides the background and practical guidance you need to do just that. Examine the major supply chain strategies of the last 30 years Remove the shortcuts that prohibit supply chain excellence Optimize your supply/demand balance in any vertical Overcome systemic weaknesses to strengthen the bottom line Inventory optimization is benefitting companies around the world, as exemplified here by case studies involving Matas, CV Voorfruit, Tesco, PWT, Wistron, and Amway. When inefficiencies are built into the system, it's only smart business to identify and remove them--and implement a new streamlined process that runs like a well-oiled machine. Demand-Driven Inventory Optimization and Replenishment is an essential resource for exceptional supply chain management\"-- Provided by publisher.
Book
The Formation of Moist Vortices and Tropical Cyclones in Idealized Simulations
The upscale aggregation of convection is used to understand the emergence of rotating, coherent midtropospheric structures and the subsequent process of tropical cyclone formation. The Cloud Model, version 1 (CM1), is integrated on an f plane with uniform sea surface temperature (SST) and prescribed uniform background flow. Deep convection is maintained by surface fluxes from an ocean with uniform surface temperature. Convection begins to organize simultaneously into moist and dry midtropospheric patches after 10 days. After 20 days, the patches begin to rotate on relatively small scales. Moist cyclonic vortices merge, eventually forming a single dominant vortex that subsequently forms a tropical cyclone on a realistic time scale of about 5 days. Radiation that interacts with clouds and water vapor aids in forming coherent rotating structures. Using the path to genesis provided by the aggregated solution, the relationship between thermodynamic changes within the vortex and changes in the character of convection prior to genesis is explored. Consistent with previous studies, the approach to saturation within the midtropospheric vortex accelerates the genesis process. A novel result is that, prior to genesis, downdrafts become widespread and somewhat stronger. The increased downdraft mass flux leads to stronger and larger surface cold pools. Shear–cold pool dynamics promote the organization of lower-tropospheric updrafts that spin up the surface vortex. It is inferred that the observed inconsistency between convective intensity and thermodynamic stabilization prior to genesis results from sampling limitations of the observations wherein the important cold pool gradients are unresolved.
Journal Article
The market oriented university : transforming higher education
\"The next decade will be transformative for the higher education sector. Government funding is decreasing. Through their marketing activities universities have created the 'student consumer.' The student consumer is prepared to shop around, compare prices and value, and once purchased expects a return on their investment. Disruptive innovations are challenging traditional forms of learning and in many cases are viewed as better alternatives to traditional learning in the classroom. Competition from private educational providers is increasing. Their cost base is lower, and their customer focus is superior. In short, universities around the world are facing a perfect storm. While experts don't expect the higher education sector to collapse under these challenges, they do believe that for some institutions the future looks bleak. If universities are to avoid closures or mergers, they will need to adopt a market-oriented approach. This timely book urges readers to view students as customers and focuses on how universities need to reinvent themselves in order to stay relevant. Striking a difference between market-oriented and marketing, the authors provide various examples of institutions around the world that are making efforts to reposition themselves. Additionally, this book delves into the issue of undervalued faculty, arguing that education practices are in desperate need of being reimagined due to the abundance of MOOCs and adaptive and experiential learning practices within universities these days.\"--Back cover.
Book
A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia
The emerging understanding of gut microbiota as ‘metabolic machinery’ influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to ‘healthy’ controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.
Journal Article
Large Scale Anthropogenic Reduction of Forest Cover in Last Glacial Maximum Europe
Reconstructions of the vegetation of Europe during the Last Glacial Maximum (LGM) are an enigma. Pollen-based analyses have suggested that Europe was largely covered by steppe and tundra, and forests persisted only in small refugia. Climate-vegetation model simulations on the other hand have consistently suggested that broad areas of Europe would have been suitable for forest, even in the depths of the last glaciation. Here we reconcile models with data by demonstrating that the highly mobile groups of hunter-gatherers that inhabited Europe at the LGM could have substantially reduced forest cover through the ignition of wildfires. Similar to hunter-gatherers of the more recent past, Upper Paleolithic humans were masters of the use of fire, and preferred inhabiting semi-open landscapes to facilitate foraging, hunting and travel. Incorporating human agency into a dynamic vegetation-fire model and simulating forest cover shows that even small increases in wildfire frequency over natural background levels resulted in large changes in the forested area of Europe, in part because trees were already stressed by low atmospheric CO2 concentrations and the cold, dry, and highly variable climate. Our results suggest that the impact of humans on the glacial landscape of Europe may be one of the earliest large-scale anthropogenic modifications of the earth system.
Journal Article
Progenitors in Peripheral Nerves Launch Heterotopic Ossification
Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)‐induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen‐regulated Wnt1‐Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by fluorescence‐activated cell sorting showed that all SP7+ cells were found in the TR+ population, whereas only about 80% of the TR+ cells expressed SP7. Pre‐chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also coexpressed TR, suggesting that the progenitor in nerves is multi‐potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO. Stem Cells Translational Medicine 2017;6:1109–1119
Journal Article