Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity

The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the ‘obesity epidemic' - the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models - the general intake model and the dual intervention point model - that address this issue and might offer better ways to understand how body fatness is controlled

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Democracy with Adjectives: Conceptual Innovation in Comparative Research

Figures The recent global wave of democratization has presented scholars with the challenge of dealing conceptually with a great diversity of postauthoritarian regimes. Although the new national political regimes in Latin America, Africa, Asia, and the former communist world share important attributes of democracy, many of them differ profoundly both from each other and from the democracies in advanced industrial countries. Indeed, many are not considered fully democratic. This article argues that scholars respond to this challenge by pursuing two potentially contradictory goals. On the one hand, researchers attempt to increase analytic differentiation in order to capture the diverse forms of democracy that have emerged. On the other hand, scholars are concerned with conceptual validity. Specifically, they seek to avoid the problem of conceptual stretching that arises when the concept of democracy is applied to cases for which, by relevant scholarly standards, it is not appropriate. 1 The result has been a proliferation of alternative conceptual forms, including a surprising number of subtypes [End Page 430] involving democracy "with adjectives." 2 Examples from among the hundreds of subtypes that have appeared include "authoritarian democracy," "neopatrimonial democracy," "military-dominated democracy," and "protodemocracy." This proliferation has occurred despite the efforts by leading analysts to standardize usage of the term democracy on the basis of procedural definitions in the tradition of Joseph Schumpeter and Robert A. Dahl. 3 In important respects this standardization has been successful. Yet as democratization has continued and attention has focused on an increasingly diverse set of cases, the proliferation of subtypes and other conceptual innovations has continued. Hence, given the risk of growing conceptual confusion, the earlier effort to standardize usage must now be supplemented by assessing the structure of meaning that underlies these diverse forms of the concept. This article initiates this assessment, focusing on qualitative categories 4 employed in the study of recent cases of democratization at the level of national political regimes, with particular attention to work on Latin America. 5 Our goal is twofold: to make more comprehensible the complex structure of the alternative strategies of conceptual innovation that have emerged and to examine the trade-offs among these strategies. We begin with Sartori's well-known strategies of moving up and down a ladder of generality--strategies aimed at avoiding conceptual stretching and increasing differentiation, respectively. Because this approach cannot be used to pursue both goals at once, we find that scholars have often turned to other strategies: creating "diminished" subtypes of democracy