Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

Population, resources, and environment: Implications of human behavioral ecology for conservation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43481/1/11111_2005_Article_BF02207996.pd

Thymus development in the zebrafish ( Danio rerio

The thymus is present in all gnathostome vertebrates and is an essential organ for the adaptive immune system via the generation of functional mature T-cells. Over the life span of mammals, the thymus undergoes morphological and functional alterations, including an age-related involution, which in humans starts in early life. Life history tradeoffs have been suggested as possible reasons for thymus involution. While in teleost fish, only a few studies have investigated alterations of thymus structure and function over different life stages, resulting in a fragmented database. Here, we investigated the thymus growth of zebrafish (Danio rerio) from early life, throughout puberty and reproductive stage, up to 1-year-old. We assessed thymus growth by histological and morphometric analyses and thymocyte numbers. Thymus function was assessed by measuring the transcripts of the thymocyte marker genes, ikaros, tcrα, and tcrδ. Additionally, we analyzed gonad maturity and tail homogenate vitellogenin concentrations to align thymus status with the status of the reproductive system. Our results showed that the zebrafish thymus, in contrast to the human thymus, grew strongly during early life and puberty but started to undergo involution when the fish reached the reproductive age. The involution was characterized by reduced thymus area and thymocyte number, altered histoarchitecture, and decreasing thymocyte marker gene transcript levels. Our findings suggest that age-related changes of the zebrafish thymus do exist and could be partly explained in terms of resource tradeoffs, but also in terms of the ontogenetically late development of a functional adaptive immune system in teleosts

The Reproductive Ecology of Industrial Societies, Part I : Why Measuring Fertility Matters.

Is fertility relevant to evolutionary analyses conducted in modern industrial societies? This question has been the subject of a highly contentious debate, beginning in the late 1980s and continuing to this day. Researchers in both evolutionary and social sciences have argued that the measurement of fitness-related traits (e.g., fertility) offers little insight into evolutionary processes, on the grounds that modern industrial environments differ so greatly from those of our ancestral past that our behavior can no longer be expected to be adaptive. In contrast, we argue that fertility measurements in industrial society are essential for a complete evolutionary analysis: in particular, such data can provide evidence for any putative adaptive mismatch between ancestral environments and those of the present day, and they can provide insight into the selection pressures currently operating on contemporary populations. Having made this positive case, we then go on to discuss some challenges of fertility-related analyses among industrialized populations, particularly those that involve large-scale databases. These include "researcher degrees of freedom" (i.e., the choices made about which variables to analyze and how) and the different biases that may exist in such data. Despite these concerns, large datasets from multiple populations represent an excellent opportunity to test evolutionary hypotheses in great detail, enriching the evolutionary understanding of human behavior