A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase inhibitor.

ZD1694 ('Tomudex'), a novel, direct and specific thymidylate synthase (TS) inhibitor, was developed in a collaborative research programme between Zeneca Pharmaceuticals and the Institute of Cancer Research (UK) and entered clinical trials in 1991; phase II studies began in 1992, using 3.0 mg m-2 every 3 weeks as a short 15 min infusion. Forty-six patients entered a phase II study of ZD1694 in advanced breast cancer. A total of 74% of patients had received prior systemic therapy (either as adjuvant cytotoxic or hormonal therapy or hormone therapy for advanced disease); 39% had received prior adjuvant cytotoxic chemotherapy. All patients had measurable disease and 50% had liver metastases. In all 43 patients were evaluable for response. Of these patients 26% achieved complete (CR) or partial response (PR) (95% Cl 14-42%). A response rate of 44% was seen in liver metastases. Two patients achieved CR of 265 and 301 days' duration respectively, one in locoregional disease, and one in liver metastases. The most common grade 3/4 adverse events were nausea and vomiting (11%), diarrhoea (11%) and leucopenia (20%). Grade 3/4, self-limited and reversible increases in transaminases were seen in 22% of patients. ZD1694 has useful single agent activity in patients with hormone-refractory advanced breast cancer, comparable with that reported for other anti-metabolites, with acceptable tolerability

Ancient homeobox gene loss and the evolution of chordate brain and pharynx development: deductions from amphioxus gene expression

Homeobox genes encode a large superclass of transcription factors with widespread roles in animal development. Within chordates there are over 100 homeobox genes in the invertebrate cephalochordate amphioxus and over 200 in humans. Set against this general trend of increasing gene number in vertebrate evolution, some ancient homeobox genes that were present in the last common ancestor of chordates have been lost from vertebrates. Here, we describe the embryonic expression of four amphioxus descendants of these genes—AmphiNedxa, AmphiNedxb, AmphiMsxlx and AmphiNKx7. All four genes are expressed with a striking asymmetry about the left–right axis in the pharyngeal region of neurula embryos, mirroring the pronounced asymmetry of amphioxus embryogenesis. AmphiMsxlx and AmphiNKx7 are also transiently expressed in an anterior neural tube region destined to become the cerebral vesicle. These findings suggest significant rewiring of developmental gene regulatory networks occurred during chordate evolution, coincident with homeobox gene loss. We propose that loss of otherwise widely conserved genes is possible when these genes function in a confined role in development that is subsequently lost or significantly modified during evolution. In the case of these homeobox genes, we propose that this has occurred in relation to the evolution of the chordate pharynx and brain

Separation of breast cancer and organ microenvironment transcriptomes in metastases

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression

Head of State of Exception

During the escalation of the “German Autumn” in 1977 the Federal German government resorted to a specific form of crisis management that had been described as an undeclared state of exception. It was Federal chancellor Helmut Schmidt in the first place who oversaw the anti-terrorist measures in the situation room where the executive branch ruled for six weeks beyond any parliamentary control. This article examines the role that Helmut Schmidt had played for the creation of a “subjective state of exception” (Julius Hatschek) and how this could be seen as stemming from Schmidt’s earlier experiences and handling of crisis situations dating back to the 1960s. In this regard it has to be asked with Giorgio Agamben, if in the West German case, the state of exception had become the rule

The Origins of Concentric Demyelination: Self-Organization in the Human Brain

Baló's concentric sclerosis is a rare atypical form of multiple sclerosis characterized by striking concentric demyelination patterns. We propose a robust mathematical model for Baló's sclerosis, sharing common molecular and cellular mechanisms with multiple sclerosis. A reconsideration of the analogies between Baló's sclerosis and the Liesegang periodic precipitation phenomenon led us to propose a chemotactic cellular model for this disease. Rings of demyelination appear as a result of self-organization processes, and closely mimic Baló lesions. According to our results, homogeneous and concentric demyelinations may be two different macroscopic outcomes of a single fundamental immune disorder. Furthermore, in chemotactic models, cellular aggressivity appears to play a central role in pattern formation

Morphogenetic mechanisms forming the notochord rod: The turgor pressure‐sheath strength model

The notochord is a defining feature of chordates. During notochord formation in vertebrates and tunicates, notochord cells display dynamic morphogenetic movement, called convergent extension, in which cells intercalate and align at the dorsal midline. However, in cephalochordates, the most basal group of chordates, the notochord is formed without convergent extension. It is simply developed from mesodermal cells at the dorsal midline. This suggests that convergent extension movement of notochord cells is a secondarily acquired developmental attribute in the common ancestor of olfactores (vertebrates + tunicates), and that the chordate ancestor innovated the notochord upon a foundation of morphogenetic mechanisms independent of cell movement. Therefore, this review focuses on biological features specific to notochord cells, which have been well studied using clawed frogs, zebrafish, and tunicates. Attributes of notochord cells, such as vacuolation, membrane trafficking, extracellular matrix formation, and apoptosis, can be understood in terms of two properties: turgor pressure of vacuoles and strength of the notochord sheath. To maintain the straight rod-like structure of the notochord, these parameters must be counterbalanced. In the future, the turgor pressure-sheath strength model, proposed in this review, will be examined in light of quantitative molecular data and mathematical simulations, illuminating the evolutionary origin of the notochord