Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.

Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma

The historical development of the cell death concept is reviewed, with special attention to the origin of the terms necrosis, coagulation necrosis, autolysis, physiological cell death, programmed cell death, chromatolysis (the first name of apoptosis in 1914), karyorhexis, karyolysis, and cell suicide, of which there are three forms: by lysosomes, by free radicals, and by a genetic mechanism (apoptosis). Some of the typical features of apoptosis are discussed, such as budding (as opposed to blebbing and zeiosis) and the inflammatory response. For cell death not by apoptosis the most satisfactory term is accidental cell death. Necrosis is commonly used but it is not appropriate, because it does not indicate a form of cell death but refers to changes secondary to cell death by any mechanism, including apoptosis. Abundant data are available on one form of accidental cell death, namely ischemic cell death, which can be considered an entity of its own, caused by failure of the ionic pumps of the plasma membrane. Because ischemic cell death (in known models) is accompanied by swelling, the name oncosis is proposed for this condition. The term oncosis (derived from onkos, meaning swelling) was proposed in 1910 by von Reckling-hausen precisely to mean cell death with swelling. Oncosis leads to necrosis with karyolysis and stands in contrast to apoptosis, which leads to necrosis with karyorhexis and cell shrinkage.

Apoptosis, oncosis, and necrosis : an overview of cell death

We have used the pH-induced self-assembly of a peptide-amphiphile to make a nanostructured fibrous scaffold reminiscent of extracellular matrix. The design of this peptide-amphiphile allows the nanofibers to be reversibly cross-linked to enhance or decrease their structural integrity. After cross-linking, the fibers are able to direct mineralization of hydroxyapatite to form a composite material in which the crystallographic c axes of hydroxyapatite are aligned with the long axes of the fibers. This alignment is the same as that observed between collagen fibrils and hydroxyapatite crystals in bone.

http://science.sciencemag.org/content/sci/294/5547/1684.full.pdf

Self-assembly and mineralization of peptide-amphiphile nanofibers

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Programmed cell death (PCD) plays a key role in developmental biology and in maintenance of the steady state in continuously renewing tissues. Currently, its existence is inferred mainly from gel electrophoresis of a pooled DNA extract as PCD was shown to be associated with DNA fragmentation. Based on this observation, we describe here the development of a method for the in situ visualization of PCD at the single-cell level, while preserving tissue architecture. Conventional histological sections, pretreated with protease, were nick end labeled with biotinylated poly dU, introduced by terminal deoxy-transferase, and then stained using avidin-conjugated peroxidase. The reaction is specific, only nuclei located at positions where PCD is expected are stained. The initial screening includes: small and large intestine, epidermis, lymphoid tissues, ovary, and other organs. A detailed analysis revealed that the process is initiated at the nuclear periphery, it is relatively short (1-3 h from initiation to cell elimination) and that PCD appears in tissues in clusters. The extent of tissue-PCD revealed by this method is considerably greater than apoptosis detected by nuclear morphology, and thus opens the way for a variety of studies.

/pdf/identification-of-programmed-cell-death-in-situ-via-specific-1b2bstafua.pdf

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.

One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them.

https://www.pnas.org/content/pnas/98/5/2640.full.pdf

Top-down morphogenesis of colorectal tumors.

Comparative analysis of structurally defined heparin binding sequences reveals a distinct spatial distribution of basic residues.

Publisher Summary The basic requirements for any methodology of programmed cell death (PCD) detection include (1) resolution at the individual cell level, and (2) in situ applicability while preserving the tissue architecture. To investigate PCD in its physiological context, the chapter develops a method that satisfies both criteria that is referred to as “terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL).” This technique is based on the observation that PCD is associated with DNA degradation. Researchers have come to consider the appearance of the ladder of nucleosomal DNA on agarose gels as the hallmark of PCD. The TUNEL method relies on the in situ labeling of DNA breaks in individual nuclei in tissue sections processed through the routine procedures of histopathology. TUNEL relies on the specific binding of TdT to exposed 3′-OH ends of DNA followed by the synthesis of a labeled polydeoxynucleotide molecule. Nuclear DNA on histological sections is first exposed by proteolytic treatment; then TdT is used to incorporate biotinylated deoxyuridine into the sites of DNA breaks. The signal is amplified by avidin-peroxidase, enabling conventional histochemical identification of PCD by light microscopy.

Identification of dying cells--in situ staining.

Microsatellites are tandem repeat sequences abundant in the genomes of higher eukaryotes and hitherto considered as "junk DNA." Analysis of a human genome representative data base (2.84 Mb) reveals a distinct juxtaposition of A-rich microsatellites and retroposons and suggests their coevolution. The analysis implies that most microsatellites were generated by a 3'-extension of retrotranscripts, similar to mRNA polyadenylylation, and that they serve in turn as "retroposition navigators," directing the retroposons via homology-driven integration into defined sites. Thus, they became instrumental in the preservation and extension of primordial genomic patterns. A role is assigned to these reiterating A-rich loci in the higher-order organization of the chromatin. The disease-associated triplet repeats are mostly found in coding regions and do not show an association with retroposons, constituting a unique set within the family of microsatellite sequences.

http://www.pnas.org/content/93/13/6470.full.pdf

Shmuel A. Ben-Sasson

Papers

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.

Top-down morphogenesis of colorectal tumors.

Comparative analysis of structurally defined heparin binding sequences reveals a distinct spatial distribution of basic residues.

Identification of dying cells--in situ staining.

Microsatellite spreading in the human genome: evolutionary mechanisms and structural implications