Expression
of several inhibitor of apoptosis proteins (IAPs) was investigated in
the National Cancer Institute panel of 60 human tumor cell lines, and
the expression and prognostic significance of ...one of these, XIAP, was
evaluated in 78 previously untreated patients with acute myelogenous
leukemia (AML). XIAP and cIAP1 were expressed in most cancer lines
analyzed, with substantial variability in their relative levels. In
contrast, NAIP mRNA was not detectable, and cIAP2 was found at the mRNA
and protein levels in only 34 (56%) and 5 (8%) of the 60 tumor cell
lines analyzed, respectively. Interestingly, XIAP, cIAP1, and cIAP2
mRNA levels did not correlate with protein levels in the tumor lines,
indicating posttranscriptional regulation of expression. High levels of
XIAP protein in tumor cell lines were unexpectedly correlated with
sensitivity to some anticancer drugs, particularly cytarabine and other
nucleosides, whereas higher levels of cIAP1 protein levels were
associated with resistance to several anticancer drugs. The relevance
of XIAP to in vivo responses to cytarabine was explored in
AML, making correlations with patient outcome ( n =
78). Patients with lower levels of XIAP protein had significantly
longer survival (median, 133 versus 52.5 weeks;
P = 0.05) and a tendency toward longer remission
duration (median, 87 versus 52.5 weeks; P = 0.13) than those with higher levels of XIAP. Altogether, these
findings show that IAPs are widely but differentially expressed in
human cancers and leukemias and suggest that higher XIAP protein levels
may have adverse prognostic significance for patients with AML.
Organ specific drug targeting was explored in mice as a possible alternative to surgery to treat prostate diseases. Peptides that specifically recognize the vasculature in the prostate were ...identified from phage-displayed peptide libraries by selecting for phage capable of homing into the prostate after an i.v. injection. One of the phage selected in this manner homed to the prostate 10-15 times more than to other organs. Unselected phage did not show this preference. The phage bound also to vasculature in the human prostate. The peptide displayed by the prostate-homing phage, SMSIARL (single letter code), was synthesized and shown to inhibit the homing of the phage when co-injected into mice with the phage. Systemic treatment of mice with a chimeric peptide consisting of the SMSIARL homing peptide, linked to a proapoptotic peptide that disrupts mitochondrial membranes, caused tissue destruction in the prostate, but not in other organs. The chimeric peptide delayed the development of the cancers in prostate cancerprone transgenic mice (TRAMP mice). These results suggest that it may be possible to develop an alternative to surgical prostate resection and that such a treatment may also reduce future cancer risk.
A remarkable instability at simple repeated sequences characterizes gastrointestinal cancer of the microsatellite mutator phenotype (MMP). Mutations in the DNA mismatch repair gene family underlie ...the MMP, a landmark for hereditary nonpolyposis colorectal cancer. These tumors define a distinctive pathway for carcinogenesis because they display a particular spectrum of mutated cancer genes containing target repeats for mismatch repair deficiency. One such gene is BAX, a proapoptotic member of the Bcl-2 family of proteins, which plays a key role in programmed cell death. More than half of colon and gastric cancers of the MMP contain BAX frameshifts in a (G)8mononucleotide tract. However, the functional significance of these mutations in tumor progression has not been established. Here we show that inactivation of the wild-type BAX allele by de novo frameshift mutations confers a strong advantage during tumor clonal evolution. Tumor subclones with only mutant alleles frequently appeared after inoculation into nude mice of single-cell clones of colon tumor cell lines with normal alleles. In contrast, no clones of BAX-expressing cells were found after inoculation of homozygous cell clones without wild-type BAX. These results support the interpretation that BAX inactivation contributes to tumor progression by providing a survival advantage. In this context, survival analyses show that BAX mutations are indicators of poor prognosis for both colon and gastric cancer of the MMP.
The Euclidean ideal of mathematics as well as all the foundational schools in the philosophy of mathematics have been contested by the new approach, called the “maverick” trend in the philosophy of ...mathematics. Several points made by its main representatives are mentioned – from the revisability of actual proofs to the stress on real mathematical practice as opposed to its idealized reconstruction. Main features of real proofs are then mentioned; for example, whether they are convincing, understandable, and/or explanatory. Therefore, the new approach questions Hilbert’s Thesis, according to which a correct mathematical proof is in principle reducible to a formal proof, based on explicit axioms and logic.
Caspase-9 is critical for cytochrome c (cyto-c)-dependent apoptosis and normal brain development. We determined that this apical protease in the cyto-c pathway for apoptosis resides inside ...mitochondria in several types of cells, including cardiomyocytes and many neurons. Caspase-9 is released from isolated mitochondria on treatment with Ca2+ or Bax, stimuli implicated in ischemic neuronal cell death that are known to induce cyto-c release from mitochondria. In neuronal cell culture models, apoptosis-inducing agents trigger translocation of caspase-9 from mitochondria to the nucleus, which is inhibitable by Bcl-2. Similarly, in an animal model of transient global cerebral ischemia, caspase-9 release from mitochondria and accumulation in nuclei was observed in hippocampal and other vulnerable neurons exhibiting early postischemic changes preceding apoptosis. Loss of mitochondrial barrier function during neuronal damage from ischemia or other insults therefore may play an important role in making certain caspases available to participate in apoptosis.
This article examines the official encounters in Poland of Pope John Paul II with representatives of the Polish Jewish community. This study includes a first-hand account of the atmosphere of the ...meetings and their backgrounds. This article also offers an analysis of the Pope’s addresses.
Immunohistochemistry (IHC) was performed on archived bone marrow (BM) with a phosphospecific anti-AKT antibody. IHC on 26 BM biopsies from patients with multiple myeloma (MM) demonstrated phospho-AKT ...staining of malignant plasma cells in a cell membrane–specific pattern, whereas nonmalignant hematopoietic cells did not stain. Preabsorption of the antibody with phosphorylated AKT peptide, but not nonphosphorylated peptide, abrogated staining. Frequency of plasma cell staining in BMs of patients with stage I or smoldering MM was significantly less than that of stage III MM marrows. Plasma cells in 10 patients with monoclonal gammopathy of undetermined significance were not stained by the antibody. To investigate the significance of AKT activation, 2 cell lines initiated from cultures of primary MM cells were also studied. Both demonstrated constitutive AKT activation. Interruption of AKT activation and activity, achieved by either exposure to wortmannin or by ectopic expression of a dominant negative AKT mutant, resulted in inhibition of MM cell growth in vitro. These results indicate that activation of the AKT kinase is a characteristic of MM cells and suggest that AKT activity is important for MM cell expansion.
Philosophy should seriously take into account the presence of computers. Computer enthusiasts point towards a new Pythagoreanism, a far reaching generalization of logical or mathematical views of the ...world. Most of us try to retain a belief in the permanence of human superiority over robots. To justify this superiority, Gödel’s theorem has been invoked, but it can be demonstrated that this is not sufficient. Other attempts are based on the scope and fullness of our perception and feelings. Yet the fact is that more and more can be computer simulated. In order to secure human superiority over robots, reference to the realm of human relations and attitudes seems more promising. Insights provided by philosophy of dialogue can help. They suggest an ultimate extension of the Turing test. In addition, it seems that in order to justify the belief in human superiority one must rely on the individual experiences that indicate a realm that is not merely subjective. It makes sense to call it religious.
God’s name “Elohim,” common in the Hebrew Bible and Jewish tradition, is always used with verbs in the singular even though it is in the plural form. It is shown here that the ungrammatical usage can ...be seen as the best solution to a natural problem. Namely, tradition assumes that it should be impossible to talk about a general category of gods within which the one God could be located. The best and perhaps the only way to prevent the implicit pluralization of the unique God is to put his name in plural even though it is intended to be used as if it were singular. One cannot form the plural form of the name that is already grammatically plural! Surprisingly, this explanation seems to have been considered by neither classical nor modern commentators.
OBJECTIVES
The aim of the present study was to determine if myocytes can die by apoptosis in fibrillating and dilated human atria.
BACKGROUND
The cellular remodeling that occurs during atrial ...fibrillation (AF) may reflect a degree of dedifferentiation of the atrial myocardium, a process that may be reversible.
METHODS
We examined human right atrial myocardium specimens (n = 50) for the presence of apoptotic myocytes. We used immunohistochemical and Western blotting analysis to examine the expression of a final effector of programmed cell death, caspase-3 (CASP-3) and of regulatory proteins from the BCL-2 family.
RESULTS
Sections from atria in AF contained a high percentage of large myocytes with a disrupted sarcomeric apparatus replaced by glycogen granules (64.4 ± 6.3% vs. 12.2 ± 5.8%). These abnormal myocytes, which also predominated in atria from hearts with decreased left ventricular ejection fraction (42.3 ± 10.1%), contained large nuclei, most of which were TUNEL positive, indicating a degree of DNA breakage. None of these abnormal myocytes expressed the proliferative antigen Ki-67. A small percentage of the enlarged nuclei (4.2 ± 0.8%) contained condensed chromatin and were strongly TUNEL positive. Both the pro- and activated forms of CASP-3 were detected in diseased myocardial samples, which also showed stronger CASP-3 expression than controls. Expression of the antiapoptotic BCL-2 protein was decreased in diseased atria, whereas that of the proapoptotic BAX protein remained unchanged.
CONCLUSIONS
In fibrillating and dilated atria, apoptotic death of myocytes with myolysis contributes to cellular remodeling, which may not be entirely reversible.
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