Germline polymorphisms as modulators of cancer phenotypes

Identifying the complete repertoire of genes and genetic variants that regulate the pathogenesis and progression of human disease is a central goal of post-genomic biomedical research. In cancer, recent studies have shown that genome-wide association studies can be successfully used to identify germline polymorphisms associated with an individual's susceptibility to malignancy. In parallel to these reports, substantial work has also shown that patterns of somatic alterations in human tumors can be successfully employed to predict disease prognosis and treatment response. A paper by Van Ness et al. published this month in BMC Medicine reports the initial results of a multi-institutional consortium for multiple myeloma designed to evaluate the role of germline polymorphisms in influencing multiple myeloma clinical outcome. Applying a custom-designed single nucleotide polymorphism microarray to two separate patient cohorts, the investigators successfully identified specific combinations of germline polymorphisms significantly associated with early clinical relapse. These results raise the exciting possibility that besides somatically acquired alterations, germline genetic background may also exert an important influence on cancer patient prognosis and outcome. Future 'personalized medicine' strategies for cancer may thus require incorporating genomic information from both tumor cells and the non-malignant patient genome.     

Pathways to ischemic neuronal cell death: are sex differences relevant?

We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.     

A new gene encoding tRNAPro (GGG) is present in the chloroplast genome of black pine: a compilation of 32 tRNA genes from black pine chloroplasts

The chloroplast genome of black pine (Pinus thumbergii), a gymnosperm, contains 32 different tRNA genes, 30 of which correspond to those previously identified in tobacco and rice chloroplast genomes. Two additional genes encode tRNA^Pro (GGG) and tRNA^Arg (CCG); the former is newly identified while the latter is present in liverwort, Physcomitrella patens and Angiopteris lygodiifolia, chloroplast genomes. Moreover, a partial copy of the split tRNA^Gly (UCC) gene and full copies of tRNA^His (GUG), tRNA^Thr (GGU) and tRNA^Ser (GCU) genes are present in the large single-copy region of the genome, suggesting extensive rearrangements of the chloroplast genome during evolutio. No tRNA genes whose tRNA products can recognize codons CUU/C (Leu) and GCU/C (Ala) have been found. We propose that the 32 tRNAs are sufficient to read all the 61 sense codons in the black pine system using the two-out-of-three and the U:N wobble mechanisms.     

Sequence analyses of the 3' genome end and NP gene of human parainfluenza type 2 virus: sequence variation of the gene-starting signal and the conserved 3' end

We cloned and determined the nucleotide sequences of cDNAs against nucleocapsid protein (NP) mRNA and the genomic RNA of human parainfluenza type 2 virus (PIV-2). The 3' terminal region of genomic RNA was compared among PIV-2, mumps virus (MuV), Newcastle disease virus (NDV), measles virus (MV), PIV-3, bovine parainfluenza type 3 virus (BPIV-3), Sendai virus (SV), and vesicular stomatitis virus (VSV), and an extensive sequence homology was observed between PIV-2 and MuV. Although no significant sequence relatedness was observed between PIV-2 and other viruses, the terminal four nucleotides were identical in the viruses compared, implying a specific role of these nucleotides on the replication of paramyxoviruses. A primer extension analysis elucidated the major NP mRNA initiation site with the sequence UCUAAGCC, which showed a moderate homology with the gene-starting consensus sequences of other paramyxoviruses. On the other hand, the NP mRNA was terminated at the nucleotide stretch AAAUUCUUUUU, and this sequence was conserved in all the PIV-2 genes, indicating that the oligonucleotides will form a part of the gene attenuation signal of PIV-2. Comparisons of NP protein sequence indicated a possible subgrouping of the paramyxoviruses into two groups, one of which is a group including PIV-2, PIV-4, MuV, and NDV, and another is a group including PIV-3, BPIV-3, and SV. This result supports an idea from our previous studies using polyclonal and monoclonal antibodies. Furthermore, our data indicated that the PIV-2 NP protein sequence was more closely related to MV and CDV than to other parainfluenza viruses, PIV-3 and SV.     

Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping

Background  

Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets.     

Experimental autoimmune thyroiditis in nonobese diabetic mice lacking interferon regulatory factor-1

Interferon regulatory factor-1 (IRF-1) is pivotal in the regulation of interferon (IFN)-mediated immune reactions, and studies suggest that IRF-1 is involved in the development of autoimmune diseases. IRF-1+/+, +/-, and -/- nonobese diabetic (NOD) mice were immunized with mouse thyroglobulin (mTg) to determine whether IRF-1 is required in experimental autoimmune thyroiditis (EAT), a murine model for Hashimoto's thyroiditis (HT). IRF-1-deficient mice developed EAT and anti-mTg antibodies comparable to IRF-1+/+ and +/- mice. Whereas both CD4+ and CD8+ T cells were found in thyroids of IRF-1+/+ mice, the latter was not in IRF-1-/- mice. Major histocompatibility complex class II antigen was comparably expressed in thyroids of IRF-1+/+ and -/- mice. Lack of IRF-1 resulted in decreased CD8+ T cell number in the spleen and reduced IFNgamma production by splenocytes. Our results suggest that IRF-1 is not pivotal in EAT in NOD mice.     

Biomechanical Properties of Esophagus during Systemic Treatment with Epidermal Growth Factor in Rats

The epidermal growth factor (EGF) is a growth factor with effects on many cell types and tissue. Morphometric and passive biomechanical properties were studied in isolated segments of the esophagus in 22 EGF-treated rats and 12 control rats. The rats were divided into groups with EGF treatment for 2, 4, 7, and 14 days (n=6 for each group except n=4 for the 14 days EGF-treatment group) or saline treatment (n=3 for each group). The mechanical test was performed as a distension experiment in vitro where the whole esophagus was stretched to its in situ length and distended with pressures up to 10 cm H₂O using a ramp distension protocol. The pressure and outer diameter were recorded. Circumferential stress (force per area) and strain (deformation) were computed from the diameter and pressure data using the zero-stress state as reference. The zero-stress state was obtained by cutting esophageal rings radially. This caused the rings to open up into a sector. EGF induced pronounced morphometric changes, e.g., the wall thickness, wall cross-sectional area, and inner and outer circumferential lengths significantly increased during the EGF treatment. Histological analysis showed mucosa and submucosa growth during EGF treatment. The opening angle and residual strains increased with the highest value in the 14 days EGF-treated group (P < 0.05). The change in opening angle depended largely on the change in mucosa thickness. Furthermore, the circumferential stiffness of the esophagus reached a maximum after 7 days EGF treatment (P < 0.01). © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8717Ee     

Effects of dipyridamole on Plasmodium falciparum-infected erythrocytes

This study assessed the antimalarial activity of dipyridamole, a well-known vasodilator and inhibitor of platelet aggregation. Dipyridamole was effective against all of the erythrocytic stages such as rings, trophozoites and schizonts, and induced ultrastructural changes during the transition from trophozoite to schizont in vitro. Merozoites were also inhibited from invading dipyridamole-treated erythrocytes. It seems that dipyridamole binds to the erythrocyte membrane blocking the receptors for the merozoite. The 50% inhibitory concentration (IC(50)) of dipyridamole against Plasmodium falciparum infection was 30 nM. The IC(50) of chloroquine decreased from 97.0 nM to 13.7 nM when combined with dipyridamole (0.1 nM). Therefore, we suggest that dipyridamole has antiplasmodial activity due to its ability to arrest parasite development and by inhibiting merozoite invasion of the erythrocytes. Chloroquine activity against P. falciparum is also enhanced by the addition of dipyridamole. Treatment with a combination of chloroquine and dipyridamole may lead to a more effective treatment for chloroquine-resistant strains of P. falciparum.