TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.     

Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection

Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge.     

Vergleichende elektrophoretische Untersuchungen von Serumproteinen und löslichen Leberproteinen aus normalen und tumortragenden Goldhamstern

Zusammenfassung Es wird über die vergleichende Fraktionierung löslicher Proteine aus Lebern normaler Goldhamster und von Goldhamstern mit Nierencarcinom (Horning) sowie von Goldhamsterlebermetastasen mit Hilfe von freier und Stärkegelelektrophorese berichtet. Mit den gleichen Methoden wurden Seren von normalen und tumortragenden Goldhamstern untersucht. Mit einer starken Erhöhung der ₁-Globulinfraktion im Tumorserum gegenüber dem Normalserum geht eine geringe Erhöhung der -Globuline in der Leber desselben Tieres einher. Gleichzeitig ist der Albumingehalt der Seven von Tumortieren herabgesetzt. Als charakteristische Werte für das Verhältnis des Albumins zum ₁-Globulin ergeben sich für das Normalserum 3,5 und für das Tumortier-Serum 1,8. Verglichen mit dem Normalserum ist die elektrophoretische Beweglichkeit der Serumproteine von Tumorträgern erhöht. Die Aktivitätsverteilung der 5 LDH-Isoenzyme und das Spektrum der Esterasen und sauren Phosphatasen zeigten charakteristische Unterschiede zwischen normaler und metastatischer Leber. Die Isoenzyme der Malat-Dehydrogenase und alkalischen Phosphatase ergaben ähnliche Bilder bei Lebern verschiedener Herkunft.

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Summary The comparative fractionation of the soluble proteins of livers from normal golden hamsters, from livers of animals with a transplantable renal carcinoma (Horning) from liver metastases and of serum proteins from the same animals by means of free and starch gel electrophoresis is described. In the sera of tumorbearing animals the albumin content is decreased and the ₁-globulin content increased. The -globulin content in the livers of animals with carcinomas was increased to a smaller extent. The albumin ₁-globulin ratio in the serum of normal animals was 3.5 and in tumor-bearing animals 1.8. As compared with normal serum the electrophoretic mobility of the serum proteins from tumor-bearing animals was increased. Characteristics differences between normal and metastatic livers were found in the lactic dehydronase, esterase and acidic phosphatase isozyme patterns. The isozymes of the malic dehydrogenase and alkaline phosphatase revealed similar patterns in normal liver and in livers free of metastases from tumor-bearing animals.

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IV. Mitt. über Proteine aus Tumor- und Normalgeweben, 3. Mitt. s. Plass und Schwenke (1967).     

Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.     

Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI

Tissue pH is an indicator of altered cellular metabolism in diseases including stroke and cancer. Ischemic tissue often becomes acidic due to increased anaerobic respiration leading to irreversible cellular damage. Chemical exchange saturation transfer (CEST) effects can be used to generate pH-weighted magnetic resonance imaging (MRI) contrast, which has been used to delineate the ischemic penumbra after ischemic stroke. In the current study, a novel MRI ratiometric technique is presented to measure absolute pH using the ratio of CEST-mediated contrast from amine and amide protons: amine/amide concentration-independent detection (AACID). Effects of CEST were observed at 2.75 parts per million (p.p.m.) for amine protons and at 3.50 p.p.m. for amide protons downfield (i.e., higher frequency) from bulk water. Using numerical simulations and in vitro MRI experiments, we showed that pH measured using AACID was independent of tissue relaxation time constants, macromolecular magnetization transfer effects, protein concentration, and temperature within the physiologic range. After in vivo pH calibration using phosphorus (³¹P) magnetic resonance spectroscopy (³¹P-MRS), local acidosis is detected in mouse brain after focal permanent middle cerebral artery occlusion. In summary, our results suggest that AACID represents a noninvasive method to directly measure the spatial distribution of absolute pH in vivo using CEST MRI.