Evaluation of a novel vaccine (HVJ-liposome/HSP65 DNA+IL-12 DNA) against tuberculosis using the cynomolgus monkey model of TB

We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome (HSP65+IL-12/HVJ). This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine, on the basis of an induction of the CTL activity and improvement of the histopathological tuberculosis lesions, respectively. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. Furthermore, the combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis for human clinical trials.     

Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy

Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p < .05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p < .05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p < .01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p < .05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.     

Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant

Two GATA1-related leukemias have been described: one is an erythroleukemia that develops in mice as a consequence of diminished expression of wild-type GATA1, whereas the other is an acute megakaryoblastic leukemia (AMKL) that arises in Down syndrome children as a consequence of somatic N-terminal truncation (ΔNT) of GATA1 . We discovered that mice expressing the shortened GATA1 protein (ΔNTR mice) phenocopies the human transient myeloproliferative disorder (TMD) that precedes AMKL in Down syndrome children. In perinatal livers of the ΔNTR mutant mice, immature megakaryocytes accumulate massively, and this fraction contains cells that form hyperproliferative megakaryocytic colonies. Furthermore, showing good agreement with the clinical course of TMD in humans, ΔNTR mutant mice undergo spontaneous resolution from the massive megakaryocyte accumulation concomitant with the switch of hematopoietic microenvironment from liver to bone marrow/spleen. These results thus demonstrate that expression of the GATA1/Gata1 N-terminal deletion mutant per se induces hyperproliferative fetal megakaryopoiesis. This mouse model serves as an important means to clarify how impaired GATA1 function contributes to the multi-step leukemogenesis.     

Fixed drug eruption due to allylisopropylacetylurea

We report a case of fixed drug eruption due to allylisopropylacetylurea. A 21-year-old female developed purplish-red round eruptions on her neck and left thigh after taking an analgesic containing isopropylantipyrine, allylisopropylacetylurea, phenacetin and anhydrous caffeine. Patch testing with the analgesic and its ingredients on the eruptive area showed positive reactions to the analgesic and allylisopropylacetylurea, while patch testing on the non-eruptive area showed negative reactions, We diagnosed her condition as a fixed drug eruption due to allylisopropylacetylurea in an analgesic.