HOXA10 expression induced by Abl kinase inhibitors enhanced apoptosis through PI3K pathway in CML cells

Chronic myelogenous leukemia is characterized by the reciprocal chromosomal translocation (9;22), which generates a novel fusion gene, BCR-ABL. Bcr-Abl-expressing leukemia cells are highly resistant to apoptosis. Imatinib an Abl kinase inhibitor, is a highly effective agent for patients with CML. However, a small percentage of these patients and most advanced-phase patients relapse on imatinib therapy. It is poorly understood whether the Abl kinase inhibitors are able to eradicate CML progenitor or stem cells. In this study, we investigated the role of HOXA10 in CML cell lines and the hematopoietic progenitor cells derived from CML patients, and whether the regulation of HOXA10 eradicates Bcr-Abl(+) hematopoietic stem/progenitor cells. The Abl kinase inhibitors and PI3K inhibitor, LY294002, induced the expression of HOXA10, and it enhanced apoptosis in CML cells. Moreover, the reduction of HOXA10 expression by siRNA in CML cells inhibited apoptosis by treatment with the Abl kinase inhibitors and LY294002. These results revealed that HOXA10 had an important role in induction of apoptosis by the Abl kinase inhibitors in CML cells. Finally, we showed that the inhibition of HOXA10 expression by siRNA increased the numbers of CFU-GEMM, BFU-E, and CFU-GM when the cells were treated with the combination of BMS354825 and LY294002 compared to control cells, and HOXA10 played a critical role in the committed colony-formation in CML. This study shows for the first time that the Abl kinase inhibitor and LY294002 induced HOXA10, and HOXA10 had an important role in apoptosis or cell growth inhibition in CML cells in vitro.     

Two proliferation-related proteins, TYMS and PGK1, could be new cytotoxic T lymphocyte-directed tumor-associated antigens of HLA-A2+ colon cancer.

PURPOSE: The purpose of this work was to provide a scientific basis for specific immunotherapy of colon cancer. EXPERIMENTAL DESIGN: This study focused on identification of colon tumor-associated antigens and HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) generated from tumor-infiltrating lymphocytes of a colon cancer patient. A gene expression cloning method was used to identify genes coding for tumor antigens. Fifty-six peptides with HLA-A2-binding motifs encoded by these proteins were examined for their ability to induce HLA-A2-restricted and tumor-reactive CTLs. RESULTS: We identified the following three genes coding for proliferation-related proteins: thymidylate synthase (TYMS), which is involved in chemoresistance (5-fluorouracil); 5'-aminoimidazole-4-carboxamide-1-beta-d-ribonucleotide transfolmylase/inosinicase (AICRT/I); and phosphoglycerate kinase 1 (PKG1), which was secreted by tumor cells and involved in the angiogenic process. TYMS was preferentially expressed in tumor cells, whereas AICRT/I and PKG1 were equally expressed in both cancer cells and normal tissues at the mRNA level. Among 56 peptides with HLA-A2-binding motifs encoded by these proteins, 8 peptides were recognized by the CTLs, and 5 of 8 peptides were also recognized by the CTL precursors without ex vivo activation in the peripheral blood of colon cancer patients. Furthermore, four of them (one each from TYMS and PKG1 and two from AICRT/1) possessed the ability to induce HLA-A2-restricted and peptide-specific CTLs cytotoxic to colon tumor cells in peripheral blood mononuclear cells of colon cancer patients. CONCLUSIONS: TYMS and PGK1, as well as their epitope peptides, might be appropriate target molecules for specific immunotherapy of HLA-A2(+) colon cancer patients because of the positive role of TYMS and PGK1 in chemoresistance (5-fluorouracil) and angiogenesis of tumor cells, respectively.     

Temperature management for deliberate mild hypothermia during neurosurgical procedures

Deliberate mild hypothermia is safer from the point of view of adverse events and does not require a specific technique, unlike deep or moderate hypothermia. Therefore, mild hypothermia was widely used for neurosurgical procedures. Unfortunately, the neuroprotective efficacy of intraoperative mild hypothermia has not yet been proven; however, temperature management for intraoperative deliberate mild hypothermia has been improved over the past two decades. It is very important to achieve mild hypothermia before the commencement of the main surgery, and to maintain the patient’s body temperature until the procedure is completed. In addition, it is also important to complete rewarming by the end of the surgery so that an accurate neurological evaluation can be made. Regarding the effects of mild hypothermia on outcomes, a large randomized controlled study reported that unfavorable outcomes did not differ between participants with or without hypothermia. Apart from these unfavorable outcomes, it is known that temperature management during deliberate intraoperative mild hypothermia has contributed to improvement of anesthesia practice. The accumulation of experience in this field is important. Clinical interest in deliberate mild hypothermia is currently low; however, anesthesiologists should be prepared for the time when it is required again in the future.     

Differentiation-associated carbohydrate chain on human hematopoietic cells recognized by Clerodendron trichotomum lectin

In the screening of hematopoietic cell line cell aggregations, the extract of Clerodendron trichotomum seed was found to aggregate K-562 and KG-1 specifically. In the flow cytometric analysis using FITC-conjugated purified CTL, it was confirmed that CTL recognizes the specific carbohydrate(s) which seem to appear only in the early stages of differentiation of myeloid (KG-1) and erythroid (K-562) cell line cells and erythrocytes. The CTL binding to K-562 cells was decreased by TPA treatment which is known to induce retrodifferentiation of K-562. It is also found that this carbohydrate(s) were shaded with NANA on the differentiated cells. In the erythrocyte, CTL receptor was partially shaded by NANA.     

On the use of statistics for representing the knowledge acquired from experts in a medical consulting system

For making medical consulting systems, it is important and significant to select and devise the method for representing the knowledge acquired from professional experts. As quantities of data required for consultation are increasing according to the progress of medical science, we have to introduce some new kinds of statistics into a medical consultation system. From another point of view, since the process of diagnosis of experts is considered to be a kind of effective model for compressing (or condensing) data quantitatively and qualitatively, we discuss the use of statistics for representing the knowledge acquired from experts from the standpoint of data compression.     

Variation of frontal P20 potential due to rotation of the N20-P20 dipole moment of SEPs

Summary We have applied the artificial neural network method to estimate the N20-P20 dipole from scalp SEP potentials, and have investigated the rotation of the dipole moment caused by the compression effect of a brain tumor (para-Rolandic tumor) adjacent to the central sulcus. The variation of the frontal P20 potential was demonstrated by the rotation of the N20-P20 dipole moment in 8 cases of para-Rolandic tumor. By estimation of the rotation of the dipole moment, it may be possible to obtain preoperative information regarding the relation between the central sulcus and the tumor.     

High adiponectin concentration and its role for longevity in female centenarians

Background:   Evidence from experimental models of longevity indicates that maintenance of energy homeostasis could be indispensable for longevity across various species. In humans, it has been reported that maintenance of glucose homeostasis and vascular stability is one biomedical feature of centenarians, who have reached the maximum life-span. We hypothesized that adiponectin, a novel anti-inflammatory adipocytokine, could be a protective factor against age-related metabolic alteration and atherogeneity in centenarians.
Methods:   We measured plasma adiponectin concentration in 66 female centenarians and body mass index (BMI)-matched female controls (mean age 28.3 ± 6.3 years), followed by a genetic analysis of adiponectin locus.
Results:   As compared to BMI-matched female controls, female centenarians had significantly higher plasma adiponectin concentrations. In addition, high concentrations of plasma adiponectin in centenarians was associated with favorable metabolic indicators, and with lower levels of C-reactive protein and E-selectin. In contrast, genetic analysis of 10 single nucleotide polymorphism (SNP) at adiponectin locus did not show significant association between the adiponectin gene variation and longevity.
Conclusions:   Our results suggested that hyperadiponectinemia in centenarians could play a role in maintenance of energy homeostasis and vascular stability, and may contribute to longevity.     

Lipiodol-CT for the detection of small hypovascular HCC

To evaluate the diagnostic value of Lipiodol-CT for small hypovascular HCC, we injected 3 ml or less Lipiodol into the hepatic artery of patients with chronic liver disease and small SOL in the liver detected on echogram but not on angiogram. About seven days after injection CT was used to check for accumulation of Lipiodol in the liver SOL. We found that the sensitivity of this method for detection of hypovascular HCC is only 25%. We assume that Lipiodol does not accumulate in small hypovascular HCC lesions because they have little vascular stroma. Lipiodol-CT has high diagnostic value for the detection of small hypervascular daughter HCC lesions, but this method should not be relied on for the detection of small hypovascular HCC.