Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status

Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph⁺MPAL) is a rare type of acute leukemia having myeloid and lymphoid features. In the present study, we describe the successful treatment of a 71-year-old Japanese female patient with Ph⁺MPAL by the alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutations. The patient survived in her third complete remission (CR) for over 4 years. In her first CR, the patient was treated with multiple-agent chemotherapy and underwent maintenance therapy with imatinib and monthly vincristine and prednisolone (VP). At the first relapse, an examination of the bone marrow revealed a transformation into acute lymphoblastic leukemia and an F317L mutation in BCR-ABL1 gene, which responded preferentially to nilotinib over dasatinib. She achieved second CR, and nilotinib with VP therapy was selected for maintenance treatment. At second relapse, BCR-ABL1 mutational analysis revealed Y253H mutation instead of F317L mutation, resulting in resistance to nilotinib. The patient achieved third CR with dasatinib and VP therapy, and maintained CR with this treatment. This suggests that appropriate alternation of TKIs may contribute to long-term survival in elderly patients with Ph⁺MPAL.     

Serum DJ-1 level is positively associated with improvements in some aspects of metabolic syndrome in Japanese women through lifestyle intervention

DJ-1 is a protein that is associated with Parkinson disease and cancer, and the reduction of DJ-1 function and expression is also thought to be a cause of diabetes and hypertension. However, little is known about the association between the plasma concentration of DJ-1 and risk of metabolic syndrome. We hypothesized that a lifestyle intervention would increase serum DJ-1 and that up-regulated DJ-1 functions will result in the prevention of metabolic syndrome. The objective of our study is to examine whether the level of serum DJ-1 is associated with the risk of metabolic syndrome. Therefore, to reveal the association between DJ-1 and metabolic syndrome, this study investigated lifestyle intervention in a control group (n = 37) and intervention group (n = 45). The results showed that body mass index, body fat ratio, waist-hip ratio, waist circumference, blood pressure, and plasma glucose level were improved in the intervention group, as compared with those in the control group. Furthermore, serum levels of DJ-1 were increased in the intervention group, when compared with those in the control group. These results suggest that serum DJ-1 is increased by lifestyle intervention and that increased serum DJ-1 prevents metabolic syndrome. Thus, the level of serum DJ-1 will become one of the indexes for the risk of metabolic syndrome.     

Phorbol-ester-stimulated human lymphoid cell lines produce a plasminogen activator modulator inducing cell-bound urokinase-type plasminogen activator in malignant tumor cell lines

The importance of cell-associated plasminogen activation in tumor invasion and metastasis is becoming increasingly evident. To clarify the modulators of cell-associated plasminogen activation in malignant states, we have recently established an assay system utilizing endogenous plasminogen activators on the cell surface. In the present study using the assay system, we found that the conditioned medium from phorbol 12-myristate 13-acetate (PMA)-stimulated human lymphoid cell lines, HUT 78 and Raji, strongly enhanced plasminogen activator (PA) activity on the surface of human malignant tumor cell lines (WI-38 VA13 2RA, A431, A549 and HT-1080). The enhancing effect was inhibited by the addition of actinomycin D. By gel filtration, the active substances in PMA-stimulated HUT 78- and Raji-conditioned media were eluted in similar fractions corresponding to molecular weights of 60 to 80 kDa. The active substance was heat-labile. The enhanced PA activities were completely inhibited by anti-urokinase-type plasminogen activator (uPA) IgG. Moreover, the active substance was found to increase in cell-bound uPA antigen. These findings suggest that a population of activated lymphocytes produces a plasminogen activator modulator that induces uPA on the surface of malignant tumor cells. © 1996 Wiley-Liss, Inc.     

ASK1 signaling regulates phase-specific glial interactions during neuroinflammation

Neuroinflammation is well known to be associated with neurodegenerative diseases. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in neuroinflammation, but its precise cellular and molecular mechanisms remain unknown. In this study, we generated conditional knockout (CKO) mice that lack ASK1 in T cells, dendritic cells, microglia/macrophages, microglia, or astrocytes, to assess the roles of ASK1 during experimental autoimmune encephalomyelitis (EAE). We found that neuroinflammation was reduced in both the early and later stages of EAE in microglia/macrophage-specific ASK1 knockout mice, whereas only the later-stage neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice. ASK1 deficiency in T cells and dendritic cells had no significant effects on EAE severity. Further, we found that ASK1 in microglia/macrophages induces a proinflammatory environment, which subsequently activates astrocytes to exacerbate neuroinflammation. Microglia-specific ASK1 deletion was achieved using a CX3CR1^CreER system, and we found that ASK1 signaling in microglia played a major role in generating and maintaining disease. Activated astrocytes produce key inflammatory mediators, including CCL2, that further activated and recruited microglia/macrophages, in an astrocytic ASK1-dependent manner. Astrocyte-specific analysis revealed CCL2 expression was higher in the later stage compared with the early stage, suggesting a greater proinflammatory role of astrocytes in the later stage. Our findings demonstrate cell-type–specific roles of ASK1 and suggest phase-specific ASK1-dependent glial cell interactions in EAE pathophysiology. We propose glial ASK1 as a promising therapeutic target for reducing neuroinflammation.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that stimulates the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways, and it mediates diverse biological signals leading to cell death, differentiation, and senescence (1, 2). Deletion of ASK1 in mice suppresses neuronal cell death from injury (3, 4), and recent studies indicate that ASK1 is involved in various neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS) (5–8). MS is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Experimental autoimmune encephalomyelitis (EAE) is a classic model widely used to explore pathogenic mechanisms of MS, generated by administering a myelin basic protein peptide that induces an autoimmune response directed to myelin (9). During MS/EAE, activated microglia/macrophages are the first cells to respond to inflammatory insults within the CNS. Microglia/macrophages may be polarized into proinflammatory or antiinflammatory states, with each state having a distinct molecular phenotype and effector function, and targeting microglia/macrophages may have therapeutic benefits in MS/EAE treatment (10–12). Astrocytes, another subset of glia, are the most abundant cell population within the CNS. Astrocytes are involved in the regulation of synaptic function, plasticity, and maintaining brain homeostasis, and they are thought to contribute to the pathogenesis of MS/EAE by producing proinflammatory cytokine/chemokines such as CCL2 (13–16). In recent years, astrocytes have also been shown to polarize into different subtypes: A1 astrocytes are neurotoxic, and blocking the conversion of astrocytes into the A1 phenotype is neuroprotective (17, 18); although, nowadays, the activation state is described to be more diverse than the simple A1/A2 nomenclature (19, 20). Studies of intrinsic and external factors involved in astrocyte activation or polarization may provide information regarding how astrocytic function changes during disease, which may lead to the development of novel therapies.We previously reported that ASK1 deficiency ameliorated the severity of EAE, using conventional ASK1 knockout (ASK1 KO) mice (21). In this study, we selectively deleted ASK1 from five types of cells: T cells, dendritic cells, microglia/macrophages, microglia, and astrocytes, to dissect out the roles of ASK1 in different cell types during neuroinflammation. Our study revealed pathogenic roles of ASK1 signaling in innate immune cells and how they interact with each other in the progression of MS/EAE.     

Synthesis and Characterization of High-Entropy-Alloy-Type Layered Telluride MBi2Te4 (M = Ag,In, Sn,Pb, Bi)

Recently, high-entropy alloys (HEAs) and HEA-type compounds have been extensively studied in the fields of material science and engineering. In this article, we report on the synthesis of a layered system MBi₂Te₄ where the M site possesses low-, middle-, and high-entropy states. The samples with M = Pb, Ag_1/3Pb_1/3Bi_1/3, and Ag_1/5In_1/5Sn_1/5Pb_1/5Bi_1/5 were newly synthesized and the crystal structure was examined by synchrotron X-ray diffraction and Rietveld refinement. We found that the M-Te2 distance was systematically compressed with decreasing lattice constants, where the configurational entropy of mixing at the M site is also systematically increased. The details of structural refinements and the electrical transport property are presented.     

Efficacy of combination antihypertensive therapy with low-dose indapamide: assessment by blood pressure self-monitoring at home

We examined the effects of the addition of low-dose indapamide to antihypertensive drugs of other classes, as well as its duration of action, using blood pressure (BP) self-monitoring at home. Seventy-six patients undergoing monotherapy with a calcium channel blocker (CCB), angiotensin converting-enzyme inhibitor (ACEI), or angiotensin AT1-receptor blocker (ARB), but had an average morning home systolic BP (SBP) > or =135 mmHg or diastolic BP (DBP) > or =85 mmHg, were studied. Indapamide (1 mg) was added to their existing treatment once daily for 4 weeks. The additional hypotensive effects of indapamide were evaluated by casual and home BPs, and the results were compared among the three groups of subjects classified according to their initial drug treatment classes. The morning/evening (M/E) ratio of BP reduction was calculated to assess the duration of the effect. Overall, indapamide significantly (P < 0.001) lowered morning home BP (147 +/- 12/87 +/- 9 mmHg to 135 +/- 12/81 +/- 9 mmHg), evening home BP (138 +/- 15/79 +/- 10 mmHg to 126 +/- 12/73 +/- 9 mmHg), and casual BP (145 +/- 21/86 +/- 14 mmHg to 136 +/- 17/81 +/- 13 mmHg). All groups showed significant indapamide-induced home SBP/DBP decreases, whereas only the ACEI and ARB groups, but not the CCB group, showed a home pulse pressure (PP) reduction. Evening SBP and PP decreases were significantly greater in the ARB group than in the CCB group. The mean M/E ratio with indapamide was 0.95 for SBP and 0.85 for DBP. Low-dose indapamide used in combination can provide additional anti-hypertensive efficacy lasting for 24 h. The added effect of indapamide may be more prominent on ARBs than on CCBs.