ABSTRACT
The biogeochemistry of hypersaline environments is strongly influenced by changes in biological processes and physicochemical parameters. Although massive evaporation events have occurred repeatedly throughout Earth history, their biogeochemical cycles and global impact remain poorly understood. Here, we provide the first nitrogen isotopic data for nutrients and chloropigments from modern shallow hypersaline environments (solar salterns, Trapani, Italy) and apply the obtained insights to δ15N signatures of the Messinian salinity crisis (MSC) in the late Miocene. Concentrations and δ15N of chlorophyll a, bacteriochlorophyll a, nitrate, and ammonium in benthic microbial mats indicate that inhibition of nitrification suppresses denitrification and anammox, resulting in efficient ammonium recycling within the mats and high primary productivity. We also suggest that the release of 15N-depleted NH3(gas) with increasing salinity enriches ammonium 15N in surface brine (≈34.0). Such elevated δ15N is also recorded in geoporphyrins isolated from sediments of the MSC peak (≈20), reflecting ammonium supply sufficient for sustaining phototrophic primary production. We propose that efficient nutrient supply combined with frequent bottom-water anoxia and capping of organic-rich sediments by evaporites of the Mediterranean MSC could have contributed to atmospheric CO2 reduction during the late Miocene.
ABSTRACT
Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/epidemiology , Lymphoma/epidemiology , Lymphoma/therapy , Myelodysplastic Syndromes/epidemiology , Neoplasms, Second Primary/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Allografts , Autografts , Female , Follow-Up Studies , Humans , Male , Middle Aged , Risk FactorsABSTRACT
OBJECTIVE: Surgeries for cancer of the esophagus are still associated with a high rate of postoperative morbidity. There are few reports of perioperative nutritional support for patients undergoing esophageal cancer surgery, and there is insufficient evidence to recommend routine use of immunonutrition in these patients. The aim of this study was to determine whether preoperative immunonutrition positively influences key clinical outcomes such as postoperative infectious complications, mortality, length of hospital stay, and short-term survival in this population. DESIGN AND SETTING: We undertook a retrospective investigation of the effects of preoperative nutritional support on the postoperative course of esophageal cancer surgery at the Department of Gastroenterological Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan. PARTICIPANTS: Fifty-five patients who underwent esophagectomy for esophageal cancer were included in this study. Of the 55 patients, 26 patients consumed a liquid dietary supplement (IMPACT group) before surgery and 29 patients did not (STANDARD group). INTERVENTION: Before surgery, the IMPACT group consumed 750 ml (3 packs)/day of Impact for 5 consecutive days. MEASUREMENTS: The analysis was based on postoperative complications, hospital mortality, length of hospital stay, and short-term survival. RESULTS: Significantly fewer patients developed postoperative infections in the IMPACT group compared with the STANDARD group (p=.007): 4 of 21 patients in the IMPACT group and 10 of 29 patients in the STANDARD group. Either an infectious complication or another complication developed in 8 patients in the IMPACT group and 13 patients in the STANDARD group, with the result that 6 patients in the STANDARD group died of postoperative complications (p=.001). The duration of hospitalization was 34 days in the IMPACT group and 48 days in the STANDARD group; hence, hospitalization was significantly shorter in patients treated with Impact (p=.008). The mean 6-month survival rates for the IMPACT group and the STANDARD group were 92% (24/26) and 72% (21/29), respectively (p=.028). CONCLUSION: Simple preoperative supplementation significantly improved outcome. Administration of the supplemental diet before esophageal surgery appeared to be an effective strategy in reducing infectious complications, mortality, and hospitalization, and improving short-term survival.
Subject(s)
Esophageal Neoplasms/diet therapy , Esophageal Neoplasms/surgery , Nutritional Support , Preoperative Care , Adult , Aged , Dietary Supplements , Esophageal Neoplasms/mortality , Female , Hospital Mortality , Humans , Japan , Length of Stay/statistics & numerical data , Male , Middle Aged , Postoperative Complications/mortality , Postoperative Complications/prevention & control , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND AND PURPOSE: Although stroke patients with diabetes mellitus have a poor prognosis, the prognostic factors of patients with diabetes mellitus have not been adequately studied. The aim of this study was to determine the predisposing factors for outcome 1â year after stroke in diabetic patients. METHODS: Patients' characteristics, findings on admission and outcome 1â year after first ischaemic stroke were prospectively investigated in 452 consecutive patients with diabetes mellitus (305 males, 147 females; 69â ±â 10â years old). A poor outcome was defined as a modified Rankin Scale (mRS) score ≥â 2, 1â year after stroke onset. RESULTS: There were 286 patients with a good outcome (mRS score ≤â 1) and 166 with a poor outcome (mRS score ≥â 2). On multivariate logistic regression analysis, age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03-1.10, Pâ <â 0.001, per 1-year increase], National Institutes of Health Stroke Scale (NIHSS) score on admission (OR 1.21, 95% CI 1.11-1.32, Pâ <â 0.001, per 1-point increase), diabetic nephropathy (OR 1.93, 95% CI 1.02-3.65, Pâ =â 0.044) and hemoglobin A1c (HbA1c; OR 1.27, 95% CI 1.07-1.51, Pâ =â 0.007, per 1% increase) were independently related to poor outcome (mRS score ≥â 2) 1â year after the onset of the first stroke in diabetic patients. CONCLUSIONS: In stroke patients with diabetes mellitus, age, NIHSS score on admission, diabetic nephropathy and HbA1c were independently associated with a poor outcome 1â year after the first ischaemic stroke.
Subject(s)
Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Registries , Stroke/diagnosis , Stroke/epidemiology , Aged , Aged, 80 and over , Diabetes Mellitus/therapy , Female , Follow-Up Studies , Humans , Japan/epidemiology , Male , Middle Aged , Prospective Studies , Risk Factors , Stroke/therapy , Treatment OutcomeABSTRACT
Treatment outcomes for chronic myelogenous leukemia (CML) have shown major improvements as a result of the development of the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib for the disease-specific molecular target BCR-ABL1 tyrosine kinase (TK), but a cure of CML by BCR-ABL1 TKIs has been rarely achieved. CML cells are protected from cytotoxic insults, including those by TKIs, through various collaborative BCR-ABL1- mediated and -independent mechanisms, as well as cell-intrinsic and -extrinsic molecular mechanisms. These protective mechanisms include overlapping cell signaling pathways for normal hematopoietic proliferation, modulation of molecules associated with the BCL2 family protein-regulated programmed cell death pathway, autophagic cell protection capability, bone marrow environment-mediated cell protective signaling, abnormally upregulated genetic instability and other BCR-ABL1- independent kinase activities. To develop a more effective treatment strategy for a cure by means of total leukemic cell killing, a thorough understanding of how CML cells survive and resist cytotoxic insults is essential. In this article, we review current knowledge about multifaceted BCR-ABL1-related and -unrelated mechanisms for survival and death of CML cells and present suggestions for the development of new therapeutic strategies for complete elimination of residual CML cells during TKI treatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Molecular Targeted Therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Apoptosis Regulatory Proteins/agonists , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/biosynthesis , Apoptosis Regulatory Proteins/metabolism , Autophagy/drug effects , Cell Survival/drug effects , Chromosomal Instability/drug effects , DNA Repair/drug effects , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , Hematopoietic Cell Growth Factors/antagonists & inhibitors , Hematopoietic Cell Growth Factors/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effectsABSTRACT
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematological disorders characterized by ineffective hematopoiesis which causes peripheral cytopenias and a risk of progression to acute myeloid leukemia. Although various forms of chromosomal abnormalities have been detected in approximately 50-60% of patients with de novo MDS and in up to 80% of patients with therapy-related MDS, their molecular significance for pathogenesis and disease progression is not yet fully understood. Recent technical advances in molecular biology have disclosed more accurately details of pathological chromosomal and molecular aberrations in MDS. Such details could not be identified with conventional cytogenetical techniques, including G-banding. In particular, with recent technical advances in comparative genome hybridization or single nucleotide polymorphism array technology, several candidate genes for the pathogenesis of MDS have been identified, which are located in minimally deleted or uniparental disomy segments. Moreover, epigenetic deregulation of gene expression is also likely to be involved in the pathogenesis of MDS. Accordingly, in addition to classical oncogenic abnormalities, such as p53 abnormalities, or NRAS mutation, various molecular abnormalities, such as TET2, RPS14, or c-CBL, have been identified and/or proposed as the novel candidates for molecular basis of the development and progression of MDS. A better understanding of the causative molecular events underlying MDS pathogenesis is essential for the development and establishment of a more effective treatment resulting in a complete cure for MDS. We here review current knowledge regarding the molecular significance of chromosomal and genetic aberrations in MDS and the proposed molecular mechanisms of action of new agents for MDS, such as lenalidomide or azacitidine.
Subject(s)
Chromosome Aberrations , Myelodysplastic Syndromes/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Azacitidine/pharmacology , Azacitidine/therapeutic use , Humans , Lenalidomide , Mutation , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Thalidomide/therapeutic useABSTRACT
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies. METHODS: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied. RESULTS: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status. CONCLUSION: GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Coumarins/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lymphoma, Mantle-Cell/drug therapy , Antineoplastic Agents/therapeutic use , Blotting, Western , Boronic Acids/therapeutic use , Bortezomib , Cell Cycle/drug effects , Cyclin D1/genetics , Cyclin D1/metabolism , Drug Synergism , Drug Therapy, Combination , Flow Cytometry , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Humans , Immunoenzyme Techniques , Immunoprecipitation , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Mutation/genetics , Oncogene Protein v-akt/genetics , Oncogene Protein v-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/metabolism , Pyrazines/therapeutic use , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2 Homologous Antagonist-Killer Protein/metabolismABSTRACT
Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that ß-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/ß-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished ß-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.
ABSTRACT
The chronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was evaluated in male and female Wistar rats with dietary administration at concentrations of 0%, 0.04%, 0.2%, 1% and 5% for 52 weeks. No toxicological findings were found in the mortality, body weights, food consumption, hematology, clinical biochemistry or organ weights in either sex. Obvious clinical signs were chromaturia that could be attributed to the color of test substance in the 5% groups of both sexes. Coloration of the urine collected over 24h in the 1% and 5% groups of both sexes was noted. Increased daily urinary calcium excretion was observed in the 5% groups of both sexes and an increase in urinary calcium concentration was observed in the male 5% group. On histopathological examination, incidences of mineralization, inflammatory cell debris, inflammatory cell infiltration and/or transitional cell hyperplasia in the renal pelvis were increased in the 5% male group, whereas treated females showed no apparent difference in these incidences. Based on the above findings, the no observed adverse effect level (NOAEL) was estimated to be 1% in both sexes (542.4 mg/kg body weight/day for males and 674.0mg/kg body--weight/day for females).
Subject(s)
Rutin/toxicity , Animals , Body Weight/drug effects , Calcium/urine , Diet , Eating/drug effects , Female , Food Additives , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Kidney Diseases/urine , Male , No-Observed-Adverse-Effect Level , Quercetin/analogs & derivatives , Quercetin/metabolism , Quercetin/toxicity , Rats , Rats, Wistar , Rutin/metabolism , Specific Pathogen-Free Organisms , Toxicity Tests, ChronicABSTRACT
Galectins constitute a family of lectins that specifically exhibit the affinity for beta-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC(50) between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH(2)-terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.
Subject(s)
Galectins/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Kinase Kinases/metabolism , Multiple Myeloma/drug therapy , Proto-Oncogene Proteins/metabolism , Signal Transduction/drug effects , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blotting, Western , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Profiling , Humans , JNK Mitogen-Activated Protein Kinases/genetics , MAP Kinase Kinase Kinases/genetics , Mice , Mice, Nude , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Phosphorylation , Proto-Oncogene Proteins/genetics , Pyrazines/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant Proteins/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Whole-Body Irradiation , Xenograft Model Antitumor AssaysABSTRACT
Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl(+) leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl(+) stem cells is needed to cure leukemias caused by Bcr-Abl(+) cells. Human Bcr-Abl(+) cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl(+) sublines by selection in long-term hypoxic cultures (1.0% O(2)). Interestingly, HA-Bcr-Abl(+) cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher beta-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl(+) cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl(+) cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl(+) leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl(+) leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.
Subject(s)
Lactoylglutathione Lyase/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Neoplastic Stem Cells/drug effects , Animals , Benzamides , Cell Hypoxia , Cell Line, Tumor , Dasatinib , Humans , Imatinib Mesylate , Lactoylglutathione Lyase/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Mice , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Thiazoles/pharmacology , Transplantation, Heterologous , beta Catenin/metabolismABSTRACT
Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.
Subject(s)
Autophagy/drug effects , Fusion Proteins, bcr-abl/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Apoptosomes/drug effects , Apoptosomes/metabolism , Caspases/metabolism , Cell Line, Tumor , Chloroquine/pharmacology , Cytoprotection/drug effects , Disease Models, Animal , Enzyme Activation/drug effects , Male , Mice , Mice, SCID , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND AND PURPOSE: Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke. METHODS: Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study. RESULTS: The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907-8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P = 0.0510), and combined TT and TA genotypes (OR = 8.768, P = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes. CONCLUSIONS: The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.
Subject(s)
Brain Infarction/epidemiology , Brain Infarction/genetics , Genetic Predisposition to Disease , Microfilament Proteins/genetics , Polymorphism, Genetic , Aged , Brain Infarction/classification , Case-Control Studies , Cohort Studies , Female , Gene Frequency , Genotype , Humans , Japan/epidemiology , Japan/ethnology , Male , Middle Aged , Odds Ratio , Registries , Retrospective Studies , Risk , Risk FactorsABSTRACT
The C242T polymorphism of p22phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi-squared test revealed that the T-allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate-adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72-1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS-7 cells cotransfected with Nox4 and p22phox of each genotype. The superoxide-producing activity in those cells expressing p22phox with the T allele was not significantly different from that in cells expressing p22phox with the C allele. The present results suggest that the p22phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan.
Subject(s)
Brain Ischemia/enzymology , Brain Ischemia/genetics , NADPH Oxidases/genetics , Polymorphism, Genetic/genetics , Registries , Stroke/enzymology , Stroke/genetics , Aged , Aged, 80 and over , Animals , Brain Ischemia/epidemiology , COS Cells , Cerebral Infarction/enzymology , Cerebral Infarction/epidemiology , Cerebral Infarction/genetics , Chlorocebus aethiops , Female , Gene Frequency/genetics , Humans , Japan/epidemiology , Male , Middle Aged , Stroke/epidemiologyABSTRACT
We report a 19-year-old woman with Behcet's disease who suffered a subarachnoid hemorrhage and had bilateral peripheral middle cerebral artery aneurysms. After steroid therapy for 3 days, the smaller aneurysm disappeared. The larger aneurysm was excised and the artery reconstructed using a superficial temporary artery graft. Histological examination showed vasculitis restricted to the wall of the aneurysm. This is the first report of arterial reconstruction for an aneurysm associated with Behcet's disease. Steroid therapy before the operation may facilitate repair of the arterial wall.
Subject(s)
Behcet Syndrome/surgery , Intracranial Aneurysm/surgery , Subarachnoid Hemorrhage/surgery , Adult , Anti-Inflammatory Agents/administration & dosage , Arteries/transplantation , Behcet Syndrome/diagnosis , Behcet Syndrome/pathology , Cerebral Angiography , Female , Humans , Infusions, Intravenous , Intracranial Aneurysm/diagnosis , Intracranial Aneurysm/pathology , Magnetic Resonance Imaging , Methylprednisolone/administration & dosage , Middle Cerebral Artery/pathology , Middle Cerebral Artery/surgery , Premedication , Subarachnoid Hemorrhage/diagnosis , Subarachnoid Hemorrhage/pathologyABSTRACT
Bcr-Abl is the cause of Philadelphia-positive (Ph(+)) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph(+) leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X(L), greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph(+) leukemic cells.
Subject(s)
Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Nitrophenols/pharmacology , Piperazines/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/metabolism , Apoptosis/physiology , Benzamides , Benzoquinones/pharmacology , Biphenyl Compounds/metabolism , Boronic Acids/metabolism , Boronic Acids/pharmacology , Bortezomib , Cell Line, Transformed , Cell Line, Tumor , Humans , Imatinib Mesylate , Lactams, Macrocyclic/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Nitrophenols/metabolism , Piperazines/metabolism , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcr/metabolism , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrimidines/metabolism , Sulfonamides/metabolismABSTRACT
NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.
Subject(s)
Paclitaxel/analogs & derivatives , Paclitaxel/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Animals , Collagen Type III/metabolism , Disease Models, Animal , Female , Humans , Lung/drug effects , Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , Rats , Rats, Inbred LewABSTRACT
We analyzed serial changes in the regional cerebral blood flow (rCBF) of 13 patients with intracerebral hemorrhage by single photon emission computed tomography (SPECT) during the acute- to chronic stage (2 hr to 55 weeks). The (99m)Tc-ethyl cysteinate dimmer ((99m)Tc-ECD) was used as the nuclear mediator. The SPECT timing within 48 hours after the onset was considered to be acute stage, from 48 hours to 4 weeks to be subacute stage, and after 4 weeks to be chronic stage. The region of interest was each hemisphere in the whole brain without ventricles at the thalamic level. For semi-quantitative analysis of rCBF, we used the Brain Uptake Ratio method. Of the 13 patients (mean age 65.5 years), 3 had thalamic-, 4 putaminal-, 5 subcortical-, and one a cerebellar hemorrhage; the hematoma volume varied from 4-50 ml (<20 ml, n=9; 20-30 ml, n=1; >30 ml, n=3; mean 17 ml). The rCBF changes during the long-term follow-up were classified as increase-, decrease-, and unchanged type. Of 5 patients with increased rCBF, 4 made a good recovery and one was severely disabled; of 5 patients with decreased rCBF, 1 made a good recovery, 3 were moderately-, and one was severely disabled. All 3 patients with unchanged rCBF were moderately disabled. Our findings suggest that among patients with hypertensive intracerebral hemorrhage, those with increased rCBF over time may have a favorable outcome. We further need more cases with intracerebral hemorrhage to clarify this trend.