Allo-anti-M: Detection peaks around 2 years of age, but may be attenuated by red blood cell transfusion.

BACKGROUND: Anti-M is frequently observed as a naturally occurring antibody of little clinical significance. Naturally occurring anti-M is often found in children although the specific triggers of production, persistence, and evanescence of anti-M have yet to be elucidated. METHODS: In a retrospective, multicenter, nationwide cohort survey conducted from 2001 to 2015, alloantibody screening was performed before and after transfusion in 18,944 recipients younger than 20 years. Recipients were categorized into six cohorts based on their age at transfusion; within and among these cohorts, allo-anti-M was analyzed in regard to its production, persistence, and evanescence. RESULTS: In 44 patients, anti-M detected before and/or after transfusion was an age-related phenomenon, with a median age of 2 years and an interquartile range of 1-3 years; anti-M was most frequently detected in a cohort of children 1 to <5 years (0.77%, 31 of 4035). At least five patients were presumed to have concurrent infections. Among 1575 adolescents/young adults (15 to <20 years), no anti-M was detected. Of 29 patients with anti-M prior to transfusion, the antibody fell to undetectable levels in 17 recipients (89.5%, of whom at least 13 received only M-negative red cells) after anywhere from 5 days to 5.8 years; anti-M persisted in 2, and was not tested in 10. Only 15 recipients (0.08%) produced new anti-M after transfusion. CONCLUSION: Naturally occurring anti-M is a phenomenon of younger ages, predominantly between 1 and 3 years. After transfusion, it often falls to undetectable levels.

Three non-classical mechanisms for anemic disease of the fetus and newborn, based on maternal anti-Kell, anti-Ge3, anti-M, and anti-Jra cases.

Maternal alloantibody-mediated hemolytic disease of the fetus and newborn (HDFN) ranges from no or mild symptoms to severe hydrops and intrauterine fetal demise. Hemolytic anti-D-mediated HDFN proceeds via a long-known mechanism, to which three other pathways to fetal/neonatal anemia may be added: (0) Fetal erythrocyte destruction can proceed by extravascular phagocytosis. (1) An apoptotic pathway has been described for anti-Kell, and anti-Ge3. (2) Erythropoietic suppression may arise from altered or deformed erythroblast architecture in anti-M-mediated disease. (3) Clonal escape from erythropoietic suppression is hypothesized to arise from maternal anti-Jra immune pressure, albeit this requires further elucidation. Alloantibody-mediated anemic disease of the fetus and newborn (ADFN) is a designation we favor for cases when hemolysis or hyperbilirubinemia are not the dominant features, such as those provoked by anti-Kell, anti-Ge3, anti-M, and anti-Jra.

Production of RBC autoantibody mimicking anti-D specificity following transfusion in a patient with weak D Type 15.

BACKGROUND: Weak D-type RBCs have fewer D epitopes, but it remains unclear whether individuals with certain types of weak D produce alloanti-D directed at D epitopes absent from the RBCs, and whether it is an alloantibody or an autoantibody. We report the first case of a patient with a weak D Type 15 who produced autoantibodies mimicking alloanti-D. CASE REPORT: A 52-year-old Japanese male with weak D developed anti-D 3 months after transfusion of D-negative and -positive RBCs, and the antibody persisted for 24 months with a consistently negative direct antiglobulin test. Eluates from the patient's RBCs demonstrated anti-D specificity. The recipient did not exhibit any signs of delayed hemolytic transfusion reaction. As his anti-D was removed by the different adsorbing cells of weak D Type 15 and autologous as well as D positive, D negative, weak D Type 24, and partial DVa, it was thought to be an autoantibody mimicking anti-D rather than an alloantibody. The patient's RBCs reacted weakly with the 13 anti-D reagents used in the study. Polymerase chain reaction and nucleotide sequencing revealed that the patient had an RHD genotype of RHD*01N.01/RHD*15. CONCLUSION: Anti-D, produced in a patient with weak D Type 15 after transfusion, was found to be mimicking autoanti-D. Alloanti-D was excluded by an adsorption study with different RBC types.

Low-Dose Carbon Monoxide Inhibits Rhinovirus Replication in Human Alveolar and Airway Epithelial Cells.

Carbon monoxide (CO) and nitric oxide (NO) exhibit physiological properties that include the activation of guanylate cyclase. NO inhibits replication of rhinovirus (RV), a major cause of the common cold and exacerbation of bronchial asthma and chronic obstructive pulmonary disease. However, the anti-rhinoviral effects of CO remain unclear. This study investigated whether the exogenous application of low-dose CO could inhibit RV replication in human alveolar and airway epithelial cells. A549 human lung carcinoma cells with alveolar epithelial features and primary cultures of human tracheal epithelial (HTE) cells were pretreated with CO (100 ppm) and infected with a major group RV, type 14 RV (RV14). CO exposure reduced RV14 titers in the supernatants and RV RNA levels in A549 and HTE cells. The treatment with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, reversed the inhibitory effects of CO exposure on RV14 replication in A549 cells. Pretreatment of A549 cells with 8-Br-cGMP, a cell-permeable cGMP analog, caused the decrease in RV14 replication, while CO exposure increased cGMP production. CO exposure also increased the expression levels of interferon (IFN)-γ mRNA and protein. In contrast, pretreatment with CO did not increase DNA fragmentation and did not reduce the expression of intercellular adhesion molecule-1, the RV14 receptor, or the number of acidic endosomes, through which RV RNA enters the cytoplasm. These findings suggest that low-dose CO may decrease RV14 replication in alveolar and airway epithelial cells. IFN-γ production, which is induced by CO exposure via guanylate cyclase activation-mediated cGMP production, may be involved in RV14 replication inhibition.

Efficacy of D- red blood cell transfusion and rituximab therapy in autoimmune hemolytic anemia with anti-D and panreactive autoantibodies arising after hematopoietic stem cell transplant.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies to red blood cells (RBCs), which can be panreactive and/or specific to Rh/other blood group antigens. We report a severe case of AIHA after bone marrow transplantation (BMT) due to autoanti-D triggered by reactivation of Epstein-Barr virus (EBV) infection. A combined strategy of D- RBC transfusion and administration of anti-CD20 monoclonal antibody (MoAb) resolved the hemolysis. CASE REPORT: A 33-year-old male underwent allogeneic BMT from an ABO-identical and HLA-matched unrelated male donor. Five months later, while having mild chronic graft-versus-host disease, he manifested AIHA, with a hemoglobin (Hb) level of 5.1 g/dL on AIHA Day 2 (Posttransplant Day 156) and was refractory to D+ RBCs, with a Hb level of 2.4 g/dL on AIHA Day 6. Anti-D-like autoantibodies (titer 1280, subclass immunoglobulin G1 , monocyte monolayer assay 28.7%) and panreactive (titer 40) were identified. Changing the RBC transfusion strategy to D- increased his Hb level to 6.7 g/dL on Day 10. Administration of anti-CD20 MoAb mitigated EBV-related B-cell proliferation and reduced anti-D autoantibody titer to 320 by Day 16 with normalized Hb concentration after 6 months. CONCLUSION: In severe AIHA, when standard treatment and regular RBC transfusions are ineffective, transfusion of RBCs lacking the target antigen(s) of autoantibodies and administration of anti-CD20 MoAb should be considered.

Anti-M Antibody Induced Prolonged Anemia Following Hemolytic Disease of the Newborn Due to Erythropoietic Suppression in 2 Siblings.

Hemolytic disease of the newborn (HDN) arising from MNSs incompatibility is rare, with few reports of prolonged anemia and reticulocytopenia following HDN. We report the younger of 2 male siblings, both of whom had anti-M-induced HDN and anemia persisting for over a month. Peripheral reticulocytes remained inappropriately low for the degree of anemia, and they needed multiple red cell transfusions. Viral infections were ruled out. Corticosteroids were given for suspected pure red cell aplasia. Anemia and reticulocytopenia subsequently improved. Colony-forming unit erythroid assay revealed erythropoietic suppression of M antigen-positive erythroid precursor cells cultured with maternal or infant sera containing anti-M. In conclusion, maternal anti-M caused HDN and prolonged anemia by erythropoietic suppression in 2 siblings.

Use of glucose solution for the alleviation of gemcitabine-induced vascular pain: a double-blind randomized crossover study.

PURPOSE: Gemcitabine is widely used for chemotherapy in many types of cancers. However, vascular pain frequently occurs during its infusion, which can be serious enough to cause treatment discontinuation. This study was conducted to determine whether dissolution with 5 % glucose solution would relieve vascular pain compared with the approved use of saline as the diluent. METHODS: Patients with cancer who were treated with weekly gemcitabine were eligible. Vascular pain was assessed during two consecutive administrations in a double-blind, randomized crossover study. One group was scheduled to receive gemcitabine dissolved in saline followed by gemcitabine in 5 % glucose solution. In the other group, 5 % glucose solution was followed by saline. The primary endpoint was frequency of vascular pain for the total infusions of each solvent and the secondary endpoints were intensity, as assessed on a visual analogue scale and duration of vascular pain. RESULTS: Eighty-seven patients were randomly assigned to each treatment schedule. Frequency of vascular pain was significantly lower with 5 % glucose solution compared with saline (40 versus 63 %; p < 0.001). The intensity of vascular pain was also reduced with 5 % glucose solution compared with saline (mean, 1.3 versus 2.7 points; p < 0.001). There was no significant statistical difference in duration of vascular pain between the 5 % glucose solution and saline solution groups (mean, 21 versus 18 min; p = 0.420). CONCLUSIONS: The use of 5 % glucose solution to dissolve gemcitabine significantly reduced the frequency and the intensity of vascular pain compared with the use of saline.

Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells.

Respiratory virus infections, including infections with rhinoviruses (RVs), are related to exacerbations of chronic obstructive pulmonary disease (COPD). A new quinolone antibiotic, levofloxacin (LVFX), has been used to treat bacterial infections that cause COPD exacerbations as well as bacterial infections that are secondary to viral infection in COPD patients. However, the inhibitory effects of LVFX on RV infection and RV infection-induced airway inflammation have not been studied. We examined the effects of LVFX on type 14 rhinovirus (RV14) (a major human RV) infection of human tracheal epithelial cells pretreated with LVFX. LVFX pretreatment reduced the RV14 titer, the level of cytokines in the supernatant, the amount of RV14 RNA in the cells after RV14 infection, and the cells' susceptibility to RV14 infection. LVFX pretreatment decreased the mRNA level of intercellular adhesion molecule 1 (ICAM-1), a receptor for RV14, in the cells and the concentration of the soluble form of ICAM-1 in the supernatant before RV14 infection. LVFX pretreatment also decreased the number and the fluorescence intensity of the acidic endosomes from which RV14 RNA enters the cytoplasm. LVFX pretreatment inhibited the activation of nuclear factor κB proteins, including p50 and p65, in nuclear extracts. LVFX pretreatment did not reduce the titers of RV2 (a minor human RV) but reduced the titers of RV15 (a major human RV). These results suggest that LVFX inhibits major-group rhinovirus infections in part by reducing ICAM-1 expression levels and the number of acidic endosomes. LVFX may also modulate airway inflammation in rhinoviral infections.

Inhibitory effects of tiotropium on rhinovirus infection in human airway epithelial cells.

Infection by rhinoviruses (RVs) causes exacerbations of chronic obstructive pulmonary disease (COPD). The long-acting anti-cholinergic agent tiotropium reduces the frequency of COPD exacerbations, but the inhibitory effects of tiotropium on the COPD exacerbations induced by RVs are unclear. Likewise, the effects of tiotropium on RVs infection remain to be studied. To examine the effects of tiotropium on RV infection and RV infection-induced airway inflammation, human tracheal epithelial cells were infected with a major group RV, type 14 RV (RV14). RV14 infection increased the viral titre and the amount of pro-inflammatory cytokines, including interleukin (IL)-1ß and -6, in supernatant fluids and the amount of RV14 RNA in cells. Tiotropium reduced RV14 titres, RNA and cytokine concentrations, and susceptibility to RV14 infection. Tiotropium reduced the expression of intercellular adhesion molecule (ICAM)-1, the receptor for RV14, and the number of cellular acidic endosomes, which allow RV14 RNA to enter the cytoplasm. Tiotropium inhibited the activation of nuclear factor-(κ)B proteins, including p50 and p65, in the nuclear extracts, and it increased the cytosolic amount of inhibitory κB-α. Tiotropium may inhibit RV14 infection by reducing the levels of ICAM-1 and acidic endosomes and may also modulate airway inflammation in rhinovirus infection.

Transplantation of Mature Adipocyte-Derived Dedifferentiated Fat Cells Facilitates Periodontal Tissue Regeneration of Class II Furcation Defects in Miniature Pigs.

Adipose tissue is composed mostly of adipocytes that are in contact with capillaries. By using a ceiling culture method based on buoyancy, lipid-free fibroblast-like cells, also known as dedifferentiated fat (DFAT) cells, can be separated from mature adipocytes with a large single lipid droplet. DFAT cells can re-establish their active proliferation ability and transdifferentiate into various cell types under appropriate culture conditions. Herein, we sought to compare the regenerative potential of collagen matrix alone (control) with autologous DFAT cell-loaded collagen matrix transplantation in adult miniature pigs (microminipigs; MMPs). We established and transplanted DFAT cells into inflammation-inducing periodontal class II furcation defects. At 12 weeks after cell transplantation, a marked attachment gain was observed based on the clinical parameters of probing depth (PD) and clinical attachment level (CAL). Additionally, micro computed tomography (CT) revealed hard tissue formation in furcation defects of the second premolar. The cemento-enamel junction and alveolar bone crest distance was significantly shorter following transplantation. Moreover, newly formed cellular cementum, well-oriented periodontal ligament-like fibers, and alveolar bone formation were observed via histological analysis. No teratomas were found in the internal organs of recipient MMPs. Taken together, these findings suggest that DFAT cells can safely enhance periodontal tissue regeneration.

Safety of erlotinib treatment in outpatients with previously treated non-small-cell lung cancer in Japan.

PURPOSE: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor shown to provide a survival benefit for advanced non-small-cell lung cancer (NSCLC) patients. Adverse drug reactions of erlotinib in Japanese, which may be very different from those in Caucasians because of differences in genetic background, have not been fully reported. Therefore, we aimed to clarify the safety profile of erlotinib. METHODS: Forty-eight patients with pretreated NSCLC were treated with erlotinib between March 2008 and January 2009 in this historical cohort study at Kyoto University Hospital Outpatients Oncology Unit. Erlotinib 150 mg/day was administered until progressive disease or discontinuation due to adverse events. The primary endpoint was frequency and degree of adverse events, and secondary endpoints were clinical efficacy including response rate, disease control rate, progression-free survival and overall survival. RESULTS: Of 48 patients, 3 patients experienced erlotinib-induced interstitial pneumonitis, which appeared on day 15 and 70 in 2 patients who recovered and on day 8 in 1 patient who died. The incidences of pruritus, dry skin, diarrhea and stomatitis rapidly increased within 14 days after the start of medication with erlotinib. However, these adverse events were well controllable in outpatients treated with erlotinib. Overall response rate was 10% and disease control rate was 68%. The median progression-free survival was 58 days (95% confidence interval 30-118) and the median overall survival was 229 days (95% confidence interval 135-not available). CONCLUSIONS: Outpatients with NSCLC can be treated with initial administration of erlotinib by careful management.

Dental implant status in elderly individuals requiring domiciliary dental care in Japan.

BACKGROUND: The presence of implants is a significant burden not only for dentists but also for caregivers and families of elderly individuals requiring nursing and domiciliary dental care. However, few reports have assessed the status of domiciliary dental care or measures employed to deal with related issues. Hence, we aimed to evaluate the dental implant status in elderly patients requiring nursing and domiciliary dental care and to determine the suitable measures for overcoming the associated limitations. A questionnaire was mailed to 1000 dentists who provided domiciliary dental care in the Tokyo metropolitan area of Japan. The questions were classified into three categories: basic information of the dentists, actual implant status of patients requiring domiciliary dental care, and implants in an aging society. RESULTS: The response rate was 36.5%. Approximately 2% of patients requiring domiciliary dental care were implant patients. Many implant-related problems were associated with insufficiency or difficulty in cleaning around the implant, resulting in peri-implantitis. Prosthetic and more serious complications such as implant body fracture or loss were reported and frequently managed by routine follow-ups, cleaning the area around the implant, scaling and polishing, and/or pharmacological modalities. Oral care mainly involved simple toothbrushing instructions, which was not adequate. CONCLUSIONS: Our findings suggest the necessity of simplifying the oral environment and making oral care a simple task before aging individuals require nursing and domiciliary dental care.

Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells.

Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H(3)N(2)). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an alpha2,6-linkage (SAalpha2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAalpha2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-kappaB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-kappaB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.

Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells.

Human influenza viruses attach to sialic acid with an alpha2,6linkage (SAalpha2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A(1), a macrolide antibiotic and a specific inhibitor of vacuolar H(+)-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clinically used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1beta and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAalpha2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the number and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-kappaB (NF-kappaB) proteins, including p50 and p65, in the nuclear extracts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAalpha2,6Gal partly through the inhibition of NF-kappaB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.

Mechanical analysis of the effects of implant position and abutment height on implant-assisted removable partial dentures.

PURPOSE: An increasing number of clinical reports describe the use of dental implants as abutments in implant-assisted removable partial dentures (IARPD). We used three-dimensional finite element analysis to evaluate IARPD as a unilateral mandibular distal extension denture. Specifically, the mechanical effects of implant position and abutment height on the abutment tooth, denture, and denture-supporting tissue were assessed. METHODS: The models analyzed were defects of the left mandibular second premolar and first and second molars prosthetically treated with an IARPD using one implant for each tooth position. There were two abutment heights: one equal to that of the mucosa and another that was elevated 2 mm above the mucosa. Six models were constructed. RESULTS: For mucosal-level abutments, movement of the abutment tooth was lower for implants positioned distal to the abutment tooth than for those positioned medial to the abutment tooth. For elevated abutments, movement of the abutment tooth was lower for implants positioned medial to the abutment tooth than for those positioned distal to the abutment tooth. CONCLUSIONS: The mechanical effects on abutment teeth at the same implant position differed in relation to implant abutment height.

Mechanical effects of residual bone mass, a maxillofacial prosthesis, and a reconstruction plate on the mandible after marginal resection.

In this study, analytic models were used to simulate marginal resection in the area of the second premolar to the second molar region, and the mechanical effects on the mandible of residual bone mass, a maxillofacial prosthesis, and a reconstruction plate were evaluated by three-dimensional finite element analysis. As residual bone mass decreased, maximum principal stress increased near the anterior ramus of the mandible, and maximum shear stress increased at the anterior buccal region of the resected area. In the mandible with a maxillofacial prosthesis, the maximum principal stress distribution at the anterior ramus was lower, and the distribution of maximum shear stress at the anterior buccal region of the resected area was higher. When a reconstruction plate was used, maximum principal stress and maximum shear stress were lower. Thus, lower residual bone mass was associated with increased mandible deflection and torsion. In addition, presence of a maxillofacial prosthesis decreased deflection but increased torsion, and presence of a reconstruction plate decreased deflection and greatly decreased torsion. These findings suggest that decreased residual bone mass and maxillofacial prostheses increase fracture risk; however, presence of a reconstruction plate was effective in decreasing torsional stress, thereby reducing fracture risk in the mandible.

Carbocisteine inhibits oxidant-induced apoptosis in cultured human airway epithelial cells.

BACKGROUND AND OBJECTIVE: Increased oxidant levels have been associated with exacerbations of COPD, and L-carbocisteine, a mucolytic agent, reduces the frequency of exacerbations. The mechanisms underlying the inhibitory effects of L-carbocisteine on oxidant-induced COPD exacerbations were examined in an in vitro study of human airway epithelial cells. METHODS: In order to examine the antioxidant effects of L-carbocisteine, human tracheal epithelial cells were treated with L-carbocisteine and exposed to hydrogen peroxide (H(2)O(2)). Cell apoptosis was assessed using a cell death detection ELISA, and the pathways leading to cell apoptosis were examined by measurement of caspase-3 and caspase-9 by western blot analysis with fluorescent detection. RESULTS: The proportion of apoptotic cells in human tracheal epithelium was increased in a concentration- and time-dependent manner, following exposure to H(2)O(2). Treatment with L-carbocisteine reduced the proportion of apoptotic cells. In contrast, H(2)O(2) did not increase the concentration of LDH in supernatants of epithelial cells. Exposure to H(2)O(2) activated caspase-3 and caspase-9, and L-carbocisteine inhibited the H(2)O(2)-induced activation of these caspases. L-carbocisteine activated Akt phosphorylation, which modulates caspase activation, and the inhibitors of Akt, LY294002 and wortmannin, significantly reversed the inhibitory effects of L-carbocisteine on H(2)O(2)-induced cell apoptosis. CONCLUSIONS: These findings suggest that in human airway epithelium, L-carbocisteine may inhibit cell damage induced by H(2)O(2) through the activation of Akt phosphorylation. L-carbocisteine may have antioxidant effects, as well as mucolytic activity, in inflamed airways.

Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter.

The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper-dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper-dopaminergic transmission in the nerve terminals of dopaminergic neurons. Here, we hypothesized that tumor growth was reduced in a mouse model of schizophrenia, lacking the dopamine transporter (DAT), and investigated tumor growth and angiogenesis in DAT knockout mice. The subcutaneous tumor in mice inoculated with cancer cells was smaller in DAT-/- mice than in the wild type (p < 0.05); however, the level of plasma dopamine in DAT-/- mice was lower than that of control littermates. Using human umbilical vascular endothelial cells (HUVEC), we examined dopamine signaling through dopamine D(1) receptor (D(1)R) and D(2)R. Dopamine stimulation slightly decreased the surface expression of vascular endothelial growth factor receptor-2 (VEGF-R2) but induced the phosphorylation of VEGF-R2 through Src in HUVEC. In addition, DAT-/- mice had less D(1)R. Both pharmacological and genetic interruption of D(1)R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy.

Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer.

Hypoxia exists in solid tumor tissues due to abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, and low intratumor blood flow. Hypoxic status in solid tumor promotes accumulation of hypoxia-inducible factor-1 alpha which is promptly degraded by proteasomal ubiquitination under normoxic conditions. However, under hypoxic conditions, the ubiquitination system for HIF-1 alpha is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1 alpha. HIF-1 alpha is an important transcriptional factor that codes for hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Hypoxia and accumulation of HIF-1 alpha in solid tumor tissues have been reported to associate with resistance to chemotherapy, radiotherapy, and immunotherapy and poor prognosis. Production of vascular endothelial growth factor (VEGF) in cancer cells is regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1 alpha accumulation and promotes tumor metastasis by angiogenesis. Recently, angiogenesis targeting therapy using humanized VEGF antibody and VEGF receptor tyrosine kinase inhibitors have been used in solid cancer therapy. Nitric oxide (NO) is a unique chemical gaseous molecule that plays a role as a chemical messenger involved in vasodilator, neurotransmitter, and anti-platelet aggregation. In vivo, NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors. In cancer science, NO has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and modulator for chemo/radio/immuno-therapy. The presence and activities of all the three isoforms of NOS and were detected in cancer tissue components such as cancer cells, tumor-associated macrophages, and vascular endothelium. Overexpression of iNOS in cancer tissues has been reported to associate with poor prognosis in patients with cancers. On the other hand, NO donors such as nitroglycerin have been demonstrated to improve the effects of cancer therapy in solid cancers. Nitroglycerin has been used safely for a long time as a potent vasodilator for the treatment of ischemic heart diseases or heart failure. Therefore, we think highly of clinical use of nitroglycerin as a novel cancer therapy in combination with anticancer drugs for improvement of cancer therapeutic levels. In this review article, we demonstrate the unique physiological characteristics of malignant solid tumors, several factors in solid tumors resulting in resistance for cancer therapies, and the effects of NO from NOS or exogenous NO-donating drugs on malignant cells. Furthermore, we refer to promising therapeutic roles of NO and NO-donating drugs for novel treatments in solid tumors.

Erythromycin attenuates MUC5AC synthesis and secretion in cultured human tracheal cells infected with RV14.

BACKGROUND AND OBJECTIVE: The common cold is a major cause of asthma exacerbation and chronic obstructive lung disease. Rhinovirus is reported to be responsible for more than 50% of cases of the common cold. In a previous study, we reported that rhinovirus infection of cultured airway cells induced MUC5AC mucin overproduction and hypersecretion by activating the p44/42 mitogen-activated protein kinase (p44/42 MAPK) pathway. The aim of this study was to examine the effect of erythromycin on RV14-induced airway mucin overproduction and hypersecretion. METHODS: RV14-infected human tracheal epithelial cells were treated with erythromycin. RESULTS: Erythromycin blocked RV14-induced MUC5AC protein overproduction and hypersecretion, and also blocked RV14-induced p44/42 MAPK activation in the cells. CONCLUSIONS: Erythromycin may attenuate RV14-induced MUC5AC overproduction and hypersecretion by blocking the p44/42 MAPK pathway or its upstream regulators.