miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth.

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic area in Irian Jaya, Indonesia III. Antibodies to circumsporozoite protein and ring-infected erythrocyte surface antigen.

A two years intervention study was carried out using permethrin impregnated bed nets in a hyperendemic area, in Irian Jaya, Indonesia. To assess the influence of this intervention on natural immunity, concurrent immunological studies to determine levels of antibodies to the circumsporozoite (CS) and ring-infected erythrocyte surface antigen (RESA) proteins were conducted. Prevalence and titers of immunoglobulins (Ig)G and IgG subclasses were periodically measured in 138 individuals (30 children under the age of ten and 108 villagers ten years old and older). In the younger group, seropositivity of total IgG against CS fluctuated according to the parasite infection rates; however, IgG seropositive reaction against RESA gradually increased. In the older age group, seropositivity of both kinds of antibodies was stable during the whole study period. Nevertheless, the geometric mean titers of total IgG against CS and RESA were significantly reduced in this latter group in individuals who contained these antibodies before and after intervention. The geometric mean titer of IgG3 subclass against RESA was decreased at a highly significant level (p = 0.0005), and that of IgG4 against the same antigen was also decreased although to a lesser extent (p = 0.02).

Superselective arterial embolization for the treatment of lower gastrointestinal hemorrhage.

PURPOSE: To evaluate the technical feasibility, efficacy of hemostasis, recurrent bleeding, and ischemia resulting from superselective embolization of acute lower gastrointestinal (GI) hemorrhage. MATERIALS AND METHODS: Fifty-two superselective mesenteric artery catheterization procedures were undertaken in 48 patients with angiographic evidence of lower GI bleeding. Embolization was performed only if the arterial recta leading to the bleed could be successfully catheterized (n = 39). The lesions treated were located in the colon (n = 33) and jejunum (n = 6). In 28 of 39 procedures, embolization was achieved by delivering polyvinyl alcohol (PVA) particles (150-500 microm) through a microcatheter. Microcoils were used as the sole embolic agent in four procedures and a combination of microcoils and PVA particles were used in another four. Gelfoam particles were used in three of our earliest procedures. Of the 35 patients who underwent embolization, 25 were evaluated for objective evidence of ischemia by endoscopy (n = 16) and/or histologic evaluation of the surgical specimen (n = 9); the remaining 10 patients were followed clinically. RESULTS: Embolization was successful in 39 procedures involving 35 patients. Immediate hemostasis was achieved after embolization in all but two patients. Recurrent bleeding occurred in 12 other patients, eight patients underwent surgery, three were managed medically, and one underwent successful repeat embolization. Of the 25 patients evaluated for ischemia, mucosal ischemia was demonstrated in six (24%), but they remained asymptomatic and developed no sequelae as a result of ischemic changes on long-term follow-up. There was no incidence of clinically significant intestinal ischemia. Embolization alone was the definitive treatment in 44% patients (21 of 48). Reasons for unsuccessful superselective catheterization (27%) were small vessel spasm, cessation of bleeding, and vessel tortuosity. CONCLUSION: Superselective embolization is a feasible, safe, and effective technique for treating acute lower GI hemorrhage.

Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic area in Irian Jaya, Indonesia: influence of seasonal rainfall fluctuations.

A malaria intervention study was carried out using permethrin impregnated bed nets in the south-central part of Irian Jaya with perennial transmission, from April 1993 to April 1995. Malariometric surveys were carried out periodically for parasite prevalence by species and for spleen rates. Prior to intervention, the percentage of Plasmodium falciparum infected inhabitants was significantly higher in Hiripau, where permethrin-impregnated bed nets were used during the study, than in the placebo-treated control village, Kaugapu. After two years of intervention the situation was reversed and figures higher in the control village (RR 0.19, 95% CI 0.10-0.36, p < 0.0001). Similarly, P. vivax infection rates, 12.4% in Hiripau vs 5.7% in Kaugapu in April 1993. were reversed in April 1995 (3.6% in Hiripau and 11.3% in Kaugapu, p < 0.001). In the treated village, pre-control hyperendemicity was reduced to a low mesoendemic level (spleen rate 12.5%) during two years of intervention, whereas the level was mesoendemic (spleen rate 35.2%) in the control village. Impregnated bed nets were found an effective intervention both in moderate (April 1993 through April 1994, 1,626 mm rainfall) and high (April 1994 through April 1995/1995, 3,321 mm) transmission seasons.

Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic area in Irian Jaya, Indonesia: differentiation between two age groups.

A malaria intervention trial was conducted for two years to evaluate the efficacy of permethrin-impregnated bed nets in reducing malaria infection and splenomegaly in two different age groups, ie below and over age of ten, in a hyperendemic area in Irian Jaya, Indonesia. Permethrin-impregnated or placebo-treated bed nets were provided to a treated and a control village, respectively. Immediately after periods with moderate rainfall in the first year, treated bed nets decreased P. falciparum and P. vivax density in the blood of children <10 years (group 1) but did not reduce the percentage of infection with either species. Children >10 and adults (group 2) showed significant reduction only in P. falciparum infection rates and density, whereas P. vivax was not influenced. After an excessive rainfall season in the second year, the risk for P. falciparum infections in both age groups using treated nets was less than half of that in the control village. P. vivax infection rates were significantly lower in the treated village at the beginning of and after these heavy rainfalls. In the treated village, spleen enlargement was markedly reduced in the younger age group during the second year.

Identification of HCV core mimotopes: improved methods for the selection and use of disease-related phage-displayed peptides.

Disease-specific epitope discovery from random peptide libraries displayed on phage using sera from patients involves a number of screening steps with many immune and non-immune sera. To rapidly identify mimotopes of the human hepatitis C virus (HCV) core protein, we have used an anti-core human monoclonal antibody (mAb; B12.F8) as a probe in screening phage that were affinity-selected using a serum from an HCV infected patient. Three different positive phage were isolated displaying low or no homology with the natural antigen, but which still efficiently bound to the antigen binding site of the B12.F8 antibody. Testing the reactivity of these phage with forty-five sera from HCV infected patients showed that antibodies recognizing them are present in more than 80% of this population. These antibodies showed distinct fine specificity, as they bound the selected phage in a mutually exclusive fashion. Co-expression of two mimotopes in the same cells led to chimeric particles which were recognized by antibodies of different specificity. These data provide novel information on the potential use of the phage display technology for the characterization of antibody specificity as well as disease diagnosis and prevention.