FZD10-targeted α-radioimmunotherapy with 225Ac-labeled OTSA101 achieves complete remission in a synovial sarcoma model

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β-radioimmunotherapy (RIT) with the 90Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y-labeled OTSA101. 90Y- and 225Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma

Knockdown of COPA, Identified by Loss-of-Function Screen, Induces Apoptosis and Suppresses Tumor Growth in Mesothelioma Mouse Model

AbstractMalignant mesothelioma is a highly aggressive tumor arising from serosal surfaces of the pleura and is triggered by past exposure to asbestos. Currently, there is no widely accepted treatment for mesothelioma. Development of effective drug treatments for human cancers requires identification of therapeutic molecular targets. We therefore conducted a large-scale functional screening of mesothelioma cells using a genome-wide small interfering RNA library. We determined that knockdown of 39 genes suppressed mesothelioma cell proliferation. At least seven of the 39 genes—COPA, COPB2, EIF3D, POLR2A, PSMA6, RBM8A, and RPL18A—would be involved in anti-apoptotic function. In particular, the COPA protein was highly expressed in some mesothelioma cell lines but not in a pleural mesothelial cell line. COPA knockdown induced apoptosis and suppressed tumor growth in a mesothelioma mouse model. Therefore, COPA may have the potential of a therapeutic target and a new diagnostic marker of mesothelioma

High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aβ1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aβ1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aβ1-42 were significantly greater than those of LMW-Aβ1-42. Therapeutic reduction of HMW-Aβ1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage

Reduction of 223Ra retention in the Large Intestine During Targeted Alpha Therapy with 223RaCl2 by Oral BaSO4 Administration in Mice

Background: Targeted alpha therapy with 223RaCl2 is used to treat skeletal metastases of hormone-refractory prostate cancer. The intravenous injection of 223RaCl2 causes gastrointestinal disorders such as nausea, abdominal discomfort, and diarrhea as frequent clinical adverse events caused by radiation. BaSO4 is known to display Ra2+ ion uptake in its structure and is clinically used as a contrast agent for X-ray imaging following oral administration. Here, we investigated the feasibility of a method to reduce 223Ra retention in the large intestine with BaSO4 by biodistribution studies in mice. Methods: 223RaCl2 biodistribution was examined in ddY mice after intravenous administration (10 kBq/mouse).BaSO4 (100 mg/mouse) was orally administered 1 h before 223RaCl2 injection. We also investigated the effect of laxative treatment on BaSO4 activity, since laxatives are clinically used with BaSO4 to avoid impaction in the large intestine. Results: BaSO4 significantly reduced 223Ra retention in the large intestine after 223RaCl2 injection in mice when compared with the control without BaSO4 administration (P < 0.05). Excretion of 223Ra into the feces was significantly increased by BaSO4 administration (P < 0.05). Laxative treatment did not affect BaSO4 activity in reducing 223Ra retention, although no additional effect of laxative treatment to 223Ra excretion was observed in mice. Conclusions. BaSO4 administration was effective in reducing 223Ra retention in the large intestine during 223RaCl2 therapy, and laxative treatment did not attenuate BaSO4 activity. This method could be useful in reducing adverse events caused by radiation exposure to the large intestine during 223RaCl2 therapy

Defective repair of radiation-induced DNA damage is complemented by a CHORI-230-65K18 BAC clone on rat chromosome 4

AbstractThe Long Evans cinnamon (LEC) rat is highly susceptible to X-irradiation due to defective DNA repair and is thus a model for hepatocellular carcinogenesis. We constructed a bacterial artificial chromosome (BAC) contig of rat chromosome 4 completely covering the region associated with radiation susceptibility. We used transient and stable transfections to demonstrate that defective DNA repair in LEC cells is fully complemented by a 200-kb BAC, CHORI-230-65K18. Further analysis showed that the region associated with radiation susceptibility is located in a 128,543-bp region of 65K18 that includes the known gene Rpn1. However, neither knockdown nor overexpression of Rpn1 indicated that this gene is associated with radiation susceptibility. We also mapped three ESTs (TC523872, TC533727, and CB607546) in the 128,543-bp region, suggesting that 65K18 contains an unknown gene associated with X-ray susceptibility in the LEC rat

A Pilot Study on Developing Mucosal Vaccine against Alveolar Echinococcosis (AE) Using Recombinant Tetraspanin 3: Vaccine Efficacy and Immunology

Humans and rodents become infected with E. multilocularis by oral ingesting of the eggs, which then develop into cysts in the liver and progress an endless proliferation. Untreated AE has a fatality rate of >90% in humans. Tetraspanins have been identified in Schistosoma and showed potential as the prospective vaccine candidates. In our recent study, we first identified seven tetraspanins in E. multilocularis and evaluated their protective efficacies as vaccines against AE when subcutaneously administered to BALB/c mice. Mucosal immunization of protective proteins is able to induce strong local and systemic immune responses, which might play a crucial role in protecting humans against E. multilocularis infection via the intestine, blood and liver. We focused on Em-TSP3, which achieved significant vaccine efficacy via both s.c. and i.n. routes. The adjuvanticity of nontoxic CpG OND as i.n. vaccine adjuvant was evaluated. The widespread expression of Em-TSP3 in all the developmental stages of E. multilocularis, and the strong local and systemic immune responses evoked by i.n. administration of rEm-TSP3 with CpG OND adjuvant suggest that this study might open the way for developing efficient, nontoxic human mucosal vaccines against AE

Dietary patterns associated with fall-related fracture in elderly Japanese: a population based prospective study

<p>Abstract</p> <p>Background</p> <p>Diet is considered an important factor for bone health, but is composed of a wide variety of foods containing complex combinations of nutrients. Therefore we investigated the relationship between dietary patterns and fall-related fractures in the elderly.</p> <p>Methods</p> <p>We designed a population-based prospective survey of 1178 elderly people in Japan in 2002. Dietary intake was assessed with a 75-item food frequency questionnaire (FFQ), from which dietary patterns were created by factor analysis from 27 food groups. The frequency of fall-related fracture was investigated based on insurance claim records from 2002 until 2006. The relationship between the incidence of fall-related fracture and modifiable factors, including dietary patterns, were examined. The Cox proportional hazards regression model was used to examine the relationships between dietary patterns and incidence of fall-related fracture with adjustment for age, gender, Body Mass Index (BMI) and energy intake.</p> <p>Results</p> <p>Among 877 participants who agreed to a 4 year follow-up, 28 suffered from a fall-related fracture. Three dietary patterns were identified: mainly vegetable, mainly meat and mainly traditional Japanese. The moderately confirmed (see statistical methods) groups with a Meat pattern showed a reduced risk of fall-related fracture (Hazard ratio = 0.36, 95% CI = 0.13 - 0.94) after adjustment for age, gender, BMI and energy intake. The Vegetable pattern showed a significant risk increase (Hazard ratio = 2.67, 95% CI = 1.03 - 6.90) after adjustment for age, gender and BMI. The Traditional Japanese pattern had no relationship to the risk of fall-related fracture.</p> <p>Conclusions</p> <p>The results of this study have the potential to reduce fall-related fracture risk in elderly Japanese. The results should be interpreted in light of the overall low meat intake of the Japanese population.</p

Research and Development for Cyclotron Production of 225Ac from 226Ra&mdash;The Challenges in a Country Lacking Natural Resources for Medical Applications

The high therapeutic effect of targeted radioisotope/radionuclide therapy (TRT) using &alpha;-emitters, especially 225Ac, is attracting attention worldwide. However, the only 225Ac production method that has been put into practical use is extraction from a 229Th generator derived from the nuclear fuel 233U, and it is unlikely that this method alone is able to meet future global medical demand. Development towards new 225Ac production methods is in progress. These new 225Ac production methods require the irradiation of 232Th or 226Ra using an accelerator or a nuclear reactor. Global competition has already begun in the race to secure a reliable supply of 232Th and 226Ra, as well as 229Th for the conventional production method. Japan is a &ldquo;resource-poor country&rdquo; that depends on foreign countries for most of its needs. As such, it is difficult for Japan to secure raw materials such as 232Th and 226Ra for medical application. In this paper, we look back on our research at the National Institutes for Quantum Science and Technology (QST) in the fields of 225Ac production and 225Ac-labeled pharmaceutical development. We present the history and details of our research from 2011, as well as the development of a collaboration between QST and Nihon Medi-Physics that focuses on research into 225Ac production via 226Ra(p,2n)225Ac reaction using an accelerator. Furthermore, we review the valuable discussion at the 2018 Joint IAEA-JRC Workshop&mdash;&ldquo;Supply of Actinium-225&rdquo;, an international conference that we participated in. Overall, the statuses of external 225Ac supply, domestic production, and distribution are discussed, as are the latest developments in 225Ac production methods, 225Ac pharmaceuticals, and future prospects for the domestic production of 225Ac in Japan, a country lacking natural resources for medical applications

AHNAK is highly expressed and plays a key role in cell migration and invasion in mesothelioma.

The worldwide incidence of the highly aggressive tumor mesothelioma is expected to increase. Mesothelioma is classified into three main histological subtypes: epithelioid, sarcomatoid and biphasic. Although the pathological diagnostic markers for epithelioid are established, to date no adequate marker for sarcomatoid mesothelioma has been found. Thus, a reliable diagnostic marker of sarcomatoid mesothelioma is necessary. In this study, to identify an unknown protein with 120 kDa expressed only in the mesothelioma cell line 211H, we conducted proteomic analysis and found five candidate proteins. One such protein, AHNAK, was highly expressed in all seven mesothelioma cell lines (211H, H28, H226, H2052, H2452, MESO1 and MESO4), but not in the mesothelial cell line MeT-5A by RT-PCR and immunofluorescence staining. Furthermore, we confirmed high AHNAK expression not only in xenografts but also in human mesothelioma specimens including sarcomatoid, epithelioid and biphasic mesothelioma using immunohistochemical staining. These findings suggest that AHNAK has the potential to be a new marker for detecting mesothelioma. Since AHNAK is involved in cell migration and invasion in other metastatic tumor cells, we conducted migration and invasion assays in mesothelioma cell lines. The number of migrating cells in six of seven mesothelioma cell lines and the number of invading cells in all seven cell lines were significantly increased compared with those in MeT-5A. Knockdown of AHNAK significantly reduced the cell migration and invasion ability in all seven mesothelioma cell lines. These results support further clinical evaluation of the association of AHNAK and metastasis in mesothelioma