Men are at a higher risk of developing bladder cancer than women. Since bladder cancer cell lines and tissues were found to express the androgen receptor, efforts have been made to inspect whether androgen-mediated androgen receptor signals are implicated in bladder carcinogenesis as well as cancer progression. Mounting evidence supports the view that bladder cancer is a member of the endocrine-related tumors and may clearly explain the gender-specific difference in the incidence. However, the underlying mechanisms of how androgen receptor signals regulate bladder cancer growth are still far from fully characterized. Moreover, it remains controversial whether the androgen receptor pathway always plays a dominant role in bladder cancer progression. In this review, we summarize the available data on the involvement of androgen receptor signaling in bladder cancer. In particular, current evidence demonstrating the stimulatory effects of androgens on tumor progression or, more convincingly, tumorigenesis via the androgen receptor pathway may offer great potential for androgen deprivation as a therapeutic or chemopreventive option in patients with bladder cancer.

Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.

Objective: We compared high-sensitivity KRAS mutation testing with direct sequencing for predicting the efficacy of antiepidermal growth factor receptor antibodies in patients with metastatic colorectal cancer (mCRC). Methods: We analyzed the KRAS status in 61 tumors from cetuximab-treated mCRC patients by both direct sequencing and a high-sensitivity method: 2-step PCR restriction fragmentation length polymorphism (RFLP). Therapeutic effects in each mutational status were evaluated. Results: The incidences of KRAS mutations determined by direct sequencing and 2-step PCR RFLP were 34.4 and 52.5%, respectively (p = 0.02). Patients were categorized into 3 groups [W/W, wild-type by both methods (n = 29); W/M, wild-type by direct sequencing, detected mutation by 2-step PCR RFLP (n = 11); M/M, mutant-type by both methods (n = 21)]. The response rate for cetuximab in the W/M group (0%) was the same as that in the M/M group, and was significantly lower than in the W/W group (41.4%)(p < 0.001). Progression-free survival in the W/M group (11.0 weeks) was similar to that in the M/M group (8.0 weeks), and was significantly shorter than in the W/W group (18.0 weeks)(p < 0.002). Conclusion: High-sensitivity KRAS mutation testing is useful for selecting true responders to cetuximab.

Human nucleotide oligomerization domain-like receptor family apoptosis inhibitory protein (NAIP) prevents apoptosis by inhibiting caspase-3,-7, and -9. Four functional Naip exist in the murine genome, each of which is equally similar to human NAIP. Among them, Naip5 induces pyroptosis by promoting caspase-1 activation in response to Legionella pneumophila infection in macrophages. However, the contribution of human NAIP to this response is unclear. To investigate the role of human NAIP in macrophage survival, we stably expressed human NAIP in RAW264.7 macrophages. Human NAIP inhibited camptothecin-induced apoptosis in macrophages; however, it promoted cytotoxicity in L. pneumophila-infected cells. This cytotoxicity was associated with caspase-1. In addition, human NAIP restricted the intracellular growth of L. pneumophila. L. pneumophila flagellin was required for cytotoxicity, caspase-1 activation, and restriction of intracellular bacterial growth. Expression of murine Naip5 produced comparable results. These data indicate that human NAIP regulates the host response to L. pneumophila infection in a manner similar to that of murine Naip5 and that human NAIP and murine Naip5 regulate cell survival by inhibiting apoptosis or by promoting pyroptosis in response to specific cellular signals.

The Tōhoku earthquake and tsunami of March 11, 2011, resulted in unprecedented radioactivity releases from the Fukushima Dai-ichi nuclear power plants to the Northwest Pacific Ocean. Results are presented here from an international study of radionuclide contaminants in surface and subsurface waters, as well as in zooplankton and fish, off Japan in June 2011. A major finding is detection of Fukushima-derived (134)Cs and (137)Cs throughout waters 30-600 km offshore, with the highest activities associated with near-shore eddies and the Kuroshio Current acting as a southern boundary for transport. Fukushima-derived Cs isotopes were also detected in zooplankton and mesopelagic fish, and unique to this study we also find (110m)Ag in zooplankton. Vertical profiles are used to calculate a total inventory of ∼2 PBq (137)Cs in an ocean area of 150,000 km(2). Our results can only be understood in the context of our drifter data and an oceanographic model that shows rapid advection of contaminants further out in the Pacific. Importantly, our data are consistent with higher estimates of the magnitude of Fukushima fallout and direct releases [Stohl et al.(2011) Atmos Chem Phys Discuss 11:28319-28394; Bailly du Bois et al.(2011) J Environ Radioact, 10.1016/j.jenvrad.2011.11.015]. We address risks to public health and marine biota by showing that though Cs isotopes are elevated 10-1,000× over prior levels in waters off Japan, radiation risks due to these radionuclides are below those generally considered harmful to marine animals and human consumers, and even below those from naturally occurring radionuclides.

NO (3)(-) is a major nitrogen source for plant nutrition, and plant cells store NO (3)(-) in their vacuoles. Here, we report that a unique compost made from marine animal resources by thermophiles represses NO (3)(-) accumulation in plants. A decrease in the leaf NO (3)(-) content occurred in parallel with a decrease in the soil NO (3)(-) level, and the degree of the soil NO (3)(-) decrease was proportional to the compost concentration in the soil. The compost-induced reduction of the soil NO (3)(-) level was blocked by incubation with chloramphenicol, indicating that the soil NO (3)(-) was reduced by chloramphenicol-sensitive microbes. The compost-induced denitrification activity was assessed by the acetylene block method. To eliminate denitrification by the soil bacterial habitants, soil was sterilized with γ irradiation and then compost was amended. After the 24-h incubation, the N(2)O level in the compost soil with presence of acetylene was approximately fourfold higher than that in the compost soil with absence of acetylene. These results indicate that the low NO (3)(-) levels that are often found in the leaves of organic vegetables can be explained by compost-mediated denitrification in the soil.

To investigate the role of frozen section assessment in sparing unnecessary orchiectomy for suspected lesions, we retrospectively reviewed intraoperative testicular and paratesticular frozen section assessments performed at our institution between the years 1993 and 2010. Frozen section assessments were performed on 45 testicular lesions (age, 5-60 [mean, 32.2] years; lesion size, 0.5-9.7 [mean, 2.1] cm) and 20 paratesticular lesions (age, 26-76 [mean, 43.5] years; lesion size, 0.4-11.0 [mean, 2.8] cm) before the decision to complete radical orchiectomy. Benign/malignant frozen section assessment diagnoses were reported in 26/19 testicular cases and 17/3 paratesticular cases, respectively. Of the 26 benign testicular frozen section assessments, 5 cases resulted in orchiectomy, where permanent diagnoses included epidermoid cyst, large cell calcifying Sertoli cell tumor, fibrous pseudotumor, abscesses, and sarcoidosis, caused by a concern for potential malignancy or questionable viability of the testicles. Of the 19 malignant testicular frozen section assessments, orchiectomy was performed in 16 cases with germ cell tumor, but not in the remaining 3 cases with lymphoma. Of the 17 benign paratesticular frozen section assessments, 2 cases, both fibrous pseudotumors, resulted in orchiectomy. There were statistically significant differences in the size of the testicular (P <.001) or paratesticular (P <.001) lesions between benign and malignant frozen section assessments. Thus, in 36 (83.7%) of 43 cases with benign frozen section assessments, in addition to all 3 cases of lymphoma, orchiectomy was successfully avoided. These results suggest that frozen section assessment is useful for permitting testicular preservation, especially in men with small, nonpalpable, incidentally found masses as well as other benign lesions where a clinical diagnosis of malignancy is in doubt.

Early studies suggested androgen receptor (AR) splice variants might contribute to the progression of prostate cancer (PCa) into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR) and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown) cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

A 60-year-old woman with rheumatoid arthritis, who had been treated with infliximab, presented with uncontrollable wrist arthritis. Fungal arthritis caused by Candida parapsilosis was confirmed by examining her aspirated joint fluid. Her infliximab therapy was interrupted, and antifungal therapy with fluconazole was started. After the fungal infection had been ameliorated, surgical debridement and arthrodesis of the wrist joint were conducted, and her symptoms completely resolved. Although fungal arthritis is rare, it should be considered as a differential diagnosis of exacerbated monoarthritis in patients treated with biological agents.