2-methoxyestradiol enhances p53 protein transduction therapy-associated inhibition of the proliferation of oral cancer cells through the suppression of NFkappaB activity.

Protein transduction therapy using poly-arginine peptide can deliver the biologically active proteins. A previous study showed that 11 poly-arginine fused p53 protein (11R-p53) effectively penetrated across the plasma membrane and inhibited the proliferation of oral cancer cells. However, the intracellular half-life of the delivered protein was less than 36 h. Previous studies also showed that 2-methoxyestradiol (2-ME), an endogenous non-toxic estrogenic metabolite, induces the stabilization of the wild-type p53 protein in human cancer cells posttranscriptionally. In the present study, we examined whether 2-ME induced the stabilization of 11R-p53 and had an inhibitory effect on the proliferation of oral cancer cells. The application of 2-ME significantly enhanced the inhibitory effect of 11R-p53 on the proliferation of oral cancer cells. However, 2-ME had no effect on the intracellular half-life of 11R-p53 in oral cancer cells. Of interest is the finding that 2-ME suppressed the transcriptional activity of NFkappaB, which has an important role in tumorigenesis, but did not affect p53 transcriptional activity. These results suggest that 2-ME synergistically enhances the 11R-p53-induced inhibition of the proliferation of oral cancer cells through the suppression of NFkB transcription.</p

Daily low-dose cisplatin and concurrent thoracic irradiation for poor-risk patients with unresectable non-small-cell lung cancer.

A pilot study was conducted to assess the efficacy and feasibility of daily low-dose cisplatin with concurrent thoracic irradiation for clinically unresectable non-small-cell lung cancer (NSCLC). Patients with inoperable NSCLC who had poor risk factors such as advanced age, poor performance status, poor lung function, or concomitant active malignancy were entered into the study. Low-dose cisplatin (6 mg/m2) was administered daily before concurrent thoracic irradiation (2 Gy/day; total dose of 60 Gy) was given. Twenty-five patients were registered. The majority of the patients had either stage IIIA (24.0%) or stage IIIB (60.0%) disease. Fifteen patients (60.0%) completed the planned treatment. Both chemotherapy and radiotherapy were stopped in 3 patients (12.0%) due to poor response, and 7 patients (28.0%) partly received radiotherapy alone as a result of their toxicity response. The proportion of total administered dose to planned dose was 90.9% for chemotherapy and 99.3% for radiotherapy, which were comparable to those in previous studies for LA-NSCLC patients without poor risk factors. Grade 3 leukopenia and neutropenia developed in 14 patients (56.0%) and 10 patients (40.0%), respectively, but grade 4 toxicity was not encountered. Grade 3 pneumonitis and esophagitis were observed in 4 patients (16.0%) and 2 patients (8.0%), respectively. The overall response rate was 60.0%. The median survival time was 22 months, and the 2-year survival rate was 50.3%. Daily low-dose cisplatin and concurrent thoracic irradiation were well tolerated even by poor-risk patients with NSCLC, and showed a therapeutic efficacy similar to that for good-risk patients.</p

Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis

BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1(G93A) mice). FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1(G93A) mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1(G93A) mice. CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1(G93A) mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-014-0179-2) contains supplementary material, which is available to authorized users

Formation of a transdisciplinary community of practice in rural areas, with an interactive database of co-created knowledge: A case study in Noto, Japan

Many rural areas suffer from severe depopulation, and the absence of a university is one reason for outmigration. Where research and education are valued, however, such rural areas can attract scholars and students visiting from universities and other external institutions. Scholarly outputs of research, such as research articles and project reports, particularly those from community-based research (CBR), can themselves become an asset for use by local communities. We consider that CBR can contribute to asset-based community development (ABCD) when a transdisciplinary community of practice (TDCOP) emerges and drives the processes of collaborative creation and use of the knowledge. A particularly critical mechanism, which is currently lacking, is to allow the local community to collect knowledge outputs and make them easily available to interested actors within and outside of the community. We assume that a core tool in this mechanism is an interactive database. It can be equipped with a user interface, allowing enjoyable and active searches, and possibly a mechanism by which users themselves can contribute to gradual development of the database. We formed a study group of researchers and practitioners to conduct a case study in the Noto region of Japan. We identified the existing assets in Noto, including the knowledge created through CBR, and then collected and shared our own experiences and practices, as well as lessons learned from other regions in Japan, to explore the principles of designing a database. A CBR database should not only be a static inventory of past research, but also capable of facilitating new cycles of knowledge co-creation. With a comprehensive and easily accessible inventory of knowledge in place, we conclude that there is high potential in enabling CBR itself to be an asset, which can help achieve ABCD in rural communities

Multiwalled carbon nanotubes grown in hydrogen atmosphere : An x-ray diffraction study

X-ray diffraction study of multiwalled carbon nanotube (MWNT) grown by arc discharge in hydrogen atmosphere is presented. It is found that the thermal-expansion coefficient along the radial direction of MWNT is widely distributed in a range from 1.6×10-5 K-1 to 2.6×10-5 K-1, indicating the existence of both of Russian doll MWNT and highly defective MWNT. Russian doll MWNT is suggested to have the outer diameter less than ∼100  Å . Thicker MWNT's are typically highly defective, and may have the jelly roll (scroll) or defective polygonal structure consisting of flat graphite domains

Thermal expansion of single-walled carbon nanotube (SWNT) bundles: X-ray diffraction studies

Thermal expansion coefficient in single-walled carbon nanotube bundles was determined as (-0.15±0.20)×10-5 (1/K) for the tube diameter and (0.75±0.25)×10-5 (1/K) for the triangular lattice constant by means of x-ray scattering between 300 K to 950 K. The value for the intertube gap was (4.2±1.4)×10-5 (1/K), which is larger than 2.6×10-5 (1/K) for the c-axis thermal expansion in graphite. The results reveal the presence of a remarkably larger lattice anharmonicity in nanotube bundles than that of graphite. The small value for the tube diameter is consistent with the seamless tube structure formed by a strong covalent bond between carbon atoms comparable to that in graphite

Current Performance and On-Going Improvements of the 8.2 m Subaru Telescope

An overview of the current status of the 8.2 m Subaru Telescope constructed and operated at Mauna Kea, Hawaii, by the National Astronomical Observatory of Japan is presented. The basic design concept and the verified performance of the telescope system are described. Also given are the status of the instrument package offered to the astronomical community, the status of operation, and some of the future plans. The status of the telescope reported in a number of SPIE papers as of the summer of 2002 are incorporated with some updates included as of 2004 February. However, readers are encouraged to check the most updated status of the telescope through the home page, http://subarutelescope.org/index.html, and/or the direct contact with the observatory staff.Comment: 18 pages (17 pages in published version), 29 figures (GIF format), This is the version before the galley proo

Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues

Nonimmersive Virtual Reality Mirror Visual Feedback Therapy and Its Application for the Treatment of Complex Regional Pain Syndrome: An Open-Label Pilot Studyp me_819 622..629

Abstract Objective. Chronic pain conditions such as phantom limb pain and complex regional pain syndrome are difficult to treat, and traditional pharmacological treatment and invasive neural block are not always effective. Plasticity in the central nervous system occurs in these conditions and may be associated with pain. Mirror visual feedback therapy aims to restore normal cortical organization and is applied in the treatment of chronic pain conditions. However, not all patients benefit from this treatment. Virtual reality technology is increasingly attracting attention for medical application, including as an analgesic modality. An advanced mirror visual feedback system with virtual reality technology may have increased analgesic efficacy and benefit a wider patient population. In this preliminary work, we developed a virtual reality mirror visual feedback system and applied it to the treatment of complex regional pain syndrome. Design. A small open-label case series. Five patients with complex regional pain syndrome received virtual reality mirror visual feedback therapy once a week for five to eight sessions on an outpatient basis. Patients were monitored for continued medication use and pain intensity. Results. Four of the five patients showed &gt;50% reduction in pain intensity. Two of these patients ended their visits to our pain clinic after five sessions. Conclusion. Our results indicate that virtual reality mirror visual feedback therapy is a promising alternative treatment for complex regional pain syndrome. Further studies are necessary before concluding that analgesia provided from virtual reality mirror visual feedback therapy is the result of reversing maladaptive changes in pain perception