Relationship between quantity of IFNT estimated by IFN-stimulated gene expression in peripheral blood mononuclear cells and bovine embryonic mortality after AI or ET

<p>Abstract</p> <p>Background</p> <p>Interferon tau (IFNT), which is secreted into the uterine cavity during the maternal recognition period (MRP), is a key factor for establishment of pregnancy. The present study aims to clarify the relationship between the ability of a bovine conceptus to produce IFNT during the MRP and the conceptus's ability to establish pregnancy.</p> <p>Methods</p> <p>In the first experiment, IFNT (0, 500, or 1000 micrograms) was administered into the uterine horn ipsilateral to the CL 16 or 17 d after standing estrus, and mRNA levels of IFN-stimulated gene 15-kDa protein (<it>ISG15</it>) and <it>Mx2 </it>in peripheral blood mononuclear cells (PBMCs) were determined. In the second experiment, we investigated <it>ISG15 </it>mRNA expression in PBMCs during the MRP in cattle after either artificial insemination (AI) or embryo transfer (ET).</p> <p>Results</p> <p>Intrauterine administration of IFNT stimulated <it>ISG15 </it>and <it>Mx2 </it>gene expressions in PBMCs in cattle, and there was a positive correlation between the expressions of peripheral markers and the quantity of IFNT administered. In pregnant and normal interestrous interval (< 25 d) cattle (nIEI cattle), expression levels of the <it>ISG15 </it>gene showed similar patterns after AI and ET, and <it>ISG15 </it>mRNA expression was increased in pregnant cattle but unchanged in nIEI cattle. In contrast, <it>ISG15 </it>gene expression in extended interestrous interval (greater than or equal to 25 d) cattle (eIEI cattle) differed after ET compared with AI. In eIEI cattle after ET, <it>ISG15 </it>gene expression increased, such that the value on day 18 was intermediate between those of pregnant and nIEI cattle. In eIEI cattle after AI, <it>ISG15 </it>gene expression did not increase throughout the observation period.</p> <p>Conclusions</p> <p>The results of the current study indicate that the quantity of conceptus-derived IFNT can be estimated by measuring <it>ISG15 </it>mRNA levels in PBMCs from cattle. Using this approach, we demonstrate that <it>ISG15 </it>gene expression during the MRP in eIEI cattle differed after ET compared with AI. In addition, the modest increase in <it>ISG15 </it>gene expression in eIEI cattle after ET suggests that late embryo losses were due to delayed or insufficient growth of the conceptus during the MRP in cattle.</p

鶏精子の凍結乾燥に関する研究 : I. 鶏精子の凍結乾燥用保護媒質について

鶏精子の凍結乾燥用保護媒質として全乳,卵ク液,ゼラチン,卵ブ液およびグリセリン卵ブ液を用いて実験を行なった結果は次の如くである. 1. グリセリン卵ブ液を保護媒質とした精液では復元後何れの場合も活力のある精子が観察され,或る実験では活力++以上を示すものが20%もあり,運動力のある精子の出現割合は平均37%であった. 2. 卵ブ液を保護媒質とした精液では活力++以上を示すもの10%の1例を除いては運動精子は観察されず,その出現割合は平均10%であった. 3. 全乳,卵ク液およびゼラチンを保護媒質とした精液では復元後全く運動精子が観察されなかった. 4. 現在の処5つの保護媒質の中でグリセリン卵ブ液が最も適した保存液のように思われる.The present experiment was undertaken in order to determine the diluents suitable for the freeze-drying and reconstitution of fowl spermatozoa. Whole milk, egg yolk citrate solution, gelatin, egg yolk glucose and glycerol egg yolk glucose solution were used for the extender of semen. The results are as follows; 1. In the semen samples diluted with glycerol egg yolk glucose solution, motile spermatozoa were observed at every experiment and the spermatozoa in some case showed 20 percent motility (over ++) and the percentage of motile spermatozoa recovered averaged 37 percent. 2. In the semen samples diluted with egg yolk glucose solution following freeze-drying and reconstitution, motile spermatozoa were not observed with the exception of one single experiment which the motility showed 10 percent (over ++) and the percentage of motile spermatozoa recovered averaged 10 percent. 3. In semen sample diluted with the other three diluents, i.e., whole milk, egg yolk citrate solution and gelatin, motile spermatozoa were not observed at all. 4. Therefore, out of above 5 diluents glycerol egg yolk glucose solution seemed to be the most adequate medium for withstanding freeze-drying preservation of fowl spermatozoa

Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition

Inhibition of epidermal growth factor receptor (EGFR) signalling has emerged as a new treatment strategy for oral squamous cell carcinoma (OSCC). Previously, we found that loss of EGFR expression in OSCC was associated with epithelial-mesenchymal transition (EMT), and may have functional implications with regard to resistance to cetuximab, a monoclonal anti-EGFR antibody. Eribulin (a microtubule inhibitor) reportedly renders breast cancer less aggressive, and less likely to metastasise, by triggering mesenchymal-to-epithelial (MET) transition. In the present study we evaluated whether eribulin-induced MET was associated with re-sensitization of resistant OSCC cell lines to cetuximab. In vitro antiproliferative activities were determined in three human OSCC lines (OSC-20, OSC-19 and HOC313) treated with eribulin. These three human OSCC represented different EMT/MET states. Interestingly, HOC313 cells (mesenchymal phenotype) were highly sensitive to eribulin in comparison with other cell lines, and significantly enhanced the anti-proliferative effect of cetuximab in response to the drug. Eribulin also underwent a MET-associated gene switch that resulted in morphological changes and high EGFR expression in HOC313 cells, and abrogated a TGF-β-induced EMT gene expression signature. Eribulin-dependent sensitization of OSCC to cetuximab is likely due to induction of MET. Combination therapies based on eribulin and cetuximab have potential as a novel treatment regimen in OSCC

Dynamical Diffraction Theory for Wave Packet Propagation in Deformed Crystals

We develop a theory for the trajectory of an x ray in the presence of a crystal deformation. A set of equations of motion for an x-ray wave packet including the dynamical diffraction is derived, taking into account the Berry phase as a correction to geometrical optics. The trajectory of the wave packet has a shift of the center position due to a crystal deformation. Remarkably, in the vicinity of the Bragg condition, the shift is enhanced by a factor $\omega /\Delta \omega$ ($\omega$: frequency of an x ray, $\Delta\omega$: gap frequency induced by the Bragg reflection). Comparison with the conventional dynamical diffraction theory is also made.Comment: 4 pages, 2 figures. Title change

Molecular Mechanism Underlying the Suppression of CPB2 Expression Caused by Persistent Hepatitis C Virus RNA Replication

The mechanisms of hepatitis C virus (HCV)-associated hepatocarcinogenesis and disease progression are unclear. We previously observed that the expression level of carboxypeptidase B2 (CPB2) gene was remarkably suppressed by persistent HCV RNA replication in human hepatoma cell line Li23-derived cells. The results of the present study demonstrated that the CPB2 expression in patients with chronic hepatitis C was inversely correlated with several risk factors of hepatic fibrosis or steatosis, although ectopic CPB2 expression did not suppress the expression of fibrogenic or lipogenic genes. The suppressed CPB2 expression was restored by treatment with 5-azacytidine. To clarify the mechanism underlying this phenomenon, we analyzed the CPB2 promoter, and the results revealed that (1) hepatocyte nuclear factor 1 (HNF1), especially HNF1α, was essential for the CPB2 promoter, and (2) CPB2 promoter was not methylated by persistent HCV RNA replication. The expression levels of HNF1α and HNF1β were also not changed by persistent HCV RNA replication. These results suggest the existence of 5-azacytidine-inducible or -reducible unknown factor(s) that can control the CPB2 expression. To evaluate this idea we performed a microarray analysis, and several gene candidates corresponding to the suggested factor(s) were identified

Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment

Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly

Spin-Hall effect: Back to the Beginning on a Higher Level

The phenomena of the spin-Hall effect, initially proposed over three decades ago in the context of asymmetric Mott skew scattering, was revived recently by the proposal of a possible intrinsic spin-Hall effect originating from a strongly spin-orbit coupled band structure. This new proposal has generated an extensive debate and controversy over the past two years. The purpose of this workshop, held at the Asian Pacific Center for Theoretical Physics, was to bring together many of the leading groups in this field to resolve such issues and identify future challenges. We offer this short summary to clarify the now settled issues on some of the more controversial aspects of the debate and help refocus the research efforts in new and important avenues.Comment: 4 pages, Summary of the APCTP Workshop on the Spin-Hall Effect and Related Issue

Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.

BackgroundProdrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.MethodsHere we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.ResultsIn both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for &gt;300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.ConclusionThese results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity