Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not ...limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 6-(3-(piperazin-1-yl)propanoyl)benzodoxazol-2(3H)-one with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.
Background
Substance P contributes to the hypersensitivity reaction (HSR) to paclitaxel in a rat model. Aprepitant acts as an inhibitor of the binding of substance P to the neurokinin-1 receptor and, ...consequently, may reduce the frequency of paclitaxel-induced HSR. While aprepitant has a prophylactic effect against vomiting caused by high-dose cisplatin, the benefits of aprepitant have not been clearly demonstrated in patients receiving paclitaxel and carboplatin (TC) combination chemotherapy.
Methods
We conducted a multicenter, placebo-controlled, double-blind, randomized study in Japanese patients with gynecologic cancer who received TC combination chemotherapy. Patients received aprepitant or placebo together with both a 5-HT
3
receptor antagonist and dexamethasone prior to chemotherapy. The primary endpoint was the proportion of patients with HSR, and the secondary endpoints were the proportion of patients with “no vomiting”, “no significant nausea”, and complete response, respectively.
Results
Of the 324 randomized patients, 297 (151 in the aprepitant group; 146 in the placebo group) were evaluated. The percentage of patients with HSR (9.2 vs. 7.5 %, respectively;
P
= 0.339) was not significantly different between the groups. The percentage of “no vomiting” patients (78.2 vs. 54.8 %;
P
< 0.0001), “no significant nausea” patients (85.4 vs. 74.7 %;
P
= 0.014), and patients showing complete response (61.6 vs. 47.3 %,
P
= 0.0073) was significantly higher in the aprepitant group than in the placebo group.
Conclusion
The administration of aprepitant did not have a prophylactic effect on the HSR but was effective in reducing nausea and vomiting in gynecologic cancer patients receiving TC combination chemotherapy.
Commissioning of liquid xenon gamma-ray detector for MEG II experiment Matsushita, Ayaka; Ban, Sei; Benmansour, Hicham ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2023, Letnik:
1047
Journal Article
Recenzirano
The liquid xenon (LXe) gamma-ray detector in the MEG II experiment measures the energy, position and timing of the gamma-ray from μ+→e+γ, and it is the key to the unprecedented sensitivity of the ...experiment. All the photo sensors of 4092 VUV MPPCs and 668 PMTs were read out for the first time and a physics data collection started in 2021. The detector response was monitored all through the beam time, and the LXe detector operated stably. The timing and energy resolution were measured using the gamma-rays from the π0 decays after charge exchange reaction of charged pions in a liquid hydrogen target. The detector has been successfully commissioned and is ready for the long physics run.
The MEG II experiment is an upgrade of the MEG experiment to search for the charged lepton flavor violating decay of muon, μ+→e+γ. The MEG II experiment is expected to reach a branching ratio ...sensitivity of 4×10−14, which is one order of magnitude better than the sensitivity of the current MEG experiment. The performance of the liquid xenon (LXe) γ-ray detector will be greatly improved with a highly granular scintillation readout realized by replacing 216 photomultiplier tubes (PMTs) on the γ-ray entrance face with 4092 Multi-Pixel Photon Counters (MPPCs). For this purpose, we have developed a new type of MPPC which is sensitive to the LXe scintillation light in vacuum ultraviolet (VUV) range, in collaboration with Hamamatsu Photonics K.K. We have measured the performance of the MPPC in LXe, and an excellent performance has been confirmed including high photon detection efficiency (>15%) for LXe scintillation light. An excellent performance of the LXe detector has been confirmed by Monte Carlo simulations based on the measured properties of the MPPC. The construction of the detector is in progress, aiming to start physics data taking in 2017.
Aim: To evaluate the usefulness of a platelet‐derived growth factor (PDGF)‐B specific monoclonal antibody (mAb) as a therapeutic agent to treat chronic liver fibrosis.
Methods: Liver fibrosis was ...induced in ICR mice by bile duct ligation (BDL) or BALB/c mice by weekly injection of concanavalin A (ConA) for 4 or 8 weeks. A mAb specific for mouse and human PDGF‐B chain, AbyD3263, was generated, tested in vitro and administered twice a week throughout the experimental period.
Results: AbyD3263 showed neutralizing activity against mouse and human PDGF‐B chain in cell‐based assays, as measured in vitro by inhibition of phosphorylation of PDGF receptor β and proliferation of hepatic stellate cells induced by PDGF‐BB. The half life of AbyD3263 in mice exceeded 7 days and dosing of animals twice a week resulted in constant plasma levels of the mAb. Induction of liver fibrosis by BDL and ConA resulted in elevated levels of alanine aminotransferase (ALT) in plasma and hydroxyproline in the liver. Treatment with AbyD3263 did not modify ALT levels, but significantly reduced hydroxyproline content in the liver with a maximum reduction of 39% and 54% in the BDL and ConA models, respectively, compared to controls.
Conclusios: Consistent with the notion that PDGF‐BB plays an important role in the progression of liver fibrosis, AbyD3263 exhibits efficacy in pre‐clinical disease models suggesting that pharmacological inhibition of PDGF‐B chain may be a therapeutic approach to treat liver fibrosis.
Aim
Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological features of non‐alcoholic steatohepatitis. We undertook this ...multicenter, cross‐sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning.
Methods
We enrolled 176 patients, of whom 132 were proven by liver biopsy as having non‐alcoholic fatty liver disease (NAFLD) and classified as non‐ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We carried out gas chromatography–mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma.
Results
As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated most significantly with the ballooning grade (correlation coefficient CC = 0.463; P < 0.001). Among the metabolic/lipidomic markers, phosphatidylcholine (PC) (aa‐44:8) correlated most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e‐18:2), was 0.846 (95% confidence interval, 0.772–0.919).
Conclusions
Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These non‐invasive metabolic/lipidomic‐based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning.
Spinal disorders affect mainly older people and cause pain, paralysis and/or deformities of the trunk and/or extremities, which could eventually disturb locomotive functions. For ensuring safe and ...high-quality treatment of spinal disorders, in 1987, the Tohoku University Spine Society (TUSS) was established by orthopedic departments in Tohoku University School of Medicine and its affiliated hospitals in and around Miyagi Prefecture. All spine surgeries have been enrolled in the TUSS Spine Registry since 1988. Using the data from this registration system between 1988 and 2012, we demonstrate here the longitudinal changes in surgical trends for spinal disorders in Japan that has rushed into the most advanced “aging society” in the world. In total, data on 56,744 surgeries were retrieved. The number of spinal surgeries has annually increased approximately 4-fold. There was a particular increase among patients aged ≥ 70 years and those aged ≥ 80 years, with a 20- to 90-fold increase. Nearly 90% of the spinal operations were performed for degenerative disorders, with their number increasing approximately 5-fold from 705 to 3,448. The most common disease for surgery was lumbar spinal stenosis (LSS) (35.9%), followed by lumbar disc herniation (27.7%) and cervical myelopathy (19.8%). In 2012, approximately half of the patients with LSS and cervical myelopathy were ≥ 70 years of age. In conclusion, the number of spinal operations markedly increased during the 25-year period, particularly among older patients. As Japan has a notably aged population, the present study could provide a near-future model for countries with aging population.
We developed two complementary ways to measure the position of SiPMs inside liquid xenon detector for MEG II experiment; one uses laser tools and the other uses an X-ray beam. We measured the ...position of all SiPMs to an accuracy of 320 μm.
•Precise alignment of SiPMs in liquid xenon detector with X-ray and laser.•The SiPM array is scanned with X-ray beam that makes a local energy deposit.•Reconstructed 3D SiPM array from an image taken by a laser scanner.•Reasonable thermal contraction was observed from the comparison.•Consistent shape of the SiPM array measured by two measurements.
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