Activation of PPARa ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased ER stress

Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and/or directly interfering with insulin signaling via activation of the JNK and IKK pathway. The present study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB, 100 mg/kg/day), a PPARa agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis and the impaired hepatic insulin signaling (pAkt and pGSK3ß). Intriguingly, both IRE1/XBP1 and PERK/eIF2a arms of the UPR signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS and SCD1 and 3H2O incorporation into lipids), FB treatment markedly increased FA oxidation (indicated by induction of ACOX1, pACC, ß-HAD activity and 14C-palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs) which is known to impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARa is able to ameliorate hepatic insulin resistance against increased ER stress

Clinical Features of High-Grade Extremity and Trunk Sarcomas in Patients Aged 80 Years and Older: Why Are Outcomes Inferior?

Background: The population of many countries is aging and a significant number of elderly patients with soft-tissue sarcoma are being seen at cancer centers. The unique therapeutic and prognostic implications of treating soft-tissue sarcoma in geriatric patients warrant further consideration in order to optimize outcomes.Patients and Methods: This is a single-institution retrospective study of consecutive non-metastatic primary extremity and trunk high-grade sarcomas surgically treated between 1996 and 2012, with at least 2 years of follow-up for survivors. Patient characteristics and oncological outcomes were compared between age groups (≥80 vs. <80 years), using Chi-square or Fisher-exact test and Log-Rank or Wilcoxon test, respectively. Deaths from other causes were censored for disease-specific survival estimation. A p< 0.05 was regarded as statistically significant.Results: A total of 333 cases were eligible for this study. Thirty-six patients (11%) were aged ≥80 years. Unplanned surgery incidence and surgical margin status were comparable between the age groups. Five-year local-recurrence-free, metastasis-free and disease-specific survivals were 72% (≥80 years) vs. 90% (<80 years) (p = 0.004), 59 vs. 70% (p = 0.07) and 55 vs. 80% (p < 0.001), respectively. A significantly earlier first metastasis after surgery (8.3 months vs. 20.5 months, mean) and poorer survival after first metastasis (p = 0.03) were observed. Cox analysis revealed “age ≥80 years” as an independent risk factor for local failure and disease-specific mortality, with hazard ratios of 2.41 (95% CI: 1.09–5.32) and 2.52 (1.33–4.13), respectively. A competing risks analysis also showed that “age ≥80 years” was significantly associated with the disease-specific mortality.Conclusions: Oncological outcomes were significantly worse in high-grade sarcoma patients aged ≥80 years. The findings of more frequent local failure regardless of a consistent primary treatment strategy, an earlier time to first metastasis after surgery, and poorer prognosis after first metastasis suggest that more aggressive tumor biology, in addition to multiple co-morbidity, may explain the inferiority

HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity

<p>Abstract</p> <p>Background</p> <p>Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.</p> <p>Results</p> <p>The <it>in vitro </it>potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 ± 0.1 and 7.5 ± 0.2 μM respectively (IC₅₀). These findings were similar to the previously reported IC₅₀of 6.2 μM against AITC activation of TRPA1 <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain.</p> <p>Conclusion</p> <p>Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.</p

Measurement of the Alpha Asymmetry Parameter for the Omega- to Lambda K- Decay

We have measured the alpha parameter of the Omega- to Lambda K- decay using data collected with the HyperCP spectrometer during the 1997 fixed-target run at Fermilab. Analyzing a sample of 0.96 million Omega- to Lambda K^-, Lambda to p pi- decays, we obtain alpha_Omega*alpha_Lambda = [1.33+/-0.33(stat)+/-0.52(syst)] x 10^{-2}. With the accepted value of alpha_Lambda, alpha_Omega is found to be [2.07+/-0.51(stat)+/-0.81(syst)] x 10^{-2}.Comment: 5 pages, 4 figures, to be appeared as a Rapid Communication in Phys. Rev.

Search for the Lepton-Number-Violating Decay Ξ−→pμ−μ−\Xi^- \to p \mu^- \mu^-

A sensitive search for the lepton-number-violating decay $\Xi^-\to p \mu^-\mu^-$ has been performed using a sample of $\sim10^9$ $\Xi^-$ hyperons produced in 800 GeV/$c$ $p$-Cu collisions. We obtain $\mathcal{B}(\Xi^-\to p \mu^-\mu^-)< 4.0\times 10^{-8}$ at 90% confidence, improving on the best previous limit by four orders of magnitude.Comment: 9 pages, 5 figures, to be published in Phys. Rev. Let

HyperCP: A high-rate spectrometer for the study of charged hyperon and kaon decays

The HyperCP experiment (Fermilab E871) was designed to search for rare phenomena in the decays of charged strange particles, in particular CP violation in $\Xi$ and $\Lambda$ hyperon decays with a sensitivity of $10^{-4}$. Intense charged secondary beams were produced by 800 GeV/c protons and momentum-selected by a magnetic channel. Decay products were detected in a large-acceptance, high-rate magnetic spectrometer using multiwire proportional chambers, trigger hodoscopes, a hadronic calorimeter, and a muon-detection system. Nearly identical acceptances and efficiencies for hyperons and antihyperons decaying within an evacuated volume were achieved by reversing the polarities of the channel and spectrometer magnets. A high-rate data-acquisition system enabled 231 billion events to be recorded in twelve months of data-taking.Comment: 107 pages, 45 Postscript figures, 14 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.

Search for CP Violation in Charged-Xi and Lambda Hyperon Decays

We have compared the proton and antiproton angular distributions in 117 million Xi-minus -> Lambda + pi-minus -> proton + pi-minus + pi-minus and 41 million anti-Xi-minus -> anti-Lamba + pi-plus -> antiproton + pi-plus + pi-plus decays using a subset of the data from the HyperCP experiment (E871) at Fermilab. We find no evidence of CP violation, with the direct-CP-violating parameter $A_{\Xi\Lambda} = \frac{\alpha_{\Xi}\alpha_{\Lambda} - \bar{\alpha}_{\Xi}\bar{\alpha}_{\Lambda}}{\alpha_{\Xi}\alpha_{\Lambda} + \bar{\alpha}_{\Xi}\bar{\alpha}_{\Lambda}} = [0.0+/-5.1(stat)+/-4.4(syst)]{\times}10^{-4}$.Comment: 4 pages, 4 figures, to be published in Phys. Rev. Let

CP violation in strange baryon decays: A report from Fermilab experiment 871

Fermilab experiment 871, HyperCP, is a search for direct CP violation in Ξ and Λ hyperon decays. A non-zero value in the asymmetry parameter A, defined in terms of the decay parameter products αΞαΛαΞαΛ and ,αΞ̄αΛ̄, would be unambiguous evidence for direct CP violation. The first data-taking run finished at the end of 1997 and accumulated over one billion Ξ−Ξ− and +Ξ̄+ decays. A sensitivity in A of ≈ 10−4≈10−4 is expected. A review of CP violation in hyperon decays is given, the HyperCP detector is described, and the status of the data analysis is discussed. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87472/2/107_1.pd

Measurement of αΩ in Ω− → ΛΚ− Decays

The HyperCP experiment (E871) at Fermilab has collected the largest sample of hyperon decays in the world. With a data set of over a million Ω− → ΛΚ− decays we have measured the product of αΩαΛ from which we have extracted αΩ. This preliminary result indicates that αΩ is small, but non‐zero. Prospects for a test of CP symmetry by comparing the α parameters in Ω− and Ω̄+ decays will be discussed. © 2003 American Institute of PhysicsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87682/2/251_1.pd