Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent

<p>Abstract</p> <p>Background</p> <p>Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target.</p> <p>Methods</p> <p>We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.</p> <p>Results</p> <p>It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines <it>in vitro</it>. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis <it>in vivo </it>revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.</p> <p>Conclusion</p> <p>These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.</p

Absence of Cretaceous hairpin in the apparent polar wander path of southwest Japan: consistency in paleomagnetic pole positions

To test the hypothesis that a Cretaceous hairpin turn is absent in the apparent polar wander path (APWP) of the inner arc of southwestern Japanese island (southwest Japan), we refined a mid-Cretaceous (100 Ma) paleomagnetic pole from southwest Japan. Red mudstone samples from the 100 Ma Hayama Formation were collected for paleomagnetic analysis from eight sites in the Hayama area in the central part of southwest Japan. A high-temperature remanent magnetization component carried by hematite was isolated from these sites and was found to be of primary mid-Cretaceous origin. The primary nature of the magnetization is supported by the detrital character of the magnetic carrier. The primary directions provided a paleomagnetic pole (35.0 degrees N, 209.6 degrees E, A(95) = 6.1 degrees, N = 8), which represented southwest Japan at 100 Ma. This pole falls into a cluster of Cretaceous poles in southwest Japan. An APWP for southwest Japan between 110 and 70 Ma was updated to ascertain the stationarity of the pole positions for this region. Therefore, it is unlikely that the APWP for southwest Japan experienced a hairpin turn during the Cretaceous

Adaptive Cation Pillar Effects Achieving High Capacity in Li-Rich Layered Oxide, Li₂MnO₃-LiMeO₂ (Me = Ni, Co, Mn)

リチウムイオン電池正極の低結晶層状構造を支える2種類の支柱. 京都大学プレスリリース. 2022-09-05.Intensive research is underway to further enhance the performance of lithium-ion batteries (LIBs). To increase the capacity of positive electrode materials, Li-rich layered oxides (LLO) are attracting attention but have not yet been put to practical use. The structural mechanisms through which LLO materials exhibit higher capacity than conventional materials remain unclear because their disordered phases make it difficult to obtain structural information by conventional analysis. The X-ray total scattering analysis reveals a disordered structure consisting of metal ions in octahedral and tetrahedral sites of Li layers as a result of cation mixing after the extraction of Li ions. Metal ions in octahedral sites act as rigid pillars. The metal ions move to the tetrahedral site of the Li layer, which functions as a Li-layer pillar during Li extraction, and returns to the metal site during Li insertion, facilitating Li diffusion as an adaptive pillar. Adaptive pillars are the specific structural features that differ from those of the conventional layered materials, and their effects are responsible for the high capacity of LLO materials. An essential understanding of the pillar effects will contribute to design guidelines for intercalation-type positive electrodes for next-generation LIBs

Disordered Cubic Spinel Structure in the Delithiated Li2MnO3 Revealed by Difference Pair Distribution Function Analysis

An archetypical Li-rich layered oxide, Li2MnO3, shows a large initial charge capacity of ~350 mAh g-1 with little oxidation of the constituent Mn ions, yet, the crystal structure of delithiated Li2MnO3 is still unclarified because the structural disorder induced by the considerable Li extraction makes the analysis challenging. X-ray pair distribution function (PDF) analysis is a powerful tool to experimentally elucidate the structure of the disordered phase. Here, we conducted a comprehensive analysis with a focus on PDF analysis in combination with the X-ray powder diffraction (XRPD), transmission electron microscopy (TEM), and X-ray absorption spectroscopy (XAS) to reveal the disordered crystalline structure of the electrochemically delithiated Li2MnO3. The XRPD and TEM analyses clarified the formation of a low-crystallinity phase in the light of the average structure. The XAS and PDF analyses further revealed that the MnO6–based framework was rearranged with maintaining the MnO6 octahedral coordination after the initial charge. The difference pair distribution function (d-PDF) technique was therefore employed to extract the structural information of the low-crystallinity disordered phase. The delithiated phase was found to have a structure similar to the cubic spinel, LiMn2O4, rather than that of delithiated LiMn2O4 (λ-MnO2). In addition, the middle-range order of the delithiated phase deteriorated after the charge, indicating a decrease of coherent domain size to a single nm order. The composite structure formed after the first charge, therefore, consists of the disordered cubic spinel structure and unreacted Li2MnO3. The formation of the composite structure “activates” the electrode material structurally and eventually induces characteristic large capacity of this material

Two Cases of Nivolumab Re-Administration after Pneumonitis as Immune-Related Adverse Events

Nivolumab is a recently approved medication for the treatment of unresectable malignant melanoma. Many immune-related adverse events (irAEs) associated with nivolumab have been reported, such as pneumonitis, hepatitis, dermatitis, and thyroiditis. Prednisolone can effectively treat irAEs. However, it is unclear how or if nivolumab should be administered to patients after they have experienced an irAE. Herein, we show 2 patients who underwent pneumonitis as irAE. Case 1 demonstrated a cryptogenic organizing pneumonia pattern in the CT scan and case 2 had a diffuse alveolar damage (DAD) pattern. Oral corticosteroids improved chest shadow of CT scan in both cases. However, when nivolumab was re-administrated, case 1 demonstrated no symptoms, but case 2 demonstrated pneumonia again. From our cases, it is difficult to re-administrate nivolumab for the patients with pneumonitis which shows a DAD pattern in CT, even if oral corticosteroids improve their symptoms

Temperature-dependent structure of methanol-water mixtures on cooling: X-ray and neutron diffraction and molecular dynamics simulations

Methanol-water liquid mixtures have been investigated by high-energy synchrotron X-ray and neutron diffraction at low temperatures. We are thus able to report the first complete sets of both X-ray and neutron weighted total scattering structure factors over the entire composition range (at 12 different methanol concentrations (xM) from 10 to 100 mol%) and at temperatures from ambient down to the freezing points of the mixtures. The new diffraction data may later be used as reference in future theoretical and simulation studies. The measured data are interpreted by molecular dynamics simulations, in which the all atom OPLS/AA force field model for methanol is combined with both the SPC/E and TIP4P/2005 water potentials. Although the TIP4P/2005 water model was found to be somewhat more successful, both combinations provide at least semi-quantitative agreement with measured diffraction data. From the simulated particle configurations, partial radial distribution functions, as well as various distributions of the number of hydrogen bonds have been determined. As a general trend, the average number of hydrogen bonds increases upon cooling. However, the number of hydrogen bonds between methanol molecules slightly decreases with lowering temperatures in the concentration range between ca. 30 and 60 mol% alcohol content. The same is valid for water-water hydrogen bonds above 70 mol% of methanol content, from room temperature down to 193 K

Adaptive Cation Pillar Effects Achieving High Capacity in Li-Rich Layered Oxide, Li2MnO3-LiMeO2 (Me = Ni, Co, Mn)

Intensive research is underway to further enhance the performance of lithium-ion batteries (LIBs). To increase the capacity of positive electrode materials, Li-rich layered oxides (LLO) are attracting attention but have not yet been put to practical use. The structural mechanisms through which LLO materials exhibit higher capacity than conventional materials remain unclear because their disordered phases make it difficult to obtain structural information by conventional analysis. The X-ray total scattering analysis reveals a disordered structure consisting of metal ions in octahedral and tetrahedral sites of Li layers as a result of cation mixing after the extraction of Li ions. Metal ions in octahedral sites act as rigid pillars. The metal ions move to the tetrahedral site of the Li layer, which functions as a Li-layer pillar during Li extraction, and returns to the metal site during Li insertion, facilitating Li diffusion as an adaptive pillar. Adaptive pillars are the specific structural features that differ from those of the conventional layered materials, and their effects are responsible for the high capacity of LLO materials. An essential understanding of the pillar effects will contribute to design guidelines for intercalation-type positive electrodes for next-generation LIBs

Properties of hydrogen bonded network in ethanol-water liquid mixtures as a function of temperature: diffraction experiments and computer simulations

New X-ray and neutron diffraction experiments have been performed on ethanol-water mixtures as a function of decreasing temperature, so that such diffraction data are now available over the entire composition range. Extensive molecular dynamics simulations show that the all-atom interatomic potentials applied are adequate for gaining insight of the hydrogen bonded network structure, as well as of its changes on cooling. Various tools have been exploited for revealing details concerning hydrogen bonding, like determining H-bond acceptor and donor sites, calculating cluster size distributions and cluster topologies, as well as computing the Laplace spectra and fractal dimensions of the networks. It is found that 5-membered hydrogen bonded cycles are dominant up to an ethanol content of 70% at room temperature, above which concentration ring structures nearly disappear. Percolation has been given special attention, so that it could be shown that at low temperature, close to the freezing point even the mixture with 90% ethanol possesses a 3D percolating network. Moreover, the water sub-network also percolates even at room temperature, with a percolation transition occurring around 50% ethanol

Oligo-recurrence from anaplastic lymphoma kinase-rearranged lung adenocarcinoma

Anaplastic lymphoma kinase rearranged non-small-cell lung cancer is a rare disease. Among them, a subset of patients exist who exhibit relatively slowly progressing symptoms and have oligo-metastases. In this article, we present two cases of ALK rearran-ged lung adenocarcinoma in patients who experienced postoperative oligo-recurrence. Both cases were treated with surgical resection and gamma knife irradiation for oligo-recurrence. After local therapy, the first patient remained disease free for over  23 months; the second for over 18 months. It appears that some patients with ALK rearranged NSCLC experience oligo-recurrence in their clinical course. For such patients, appropriate local therapy may be beneficial in improving both the quality of life and the prognosis