Description: Rationale: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. Objective: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. Methods and Results: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P =0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P =0.049), improved somatic growth ( P =0.0005), reduced heart failure status ( P =0.003), and lower incidence of coil occlusion for collaterals ( P =0.007). Conclusions: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01273857.

Description: The Western Iratsu body of the Sanbagawa belt (SW Japan) is a mafic–ultramafic complex that underwent an initial metamorphism in the amphibolite facies and a subsequent metamorphism in the eclogite facies, and represents a fossil forearc slab–mantle wedge interface in a developing subduction zone. Two generations of orthopyroxene (Opx1 and Opx2) that were formed during the amphibolite-facies (antigorite unstable) and eclogite-facies (antigorite stable) stages can be recognized in the ultramafic domain. Opx1-rich rocks contain Ni-rich relict olivine (up to 0·7 wt % NiO) and grade into dunite, suggesting that they represent metasomatic rocks derived from dunite. Opx1 can be subdivided into two types: one (Opx1L) constitutes replacive harzburgite to orthopyroxenite layers and the other (Opx1V) occurs in metasomatic reaction veins in dunite. Relatively high formation temperatures (≥750°C) of Opx1L imply that the relevant metasomatism in the ultramafic domain took place before the juxtaposition with the mafic domain preserved in the Western Iratsu body. Textural relationships and mineral trace element data suggest that Opx1L-rich rocks were formed by reactive porous infiltration of a slab-derived hydrous melt or solute-rich fluid into dunite. Subsequently, Opx1V-rich veins were formed by a prolonged flux of a Si-rich aqueous fluid (sourced from the mafic domain) through brittle fractures in dunite during the amphibolite-facies metamorphism (~660°C and 1·2 GPa). The initial formation of Opx1V-chlorite-rich selvages along the fluid conduits is likely to have limited the reaction between a Si-rich crustal fluid and host dunite, and this process can be important during the early transportation of slab-derived components into the mantle wedge. Lastly, Opx1L crystals locally show a textural replacement by Opx2 together with antigorite, indicating recrystallization in the eclogite facies (~620°C and 1·6–1·8 GPa). The Opx2-forming reaction is mainly localized in ductile shear zones, which correspond to major fluid pathways in the partially serpentinized forearc mantle.

Description: Dunite bands and dikes in ophiolitic mantle peridotites are interpreted as fossil melt channels within the suboceanic mantle. Concordant dunite bands (i.e. fossil melt channels transposed by outward transportation from the ridge axis via horizontal mantle flow) are particularly important as they possibly represent the melt channels through which the parental melts of mid-ocean ridge basalt (MORB) were transported to shallower depths beneath the paleo-ridge axis. We conducted field observations and sampling of concordant dunite bands (CDB) and their host harzburgite at selected outcrops covering a wide depth range in the mantle section along an inferred paleo-ridge segment in the northern to central part of the Oman ophiolite. The CDB increase in thickness and decrease in frequency upward. They are thicker and more frequent in the centre of the segment than near the segment ends when compared at the same stratigraphic level. The CDB consist mostly of olivine with minor spinel and very rare amounts of pyroxene. Clinopyroxene has a small grain size and an interstitial position relative to olivine. The constituent minerals in the CDB and their host harzburgite were analyzed by electron microprobe for major elements and by laser ablation inductively coupled plasma mass spectrometry for trace elements. Most of the CDB have refractory major element mineral compositions, such as high Fo [100 x Mg/(Mg + Fe)] in olivine (〉90·5), high Cr# [Cr/(Cr + Al)] in chromian spinel (〉0·50), and low Al 2 O 3 (〈3·5 wt %) in clinopyroxene. Chondrite-normalized trace element patterns of clinopyroxene in the host harzburgites consistently show a gentle decrease from heavy REE (HREE) to middle REE (MREE) and a sharp decrease from MREE to light REE (LREE) (= highly depleted), but those in the CDB show weaker LREE depletion, which is more variable depending on the stratigraphic level and position along the paleo-ridge segment. In contrast, the HREE concentrations in clinopyroxene in the CDB are higher than or similar to those of the host harzburgites. Trace element compositions of clinopyroxene in the CDB and their host harzburgites are evaluated with a one-dimensional, steady-state, open-system decompressional melting–reaction model. The modeling results suggest that an LREE-enriched melt generated at high pressure was transported upwards through melt channels to the shallow mantle (up to the Moho transition zone), where it mingled with highly depleted melts accumulated from fractionally melted peridotites to generate normal (N)-MORB-like melts. The mantle started upwelling (= melting) in the garnet stability field in the segment centre, but either in the garnet or in the spinel stability field near the segment ends. This suggests a variation of geothermal gradient along the paleo-ridge segment: higher in the segment centre and lower near the segment ends. This inference is supported by the presence of thicker (up to 250 cm) CDB as well as more frequent occurrence of CDB in the segment centre than near the segment end and by the geochemical evidence for chromatographic N-MORB-like melt percolation into the host peridotite only in the uppermost horizons near the segment ends.

Description: The catalytic behavior of various noble metal nanoparticles (NPs) supported directly on multiwalled carbon nanotubes (MWCNTs) was observed using environmental transmission electron microscopy (E-TEM). Gasification of the MWCNTs via catalytic hydrogenation or oxidation progressed at ~450°C in conjunction with certain noble metal NP catalysts at the interface between MWCNTs and the NPs. During such catalytic reactions, the NPs were observed to move rapidly over the MWCNT surfaces. The mobility and wettability of the NPs varied depending on the particular metal NPs employed and the ambient atmosphere. While rhodium NPs exhibited high wettability under both hydrogen and oxygen atmospheres, the wettability of platinum, palladium and iridium NPs on MWCNTs varied with the atmosphere. The metal NPs seemed to have high degrees of crystallinity while their morphologies fluctuated throughout the catalytic reactions.

Description: Structome analysis is a useful tool for identification of unknown microorganisms that cannot be cultured. In 2012, we discovered a unique deep-sea microorganism with a cell structure intermediate between those of prokaryotes and eukaryotes and described its features using freeze-substitution electron microscopy and structome analysis (quantitative and three-dimensional structural analysis of a whole cell at the electron microscopic level). We named it Myojin parakaryote . Here we describe, using serial ultrathin sectioning and high-voltage electron microscopy tomography of freeze-substituted specimens, the structome analysis and 3D reconstruction of another unique spiral bacteria, found in the deep sea off the coast of Japan. The bacteria, which is named as ‘Myojin spiral bacteria’ after the discovery location and their morphology, had a total length of 1.768 ± 0.478 µm and a total diameter of 0.445 ± 0.050 µm, and showed either clockwise or counter-clockwise spiral. The cells had a cell surface membrane, thick fibrous layer, ribosomes and inner fibrous structures (most likely DNA). They had no flagella. The bacteria had 322 ± 119 ribosomes per cell. This ribosome number is only 1.2% of that of Escherichia coli and 19.3% of Mycobacterium tuberculosis and may reflect a very slow growth rate of this organism in the deep sea.

Description: Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring 〉100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.

Description: No gold standard has been established as a primary endpoint in trials of initial treatment of chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease, and progressive disease were defined according to the 2014 National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in fewer than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier, and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689.

Description: Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.

Description: Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 ( NTRK1 ) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics. Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis–mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro , had acquired the G667C mutation in NTRK1 . The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1 -G667C mutation in vitro . Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER–derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1 -G667C mutation in NTRK1 fusion–positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1 -G667C mutation, including patients with brain metastases. Clin Cancer Res; 24(10); 2357–69. ©2018 AACR .

Description: Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .