90 research outputs found
YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers
Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome
PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma
The MAXI Mission on the ISS: Science and Instruments for Monitoring All Sky X-Ray Images
The MAXI (Monitor of All-sky X-ray Image) mission is the first astronomical
payload to be installed on the Japanese Experiment Module-Exposed Facility
(JEM-EF) on the ISS. It is scheduled for launch in the middle of 2009 to
monitor all-sky X-ray objects on every ISS orbit. MAXI will be more powerful
than any previous X-ray All Sky Monitor (ASM) payloads, being able to monitor
hundreds of AGN. MAXI will provide all sky images of X-ray sources of about 20
mCrab in the energy band of 2-30 keV from observation on one ISS orbit (90
min), about 4.5 mCrab for one day, and about 1 mCrab for one month. A final
detectability of MAXI could be 0.2 mCrab for 2 year observations.Comment: 12 pages, 11 figures, accepted for publication in Publications of the
Astronomical Society of Japa
MAXI GSC observations of a spectral state transition in the black hole candidate XTE J1752-223
We present the first results on the black hole candidate XTE J1752-223 from
the Gas Slit Camera (GSC) on-board the Monitor of All-sky X-ray Image (MAXI) on
the International Space Station. Including the onset of the outburst reported
by the Proportional Counter Array on-board the Rossi X-ray Timing Explorer on
2009 October 23, the MAXI/GSC has been monitoring this source approximately 10
times per day with a high sensitivity in the 2-20 keV band. XTE J1752-223 was
initially in the low/hard state during the first 3 months. An anti-correlated
behavior between the 2-4 keV and 4-20 keV bands were observed around January
20, 2010, indicating that the source exhibited the spectral transition to the
high/soft state. A transient radio jet may have been ejected when the source
was in the intermediate state where the spectrum was roughly explained by a
power-law with a photon index of 2.5-3.0. The unusually long period in the
initial low/hard state implies a slow variation in the mass accretion rate, and
the dramatic soft X-ray increase may be explained by a sudden appearance of the
accretion disk component with a relatively low innermost temperature (0.4-0.7
keV). Such a low temperature might suggest that the maximum accretion rate was
just above the critical gas evaporation rate required for the state transition.Comment: Publication of Astronomical Society of Japan Vol.62, No.5 (2010) [in
print
Reduced dose of PTCy followed by adjuvant alpha-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by alpha -galactosylceramide (alpha -GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of alpha -GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4(+)Foxp3(+) regulatory T cells. These studies indicate that alpha -GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk
Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast
Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction
A Spectral Study of the Black Hole Candidate XTE J1752-223 in the High/Soft State with MAXI, Suzaku and Swift
We report on the X-ray spectral analysis of the black hole candidate XTE\
J1752--223 in the 2009--2010 outburst, utilizing data obtained with the
MAXI/Gas Slit Camera (GSC), the Swift/XRT, and Suzaku, which work
complementarily. As already reported by Nakahira et al. (2010) MAXI monitored
the source continuously throughout the entire outburst for about eight months.
All the MAXI/GSC energy spectra in the high/soft state lasting for 2 months are
well represented by a multi-color disk plus power-law model. The innermost disk
temperature changed from 0.7 keV to 0.4 keV and the disk flux
decreased by an order of magnitude. Nevertheless, the innermost radius is
constant at 41 km, where is the
source distance in units of 3.5 kpc and the inclination. The multi-color
disk parameters obtained with the MAXI/GSC are consistent with those with the
Swift/XRT and Suzaku. The Suzaku data also suggests a possibility that the disk
emission is slightly Comptonized, which could account for broad iron-K features
reported previously. Assuming that the obtained innermost radius represents the
innermost stable circular orbit for a non-rotating black hole, we estimate the
mass of the black hole to be 5.510.28 , where the correction for the stress-free inner boundary condition
and color hardening factor of 1.7 are taken into account. If the inclination is
less than 49 as suggested from the radio monitoring of transient jets
and the soft-to-hard transition in 2010 April occurred at 1--4% of Eddignton
luminosity, the fitting of the Suzaku spectra with a relativistic
accretion-disk model derives constraints on the mass and the distance to be
3.1--55 and 2.3--22 {\rm kpc}, respectively. This confirms that the
compact object in XTE J1752--223 is a black hole.Comment: 12 pages including 7 figures and 4 tables, accepted for publication
in PAS
One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study
One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer
A Large X-ray Flare from a Single Weak-lined T Tauri Star TWA-7 Detected with MAXI GSC
We present a large X-ray flare from a nearby weak-lined T Tauri star TWA-7
detected with the Gas Slit Camera (GSC) on the Monitor of All-sky X-ray Image
(MAXI). The GSC captured X-ray flaring from TWA-7 with a flux of
ergs cm s in 2--20 keV band during the scan
transit starting at UT 2010-09-07 18:24:30.The estimated X-ray luminosity at
the scan in the energy band is 3 ergs s,indicating that
the event is among the largest X-ray flares fromT Tauri stars.Since MAXI GSC
monitors a target only during a scan transit of about a minute per 92 min
orbital cycle, the luminosity at the flare peak might have been higher than
that detected. At the scan transit, we observed a high X-ray-to-bolometric
luminosity ratio, log = ; i.e., the
X-ray luminosity is comparable to the bolometric luminosity. Since TWA-7 has
neither an accreting disk nor a binary companion, the observed event implies
that none of those are essential to generate such big flares in T Tauri stars.Comment: 4 pages, 2 figures, 1 table accepted for publication in PAS
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