Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

Cristescu, Razvan,Lee, Jeeyun,Nebozhyn, Michael,Kim, Kyoung-Mee,Ting, Jason C,Wong, Swee Seong,Liu, Jiangang,Yue, Yong Gang,Wang, Jian,Yu, Kun,Ye, Xiang S,Do, In-Gu,Liu, Shawn,Gong, Lara,Fu, Jake,Jin, Nature Publishing Group 2015 Nature medicine Vol. No.

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

Fuzzy Adaptive Sliding Mode Control for the Precision Position of Piezo-Actuated Nano Positioning Stage

Jiwen Fang,Lufan Zhang,Zhili Long,Michael Yu Wang 한국정밀공학회 2018 International Journal of Precision Engineering and Vol.19 No.10

This paper concerns hysteresis and creep of a piezo-actuated nano positioning stage. The hysteresis and creep, considered as bounded disturbance or uncertainty, are suppressed without a nonlinear model. An improved Fuzzy Adaptive Sliding Mode Control (FASMC) with a Proportional-Integral-Derivative sliding surface is designed to cancel both hysteresis and creep. However, the constant slopes of the sliding function may increase oscillations. Some variable gains with adaptive rules are introduced to overcome this drawback by changing the sliding function values online. Fuzzy control is applied to tune the switching control part to improve performance. Furthermore, an adaptation law is used to approximate the optimal value of the switching control. The stability of the sliding mode control law is proved in the sense of Lyapunov stability theorem. To eliminate chattering and obtain a smooth signal, the switching control is modified and a smooth function is introduced to substitute the signum function. An anti-saturation control is introduced to keep the input voltage within safety scope. Experimental results show that FASMC can achieve faster response for step input and sinusoid signal. Both hysteresis and creep of the piezoelectric actuator are suppressed by the proposed FASMC. Therefore, the FASMC can reduce the tracking errors of the piezo-actuated stage.

A passive vibration isolator with bio-inspired structure and inerter nonlinear effects

Jing Bian,Xu-hong Zhou,Ke Ke,Michael CH Yam,Yu-hang Wang,Yue Qiu 국제구조공학회 2023 Structural Engineering and Mechanics, An Int'l Jou Vol.88 No.3

This paper developed and examined a novel passive vibration isolator (i.e., “X-inerter”) motivated by combining a bio-inspired structure and a rack-pinion inerter. The bio-inspired structure provided nonlinear stiffness and damping owing to its geometric nonlinearity. In addition, the behavior was further enhanced by a gear inerter that produced a special nonlinear inertia effect; thus, an X-inerter was developed. As a result, the X-inerter can achieve both high-static-low-dynamic stiffness (HSLDS) and quasi-zero stiffness (QZS), obtaining ultra-low frequency isolation. Furthermore, the installed inerter can produce a coupled nonlinear inertia and damping effect, leading to an anti-resonance frequency near the resonance, wide isolation region, and low resonance peak. Both static and dynamic analyses of the proposed isolator were conducted and the structural parameters' influence was comprehensively investigated. The X-inerter was proven to be comparatively more stable in the ultra-low frequency than the benchmarking QZS isolator due to the nonlinear damping and inertia properties. Moreover, the inertia effect could suppress the bio-inspired structure's super- and sub-harmonic resonance. Therefore, the X-inerter isolator generally possesses desirable nonlinear stiffness, nonlinear damping, and unique nonlinear inertia, designed to achieve the ultra-low natural frequency, the anti-resonance property, and a wide isolation region with a low resonance peak.

A novel prismatic-shaped isolation platform with tunable negative stiffness and enhanced quasi-zero stiffness effect

Ke Ke,Jing Bian,Xu-Hong Zhou,Michael C.H. Yam,Yu-Hang Wang,Zi Gu,Miaojun Sun 국제구조공학회 2023 Smart Structures and Systems, An International Jou Vol.31 No.3

A passive prismatic-shaped isolation platform (PIP) is proposed to realize enhanced quasi-zero stiffness (QZS) effect. The design concept uses a horizontal spring to produce a tunable negative stiffness and installs oblique springs inside the cells of the prismatic structure to provide a tunable positive stiffness. Therefore, the QZS effect can be achieved by combining the negative stiffness and the positive stiffness. To this aim, firstly, the mathematical modeling and the static analysis are conducted to demonstrate this idea and provide the design basis. Further, with the parametric study and the optimal design of the PIP, the enhanced QZS effect is achieved with widened QZS range and stable property. Moreover, the dynamic analysis is conducted to investigate the vibration isolation performance of the proposed PIP. The analysis results show that the widened QZS property can be achieved with the optimal designed structural parameters, and the proposed PIP has an excellent vibration isolation performance in the ultra-low frequency due to the enlarged QZS range. Compared with the traditional QZS isolator, the PIP shows better performance with a broader isolation frequency range and stable property under the large excitation amplitude.

Research on the Rotational Accuracy Measurement of an Aerostatic Spindle in a Rolling Bearing Performance Analysis Instrument

Zhaohui Yang,Jun Hong,JinHua Zhang,Michael Yu Wang 한국정밀공학회 2014 International Journal of Precision Engineering and Vol. No.

An ultra-precision instrument is developed to measure the rotational accuracy of a rolling bearing under working conditions. Thisinstrument uses a high-precision aerostatic spindle, which has high-stiffness to support a test bearing under large axial loading. Thiswork demonstrates the capabilities of the double-probe error separation method for the measurement of aerostatic spindle errormotion at various axial forces and rotational speeds. The rotational performance of an aerostatic spindle is discussed. The resultsindicate that the error motion and the form of the error of the measurement surface are reliably separated at various axial forces androtational speeds. In addition, the error motion of the aerostatic spindle is very stable, increasing slightly and smoothly as therotational speed increases. The error motion is less than 0.18 um when the speed reaches 1920 rpm. In the future, it will be possibleto separate the error motion of an aerostatic spindle from the measurement results of a test bearing.

Effect of Isomerism on Molecular Packing and Gas Transport Properties of Poly(benzoxazole-<i>co</i>-imide)s

Zhuang, Yongbing,Seong, Jong Geun,Do, Yu Seong,Jo, Hye Jin,Lee, Moon Joo,Wang, Gang,Guiver, Michael D.,Lee, Young Moo American Chemical Society 2014 Macromolecules Vol.47 No.22

<P>A facile approach to synthesize poly(benzoxazole-<I>co</I>-imide)s without thermal rearrangement at high temperature is proposed. Poly(benzoxazole-<I>co</I>-imide)s with improved mechanical and solution-processable properties were prepared through polycondensation of 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) with three synthesized novel benzoxazole-containing diamines and a commercial diamine. These poly(benzoxazole-<I>co</I>-imide)s had high tensile strengths of 110.3–122.0 MPa and good elongation at break of 11.9–26.3%, good thermal stability and high glass transition temperatures (<I>T</I><SUB>g</SUB>s) of up 306 °C. The effect of chain isomerism on molecular packing and physical and gas transport properties of the poly(benzoxazole-<I>co</I>-imide)s was investigated. The <I>para</I>-connecting isomers exhibited higher molecular weights (<I>M</I><SUB>w</SUB>s), better mechanical properties, higher <I>T</I><SUB>g</SUB>s, higher chain packing order and better overall performance for CO<SUB>2</SUB>/CH<SUB>4</SUB> and CO<SUB>2</SUB>/N<SUB>2</SUB> separations as compared to the corresponding <I>meta</I>-connecting ones. This study guides molecular architecture to improve particular membrane separation performance by introducing either <I>para</I>- or <I>meta</I>-connections into polymeric main chains.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/mamobx/2014/mamobx.2014.47.issue-22/ma501891m/production/images/medium/ma-2014-01891m_0012.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ma501891m'>ACS Electronic Supporting Info</A></P>

Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia

Kim, Dong‐,Wook,Tan, Eugene Y.,Jin, Yu,Park, Sahee,Hayes, Michael,Demirhan, Eren,Schran, Horst,Wang, Yanfeng Blackwell Publishing Ltd 2011 British journal of clinical pharmacology Vol.71 No.2

<P> <B>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</B> </P><P>• Imatinib mesylate, a tyrosine kinase inhibitor, exhibits a weak competitive inhibition on paracetamol (acetaminophen) <I>O</I>‐glucuronidation with an inhibition constant (<I>K</I><SUB>i</SUB>) value of 59 µ<SMALL>m</SMALL>. However, the clinical significance of the inhibition has not been evaluated. The pharmacokinetics of imatinib have been studied in white patients with chronic myelogenous leukaemia (CML), but not in Korean patients with CML.</P><P> <B>WHAT THIS STUDY ADDS</B> </P><P>• Imatinib (400 mg once daily) had no clinically relevant effect on the plasma exposure and the pharmacokinetics of paracetamol (1000 mg once daily) in patients with CML.</P><P>• The pharmacokinetic profile of imatinib in Korean patients with CML was similar to that in whites.</P><P><B>AIMS</B> The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML).</P><P><B>METHODS</B> Patients (<I>n</I>= 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2–8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses.</P><P><B>RESULTS</B> The area under the plasma concentration–time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co‐administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone.</P><P><B>CONCLUSIONS</B> The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug.</P>

ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death

Han, Jaeseok,Back, Sung Hoon,Hur, Junguk,Lin, Yu-Hsuan,Gildersleeve, Robert,Shan, Jixiu,Yuan, Celvie L.,Krokowski, Dawid,Wang, Shiyu,Hatzoglou, Maria,Kilberg, Michael S.,Sartor, Maureen A.,Kaufman, Ra Nature Publishing Group, a division of Macmillan P 2013 Nature cell biology Vol.15 No.5

Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.

Boosting Responsivity of Organic–Metal Oxynitride Hybrid Heterointerface Phototransistor

Rim, You Seung,Ok, Kyung-Chul,Yang, Yang Michael,Chen, Huajun,Bae, Sang-Hoon,Wang, Chen,Huang, Yu,Park, Jin-Seong,Yang, Yang American Chemical Society 2016 ACS APPLIED MATERIALS & INTERFACES Vol.8 No.23

<P>Amorphous metal oxides are attractive materials for various sensor applications, because of high electrical performance and easy processing. However, low absorption coefficient, slow photoresponse, and persistent photoconductivity of amorphous metal oxide films from the origin of deep-level defects are obstacles to their use as photonic applications. Here, we demonstrate ultrahigh photoresponsivity of organic-inorganic hybrid phototransistors featuring bulk heterojunction polymers and low bandgap zinc oxynitride. Spontaneous formation of ultrathin zinc oxide on the surface of zinc oxynitride films could make an effective band-alignment for electron transfer from the dissociation of excitons in the bulk heterojunction, while holes were blocked by the deep highest occupied molecular orbital level of zinc oxide. These hybrid structure-based phototransistors are ultrasensitive to broad-bandwidth photons in ultraviolet to near infrared regions. The detectivity and a linear dynamic range exceeded 10(12) Jones and 122.3 dB, respectively.</P>

A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm

Dong Athena,Pan Xiaoqing,Lin Chien-Wei,Huang Yi-Wen,Krause Hayden,Pan Pan,Baim Arielle,Thomas Michael J,Chen Xiao,Yu Jianhua,Michaelis Laura,Liu Pengyuan,Wang Li-Shu,Atallah Ehab 대한암예방학회 2022 Journal of cancer prevention Vol.27 No.2

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients’ survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45+ cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/ MPN patients is warranted.