Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer

Sundar, R,Huang, K K,Qamra, A,Kim, K -M,Kim, S T,Kang, W K,Tan, A L K,Lee, J,Tan, P Oxford University Press 2019 Annals of oncology Vol.30 No.3

<P><B>Abstract</B></P><P><B>Background</B></P><P>Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer.</P><P><B>Patients and methods</B></P><P>Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (<I>N </I>=<I> </I>24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString<SUP>®</SUP> (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (<I>N </I>=<I> </I>37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival.</P><P><B>Results</B></P><P>In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (AP<SUB>high</SUB>), and this was used to define the AP<SUB>high</SUB> tertile of the second cohort (13 AP<SUB>high</SUB> of 37). AP<SUB>high</SUB> tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, <I>P </I>=<I> </I>0.03). Median progression-free survival was lower in the AP<SUB>high</SUB> group (55 versus 180 days, <I>P </I>=<I> </I>0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099–0.85, <I>P </I>=<I> </I>0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response.</P><P><B>Conclusion</B></P><P>A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy.</P><P><B>Trial Registration</B></P><P>ClinicalTrials.gov Identifier: NCT#02589496</P>

세파클러 서방정의 제조

손영택,박미영,김상린,단현광 德成女子大學校 藥學硏究所 2003 藥學論文誌 Vol.14 No.1

Cefaclor is a semisynthetic cephalosporin for oral administration. It is absorbed 50∼75% after oral administration and having a biological half life of 0.6∼0.9hours. To maintain therapeutic range, the drug should be administrated 3∼4 times a day, which leads to the saw both kinetic of the absorption and resulting in ineffective therapy. Hence many authors attempted to develop sustained/extended release dosage forms for cefaclor in order to achieve effective administrated regimens. In this study we attempted to formulate cefaclor sustained release tablet by using HPMC(hydroxypropyl methylcellulose) and vinyl pyrrolidone vinyl acetate complex, which can provide convenient administration and are economic and the drug release from HPMC matrix is uniform irrespective of the pH. The cefaclor sustained release tablets were prepared by wet granulation techinique. The wet granules were dried at 50℃ for 5 hours in a tray drier. The dried granules were passed through sieve #20, lubricated with magnesium stearate by mixing in rapid mixer granulator and compressed using 7kgf/cm² punch to get tablets. In vitro release of cefaclor form formulated tablets was carried out in 0.1N HCl for 30 minute at 37±0.5℃ and 100rpm. The formulated cefaclor tablets were kept for a short term accelerated stability study in high temperature at 20℃, 50℃ for 4 weeks. And the formulation 16 18 carried out long term stability study for 24 months.

Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection

Jin, H.-T.,Anderson, A.C.,Tan, W.G.,West, E.E.,Ha, S.-J.,Araki, K.,Freeman, G.J.,Kuchroo, V.K.,Ahmed, R. National Academy of Sciences 2010 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.107 No.33

Gradient nonlinearity calibration and correction for a compact, asymmetric magnetic resonance imaging gradient system

Tao, S,Trzasko, J D,Gunter, J L,Weavers, P T,Shu, Y,Huston III, J,Lee, S K,Tan, E T,Bernstein, M A Institute of Physics in association with the Ameri 2017 Physics in medicine & biology Vol.62 No.2

<P>Due to engineering limitations, the spatial encoding gradient fields in conventional magnetic resonance imaging cannot be perfectly linear and always contain higher-order, nonlinear components. If ignored during image reconstruction, gradient nonlinearity (GNL) manifests as image geometric distortion. Given an estimate of the GNL field, this distortion can be corrected to a degree proportional to the accuracy of the field estimate. The GNL of a gradient system is typically characterized using a spherical harmonic polynomial model with model coefficients obtained from electromagnetic simulation. Conventional whole-body gradient systems are symmetric in design; typically, only odd-order terms up to the 5th-order are required for GNL modeling. Recently, a high-performance, asymmetric gradient system was developed, which exhibits more complex GNL that requires higher-order terms including both odd- and even-orders for accurate modeling. This work characterizes the GNL of this system using an iterative calibration method and a fiducial phantom used in ADNI (Alzheimer’s Disease Neuroimaging Initiative). The phantom was scanned at different locations inside the 26 cm diameter-spherical-volume of this gradient, and the positions of fiducials in the phantom were estimated. An iterative calibration procedure was utilized to identify the model coefficients that minimize the mean-squared-error between the true fiducial positions and the positions estimated from images corrected using these coefficients. To examine the effect of higher-order and even-order terms, this calibration was performed using spherical harmonic polynomial of different orders up to the 10th-order including even- and odd-order terms, or odd-order only. The results showed that the model coefficients of this gradient can be successfully estimated. The residual root-mean-squared-error after correction using up to the 10th-order coefficients was reduced to 0.36 mm, yielding spatial accuracy comparable to conventional whole-body gradients. The even-order terms were necessary for accurate GNL modeling. In addition, the calibrated coefficients improved image geometric accuracy compared with the simulation-based coefficients.</P>

Final design of the generic upper port plug structure for ITER diagnostic systems

Pak, S.,Feder, R.,Giacomin, T.,Guirao, J.,Iglesias, S.,Josseaume, F.,Kalish, M.,Loesser, D.,Maquet, P.,Ordieres, J.,Panizo, M.,Pitcher, S.,Portales, M.,Proust, M.,Ronden, D.,Serikov, A.,Suarez, A.,Tan North-Holland ; Elsevier Science Ltd 2016 Fusion engineering and design Vol.102 No.-

The generic upper port plug (GUPP) structure in ITER is a 6m long metal box which deploys diagnostic components into the vacuum vessel. This structure is commonly used for all the diagnostic upper ports. The final design of the GUPP structure, which has successfully passed the final design review in 2013, is described here. The diagnostic port plug is cantilevered to the vacuum vessel with a heavy payload at the front, so called the diagnostic first wall (DFW) and the diagnostic shield module (DSM). Most of electromagnetic (EM) load (~80%) occurs in DFW/DSM. Therefore, the mounting design to transfer the EM load from DFW/DSM to the GUPP structure is challenging, which should also comply with thermal expansion and tolerance for assembly and manufacturing. Another key design parameter to be considered is the gap between the port plug and the vacuum vessel port. The gap should be large enough to accommodate the remote handling of the heavy port plug (max. 25t), the structural deflection due to external loads and machine assembly tolerance. At the same time, the gap should be minimized to stop the neutron streaming according to the ALARA (as low as reasonably achievable) principle. With these design constraints, the GUPP structure should also provide space for diagnostic integration as much as possible. This requirement has led to the single wall structure having the gun-drilled water channels inside the structure. Furthermore, intensive efforts have been made on the manufacturing study including material selection, manufacturing codes and French regulation related to nuclear equipment and safety. All these main design and manufacturing aspects are discussed in this paper, including requirements, interfaces, loads and structural assessment and maintenance.

Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: Analysis from the Asia Lymphoma Study Group

Kim, S.J.,Hsu, C.,Song, Y.Q.,Tay, K.,Hong, X.N.,Cao, J.,Kim, J.S.,Eom, H.S.,Lee, J.H.,Zhu, J.,Chang, K.M.,Reksodiputro, A.H.,Tan, D.,Goh, Y.T.,Lee, J.,Intragumtornchai, T.,Chng, W.J.,Cheng, A.L.,Lim, Pergamon Press 2013 European journal of cancer Vol.49 No.16

Background: Hepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas. Methods: Hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n=340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n=127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis. Results: HBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p<0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p<0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases. Conclusions: This is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.

Recent developments and challenges in welding of magnesium to titanium alloys

Auwal, S.T.,Ramesh, S.,Tan, Caiwang,Zhang, Zequn,Zhao, Xiaoye,Manladan, S.M. Techno-Press 2019 Advances in materials research Vol.8 No.1

Joining of Mg/Ti hybrid structures by welding for automotive and aerospace applications has attracted great attention in recent years due mainly to its potential benefit of energy saving and emission reduction. However, joining them has been hampered with many difficulties due to their physical and metallurgical incompatibilities. Different joining processes have been employed to join Mg/Ti, and in most cases in order to get a metallurgical bonding between them was the use of an intermediate element at the interface or mutual diffusion of alloying elements from the base materials. The formation of a reaction product (in the form of solid solution or intermetallic compound) along the interface between the Mg and Ti is responsible for formation of a metallurgical bond. However, the interfacial bonding achieved and the joints performance depend significantly on the newly formed reaction product(s). Thus, a thorough understanding of the interaction between the selected intermediate elements with the base metals along with the influence of the associated welding parameters are essential. This review is timely as it presents on the current paradigm and progress in welding and joining of Mg/Ti alloys. The factors governing the welding of several important techniques are deliberated along with their joining mechanisms. Some opportunities to improve the welding of Mg/Ti for different welding techniques are also identified.

Report on APMP key comparison: calibration of angle standards

Kang, C -S,Kruger, O A,Cox, P,Xue, Z,Liou, P,Wong, S Y,Chaudhary, K P,Alfiyati, N,Watanabe, T,Eom, T,Halim, R M,Tan, S L,Tonmueanwai, A,Dibo, M IOP Publishing 2016 METROLOGIA -BERLIN- Vol.53 No.1

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC

Ko, J J,Choueiri, T K,Rini, B I,Lee, J-L,Kroeger, N,Srinivas, S,Harshman, L C,Knox, J J,Bjarnason, G A,MacKenzie, M J,Wood, L,Vaishampayan, U N,Agarwal, N,Pal, S K,Tan, M-H,Rha, S Y,Yuasa, T,Donskov, Nature Publishing Group 2014 The British journal of cancer Vol.110 No.8

<P><B>Background:</B></P><P>Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.</P><P><B>Methods:</B></P><P>Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.</P><P><B>Results:</B></P><P>In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (<I>P</I><0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, <I>P</I><0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.</P><P><B>Conclusions:</B></P><P>Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.</P>

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials

Heng, D. Y. C.,Choueiri, T. K.,Rini, B. I.,Lee, J.,Yuasa, T.,Pal, S. K.,Srinivas, S.,Bjarnason, G. A.,Knox, J. J.,MacKenzie, M.,Vaishampayan, U. N.,Tan, M. H.,Rha, S. Y.,Donskov, F.,Agarwal, N.,Kollma Oxford University Press 2014 ANNALS OF ONCOLOGY Vol.25 No.1

<P>This study focuses on the outcomes of a large international cohort of patients with metastatic RCC who would not have met the eligibility criteria for clinical trials and compares these to those that would have eligible. The proportion of patients who would have been ineligible and the reason for ineligibility are also discussed.</P>