Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Beyond Progressive Disease: A Retrospective Analysis for Japanese Patients with Activating EGFR Mutations

IntroductionIt is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug.MethodsWe retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non–small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0–1/ 2–4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second).ResultsA total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42–86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21–0.83, p = 0.013) was associated with improved survival.ConclusionContinuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results

Distance to Orion KL Measured with VERA

We present the initial results of multi-epoch VLBI observations of the 22 GHz H2O masers in the Orion KL region with VERA (VLBI Exploration of Radio Astrometry). With the VERA dual-beam receiving system, we have carried out phase-referencing VLBI astrometry and successfully detected an annual parallax of Orion KL to be 2.29+/-0.10 mas, corresponding to the distance of 437+/-19 pc from the Sun. The distance to Orion KL is determined for the first time with the annual parallax method in these observations. Although this value is consistent with that of the previously reported, 480+/-80 pc, which is estimated from the statistical parallax method using proper motions and radial velocities of the H2O maser features, our new results provide the much more accurate value with an uncertainty of only 4%. In addition to the annual parallax, we have detected an absolute proper motion of the maser feature, suggesting an outflow motion powered by the radio source I along with the systematic motion of source I itself.Comment: 7 pages, 3 figures. PASJ, in press (Vol. 59, No. 5, October 25, 2007 issue

Absolute Proper Motions of H2O Masers Away from the Galactic Plane Measured with VERA in the "Superbubble" Region NGC 281

We report on absolute proper-motion measurements of an H2O maser source in the NGC 281 West molecular cloud, which is located ~320 pc above the Galactic plane and is associated with an HI loop extending from the Galactic plane. We have conducted multi-epoch phase-referencing observations of the maser source with VERA (VLBI Exploration of Radio Astrometry) over a monitoring period of 6 months since May 2006. We find that the H2O maser features in NGC 281 West are systematically moving toward the southwest and further away from the Galactic plane with a vertical velocity of ~20-30 km/s at its estimated distance of 2.2-3.5 kpc. Our new results provide the most direct evidence that the gas in the NGC 281 region on the HI loop was blown out from the Galactic plane, most likely in a superbubble driven by multiple or sequential supernova explosions in the Galactic plane.Comment: 10 pages, 5 figures, PASJ in press (Vol. 59, No. 4; August 25, 2007 issue

VLBI Astrometry of AGB Variables with VERA -- A Semiregular Variable S Crateris --

We present a distance measurement for the semiregular variable S Crateris (S Crt) based on its annual parallax. With the unique dual beam system of the VLBI Exploration for Radio Astrometry (VERA) telescopes, we measured the absolute proper motion of a water maser spot associated with S Crt, referred to the quasar J1147-0724 located at an angular separation of 1.23$^{\circ}$. In observations spanning nearly two years, we have detected the maser spot at the LSR velocity of 34.7 km s$^{-1}$, for which we measured the annual parallax of 2.33$\pm$0.13 mas corresponding to a distance of 430$^{+25}_{-23}$ pc. This measurement has an accuracy one order of magnitude better than the parallax measurements of HIPPARCOS. The angular distribution and three-dimensional velocity field of maser spots indicate a bipolar outflow with the flow axis along northeast-southwest direction. Using the distance and photospheric temperature, we estimate the stellar radius of S Crt and compare it with those of Mira variables.Comment: 9 pages, 4 figures, accepted for publication in PASJ (Vol.60, No.5, October 25, VERA special issue

Distance to VY Canis Majoris with VERA

We report astrometric observations of H2O masers around the red supergiant VY Canis Majoris (VY CMa) carried out with VLBI Exploration of Radio Astrometry (VERA). Based on astrometric monitoring for 13 months, we successfully measured a trigonometric parallax of 0.88 +/- 0.08 mas, corresponding to a distance of 1.14 +0.11/-0.09 kpc. This is the most accurate distance to VY CMa and the first one based on an annual parallax measurement. The luminosity of VY CMa has been overestimated due to a previously accepted distance. With our result, we re-estimate the luminosity of VY CMa to be (3 +/- 0.5) x 10^5 L_sun using the bolometric flux integrated over optical and IR wavelengths. This improved luminosity value makes location of VY CMa on the Hertzsprung-Russel (HR) diagram much closer to the theoretically allowable zone (i.e. the left side of the Hayashi track) than previous ones, though uncertainty in the effective temperature of the stellar surface still does not permit us to make a final conclusion.Comment: 7 pages, 4 figures, accepted for publication in PASJ, VERA special issu

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Temporally controlled multistep division of DNA droplets for dynamic artificial cells

Bio-soft matter droplets formed via liquid-liquid phase separation (LLPS) of biopolymers have been found in living cells. Synthetic LLPS droplets have recently been employed in nanobiotechnology for artificial cell construction, molecular robotics, molecular computing, diagnosis, and therapeutics. Controlling the dynamics of bio-soft matter droplets is essential for developing such bio-inspired functional systems because living systems maintain their functions based on the temporally controlled dynamics of biomolecular reactions and assemblies. Recently, the dynamics of bio-soft matter droplets have been revealed; however, their temporal control has not yet been achieved. This paper reports the temporal control of DNA-based LLPS droplets (DNA droplets). We demonstrate the timing-controlled division of DNA droplet-based artificial cells via time-delayed division triggers regulated by non-equilibrium chemical reactions. We also investigated it using a reaction-diffusion model. We regulated the release order of multiple division triggers, resulting in order control of the multistep droplet division, that is, pathway control of the droplet division in a reaction landscape. Finally, we demonstrate an application of the timing-controlled division of DNA droplet-based artificial cells: a molecular computing element to compare the concentrations of microRNA sequences (called molecular comparators). We believe that temporal control of DNA droplets will promote the design of more dynamic artificial cells/molecular robots and more sophisticated biomedical applications