Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance

Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner

Dietary Supplementation with Monosodium Glutamate Suppresses Chemotherapy-Induced Downregulation of the T1R3 Taste Receptor Subunit in Head and Neck Cancer Patients

(Background) We investigated the effect of dietary supplementation with monosodium glutamate (MSG) on chemotherapy-induced downregulation of the T1R3 taste receptor subunit expression in the tongue of patients with advanced head and neck cancer. (Methods) Patients undergoing two rounds of chemoradiotherapy were randomly allocated to a control or intervention group (dietary supplementation with MSG at 2.7 g/day during the second round of chemotherapy). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative polymerase chain reaction analysis. Dysgeusia was assessed with a visual analog scale and daily energy intake was evaluated. (Results) T1R3 expression levels in the tongue, taste sensitivity, and daily energy intake were significantly reduced after the first round of chemotherapy compared with before treatment. Furthermore, these parameters significantly decreased after the second round of chemotherapy, but the extent of decrease was significantly attenuated in the MSG group compared with the control group. (Conclusions) MSG supplementation suppresses chemotherapy-induced dysgeusia, possibly due to the inhibition of the T1R3-containing taste receptor downregulation in the tongue, thereby increasing energy intake in patients with advanced head and neck cancer

monosodium glutamate increases T1R3 expression

We previously showed that chemotherapy-induced dysgeusia was associated with lingual taste receptor gene expression, and monosodium glutamate (MSG) improved dysgeusia by upregulating taste 1 receptor 3 (T1R3) gene expression. In recent years, decreased taste sensitivity has also been reported in some young people, and these are partly due to their disordered eating habits. From these background, we investigated the effects of MSG supplementation on taste receptor expression and dietary intake in healthy females. Fifteen young healthy volunteers were enrolled for the present crossover study and divided in two groups (dietary supplementation with MSG at 2.7 g / day or 0.27 g / day). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative PCR analysis. Food intake was assessed by food frequency questionnaire (FFQg), and body composition was measured using Omron HBF-701. T1R3 expression levels in the tongue and taste sensitivity increased significantly in participants who consumed 10 g of MSG daily. Furthermore, protein, fat, and carbohydrate (PFC) balance and salt and sugar intake improved by MSG supplementation. In conclusion, MSG supplementation increased T1R3 expression in the tongue and improved dietary balance

VERTECS: 6U CubeSat Mission to Study Star-Formation History by Observation of Visible Extragalactic Background Light

We describe an astronomical 6U CubeSat mission VERTECS (Visible Extragalactic background RadiaTion Exploration by CubeSat). The scientific purpose of VERTECS is to reveal star-formation history of the universe by observation of the extragalactic background light (EBL) in visible wavelengths. Earlier observations by sounding rockets and infrared astronomical satellites have shown that the near-infrared EBL is several times brighter than the integrated light of known galaxies. As candidates for the excess light, first-generation stars in the early universe or low-redshift intra-halo light have been proposed, but it has not been concluded. Since these objects are expected to show different emission spectra in visible wavelengths, precise visible observation is important to reveal the origin of excess light. Since detection sensitivity of the EBL is determined by the product of telescope aperture and field of view, a small wide-field telescope system enables the EBL observation with high sensitivity. In VERTECS mission, we develop a 6U CubeSat equipped with a 3U size telescope optimized for observation of visible EBL. The telescope is composed of lens optics and a CMOS sensor of 3k times 3k array format, which is designed to observe the sky in four photometric bands in 400-800nm. The satellite bus is composed of on-board computer (OBC), electric power system (EPS), communication (COM), attitude determination and control system (ACDS), and thermal structure. Design of OBC and EPS is based on heritage of CubeSats developed at Kyushu Institute of Technology, but deployable solar array wings is added to EPS to supply sufficient power to the VERTECS subsystems. In COM system, S-band is used for command uplink and X-band is used for high-speed downlink of large-size images captured by the telescope. Since the EBL measurement need discrimination of the background light from discrete foreground stars, VERTECS requires 10 arcseconds pointing stability (1 sigma) over 1 minute exposure. In 2022, VERTECS was selected for JAXA-Small Satellite Rush Program (JAXA-SMASH Program), a new program that encourages universities, private companies and JAXA to collaborate to realize small satellite missions utilizing commercial small launch opportunities, and to diversify transportation services in Japan. We have been working on functionality and interface teast using Bread Board Model (BBM), and enviroonmental tests by using the satellite structure thermal model. Launch of the satellite is planned in FY2025. We aim at developing the satellite and obtaining scientific results much more quickly than recent large astronomical-satellite missions

A new synaptic player leading to autism risk: Met receptor tyrosine kinase

The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD

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

Biopsychosocial approaches to a patient with vomiting of 10 years' duration – a case of temporal lobe epilepsy

Abstract Background Vomiting is commonly encountered in clinical medicine. When organic gastrointestinal, metabolic, and brain diseases are ruled out, many cases are considered to be functional. We experienced an adult patient with epilepsy whose main symptom was vomiting. Biopsychosocial approaches were needed to control the symptoms. Case presentation A 26-year-old female with a 10-year history of persistent vomiting was found to have temporal lobe epilepsy (TLE). Throughout this time, during which the vomiting had become part of a vicious cycle, her epilepsy was poorly controlled by medication. Biopsychosocial approaches were employed successfully and the patient subsequently undertook training to become a home-helper, started a job, and was able to leave her parents' house and live independently. All of her symptoms resolved after she became self-sufficient. Discussion Vomiting without impaired consciousness is seldom considered to be a manifestation of epilepsy. Difficulty in recording an electroencephalogram (EEG) because of the presence of persistent vomiting delayed the diagnosis. The improvement of symptoms was thought to have been due to the patient's emotional stabilization and physical improvement, which may have stabilized the limbic system. Conclusion When an illness persists for many years and conditioning and a vicious cycle occur secondarily, systematic biopsychosocial approaches are needed in addition to general treatment. Also, secondary symptoms make the diagnosis more difficult when efforts at treatment are ineffective.</p

Robo4 plays a role in bone marrow homing and mobilization, but is not essential in the long-term repopulating capacity of hematopoietic stem cells.

Roundabout (Robo) family proteins are immunoglobulin-type surface receptors critical for cellular migration and pathway finding of neuronal axons. We have previously shown that Robo4 was specifically expressed in hematopoietic stem and progenitor cells and its high expression correlated with long-term repopulating (LTR) capacity. To reveal the physiological role of Robo4 in hematopoiesis, we examined the effects of Robo4 disruption on the function of hematopoietic stem cells (HSCs) and progenitors. In Robo4-deficient mice, basic hematological parameters including complete blood cell count and differentiation profile were not affected. In contrast to the previous report, HSC/hematopoietic progenitor (HPC) frequencies in the bone marrow (BM) were perfectly normal in Robo4(-/-) mice. Moreover, Robo4(-/-) HSCs were equally competitive as wild-type HSCs in transplantation assays and had normal long-term repopulating (LTR) capacity. Of note, the initial engraftment at 4-weeks after transplantation was slightly impaired by Robo4 ablation, suggesting a marginal defect in BM homing of Robo4(-/-) HSCs. In fact, homing efficiencies of HSCs/HPCs to the BM was significantly impaired in Robo4-deficient mice. On the other hand, granulocyte-colony stimulating factor-induced peripheral mobilization of HSCs was also impaired by Robo4 disruption. Lastly, marrow recovery from myelosuppressive stress was equally efficient in WT- and Robo4-mutant mice. These results clearly indicate that Robo4 plays a role in HSC trafficking such as BM homing and peripheral mobilization, but is not essential in the LTR and self-renewal capacity of HSCs