Feasibility of methotrexate discontinuation following tocilizumab and methotrexate combination therapy in patients with long-standing and advanced rheumatoid arthritis: a 3-year observational cohort study

Objectives: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. Methods: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. Results: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). Conclusions: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression

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

Detection of Acetaminophen and Its Glucuronide in Fingerprint by SALDI Mass Spectrometry Using Zeolite and Study of Time-Dependent Changes in Detected Ion Amount

The ingredients of an antipyretic (acetaminophen, AAP) and their metabolites excreted into fingerprint were detected by surface-assisted laser desorption ionization (SALDI) mass spectrometry using zeolite. In the fingerprint taken 4 h after AAP ingestion, not only AAP but also the glucuronic acid conjugate of AAP (GAAP), caffeine (Caf), ethenzamide (Eth), salicylamide (Sala; a metabolite of Eth), and urea were detected. Fingerprints were collected over time to determine how the amounts of AAP and its metabolite changed with time, and the time dependence of the peak intensities of protonated AAP and GAAP was measured. It was found that the increase of [GAAP+H]+ peak started later than that of [AAP+H]+ peak, reflecting the metabolism of AAP. Both AAP and GAAP reached maximum concentrations approximately 3 h after ingestion, and were excreted from the body with a half-life of approximately 3.3 h. In addition, fingerprint preservation was confirmed by optical microscopy, and fingerprint shape was retained even after laser irradiation of the fingerprint. Our method may be used in fingerprint analysis

Novel strategy for hepatocyte transplantation using resected organ with hepatocellular carcinoma or cholangiocarcinoma after hepatectomy

OBJECTIVES: Although large hepatectomy (i.e., resection of 2–3 segments) is an increasingly common treatment for hepatocellular carcinoma and cholangiocarcinoma, it can lead to liver failure. However, a resected liver may contain large quantities of both normal hepatocytes (NHs) and carcinoma cells. We investigated separating these cell types so that NHs could be used as transplantable cells. MATERIALS AND METHODS: Cancer cells were developed by immortalizing rat hepatocytes, using an artificial chromosome vector. Cancer cells and primary hepatocytes (PHs) were mixed in a 1:1 ratio, then separated into two groups using fluorescence activated cell sorting (FACS). Normal hepatocytes after FACS (NHaF) and cancer cells after FACS (CAaF) were transplanted into two spots on opposite sides of the backs of nude mice; and also into the spleens of three groups (NHaF, CAaF and controls) of non-albumin rats (NARs), from which we measured blood albumin levels, using ELISA. RESULT: The PH and cancer cells were successfully separated using FACS. After separation, cancer cells transplanted subcutaneously in nude mice formed tumors, whereas transplanted PH cells in NARs only produced higher albumin levels. CONCLUSION: Transplanted NHaF cells did not produce tumors. However, this cells function was not enough in power for transplant source by this method. Nevertheless, we believe this technique can be improved and used to treat patients successfully

Transcranial Direct Current Stimulation Combined with Action Observation and Electromyographic Biofeedback Training in a Patient with Writer’s Cramp

We present a 47-year-old right-handed woman with a 15-year history of writer’s cramp who was provided with six sessions of cathodal transcranial direct current stimulation (tDCS) combined with observation of writing actions performed by a healthy subject and electromyographic (EMG) biofeedback training to decrease EMG activities in her right forehand muscles while writing for 30 min for 4 weeks. She showed improvement in dystonic posture and writing speed after the intervention. The writing movement and writing speed scores on a writer’s cramp rating scale decreased, along with writing time. Our findings demonstrated that cathodal tDCS combined with action observation and EMG biofeedback training might improve dystonic writing movements in a patient with writer’s cramp

Perception of Translucency and Glossiness: Influence of the Optical Scattering Properties on Sensory Evaluation

In the cosmetics industry, fine particles suspended or dispersed in a medium are widely used. Optical properties of the medium can be an indicator for evaluating the performance of cosmetic product, such as the ultraviolet protection capacity of sunscreens and also its appearance. However, the relationship between the optical properties and the appearance of the product has not been clarified. In this study, dispersions of fine particles with titanium dioxide or zinc oxide were used as scattering medium to clarify the relation between their scattering properties and changes in visual perception. For visual perception, sensory tests with human panelists were performed using a custom-designed apparatus to inspect the samples and evaluate the two visual sensory quantities, &ldquo;glossiness&rdquo; and &ldquo;translucency&rdquo;. The sensory test employed Thurston&rsquo;s one-pair comparison method, and a total of 18 panelists were asked to evaluate the samples. The sensory tests showed that the translucency became stronger as the scattering coefficient decreased. On the other hand, only the samples in the group with the highest scattering coefficient showed a slightly low glossiness. In contrast, the other samples showed little difference in glossiness due to the difference in scattering coefficients. The results of this study indicate that the appearance of cosmetics products can be influenced by controlling the scattering properties of the medium

Perception of Translucency and Glossiness: Influence of the Optical Scattering Properties on Sensory Evaluation

In the cosmetics industry, fine particles suspended or dispersed in a medium are widely used. Optical properties of the medium can be an indicator for evaluating the performance of cosmetic product, such as the ultraviolet protection capacity of sunscreens and also its appearance. However, the relationship between the optical properties and the appearance of the product has not been clarified. In this study, dispersions of fine particles with titanium dioxide or zinc oxide were used as scattering medium to clarify the relation between their scattering properties and changes in visual perception. For visual perception, sensory tests with human panelists were performed using a custom-designed apparatus to inspect the samples and evaluate the two visual sensory quantities, “glossiness” and “translucency”. The sensory test employed Thurston’s one-pair comparison method, and a total of 18 panelists were asked to evaluate the samples. The sensory tests showed that the translucency became stronger as the scattering coefficient decreased. On the other hand, only the samples in the group with the highest scattering coefficient showed a slightly low glossiness. In contrast, the other samples showed little difference in glossiness due to the difference in scattering coefficients. The results of this study indicate that the appearance of cosmetics products can be influenced by controlling the scattering properties of the medium