Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, butmight be useful for various other physical symptoms, including nausea, fatigue,dyspnea, and constipation. However, few studies have used TENS for treating thephysical symptoms of patients with advanced cancer. In this crossover trial, we assessthe effects of TENS on pain and other physical symptoms in 20 in-patients withadvanced cancer receiving palliative care. For 5-day phases between wash out periodsof 5 days, patients received TENS or non-TENS. TENS was delivered at four points: thecenter of the back for mainly nausea and dyspnea, on the back at the same dermatomallevel as the origin of the pain (100 Hz), and on both ankle joints for constipation (10Hz). The intensity of pain and the total opioid dose used during phases were recorded.Physical symptoms were evaluated using the European Organization for Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care(QLQ-C15-PAL). Hematological and biochemical data were recorded before and afterthe TENS phase. The average pain and total number of opioid rescue doses weresignificantly reduced by TENS. TENS tended to improve nausea and appetite loss, butnot constipation. There were no effects on hematological and biochemical parameters.Use of TENS could safely improve pain, nausea, and appetite loss in patients withadvanced cancer. Although it cannot be used as a substitute for opioids and otherpharmaceutical treatment, it may be useful to support palliative care

Pathway-Specific Utilization of Synaptic Zinc in the Macaque Ventral Visual Cortical Areas

Synaptic zinc is an activity-related neuromodulator, enriched in hippocampal mossy fibers and a subset of glutamatergic cortical projections, exclusive of thalamocortical or corticothalamic. Some degree of pathway specificity in the utilization of synaptic zinc has been reported in rodents. Here, we use focal injections of the retrograde tracer sodium selenite to identify zinc-positive (Zn+) projection neurons in the monkey ventral visual pathway. After injections in V1, V4, and TEO areas, neurons were detected preferentially in several feedback pathways but, unusually, were restricted to deeper layers without involvement of layers 2 or 3. Temporal injections resulted in more extensive labeling of both feedback and intratemporal association pathways. The Zn+ neurons had a broader laminar distribution, similar to results from standard retrograde tracers. After anterograde tracer injection in area posterior TE, electron microscopic analysis substantiated that a proportion of feedback synapses was colabeled with zinc. Nearby injections, Zn+ intrinsic neurons concentrated in layer 2, but in temporal areas were also abundant in layer 6. These results indicate considerable pathway and laminar specificity as to which cortical neurons use synaptic zinc. Given the hypothesized roles of synaptic zinc, this is likely to result in distinct synaptic properties, possibly including differential synaptic plasticity within or across projections

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

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

第一志望の大学に入学できなかった大学生における Benefit Finding

Benefit finding describes the process in which people who experienced negative events found a positive meaning after revaluating the experience. The purpose of this study is to reveal, using the concept of benefit finding, the sequence of processes that lead to meaning-making and personal growth, while taking in consideration the specific negative event and its context. To achieve this purpose, we examined the benefit finding of university students who went to a university that was not their first choice. In study 1, we classified the sample who engaged in benefit finding in university entrance exams. Through cluster analysis of the scale for perception of university entrance exams for university students (N=127), three clusters were identified: passive attitude (Group 1); positive and negative perceptions (Group 2); and positive perceptions (Group 3). In study 2, we conducted semi-structured interviews about awareness over the university entrance exams with university students who attended a university that was not their first choice and belonged Groups 2 or 3, and respondents who answered that they gained awareness during university entrance exams (N=8). The results of the thematic analysis revealed that participants in study 2 acquire two benefit findings, “Acquisition of personal skills for growth through teacher or parental support” and “Acquisition of new perspectives through comparisons between classmates’ and their own university exam experiences”. These studies provide clinical and educational implications for helping students who unwillingly enroll in their university

Thiopental Elevates Steady-State Levels of Intracellular Ca2+ and Zn2+ in Rat Thymic Lymphocytes: Toxicity test of thiopental on rat thymic lymphocytes

Thiopental is an ultra-short-acting barbiturate and has been used commonly in the induction phase of general anesthesia. However, the toxic effect of thiopental is not completely clear.?The effect of thiopental on intracellular Ca2+ ([Ca2+]i) levels was investigated in non-excitable cells. Experiments were carried out using a flow-cytometric technique, rat thymic lymphocytes (as non-excitable cells), and appropriate fluorescent probes. Treatment of cells with 300 µM thiopental increased Fluo-3 fluorescence intensity, indicating elevation of [Ca2+]i. This increase was partially attenuated by a chelator of intracellular Zn2+. Thus, thiopental elevated both [Ca2+]i and intracellular Zn2+ ([Zn2+]i) levels. Under intracellular Zn2+-free conditions, 100–300 µM thiopental was still able to induce a statistically significant increase in [Ca2+]i, whereas removal of extracellular Ca2+ greatly reduced the increase in [Ca2+]i induced by this dose of thiopental. Therefore, the thiopental-induced increase in [Ca2+]i was mainly due to an increased influx of Ca2+. Treatment of cells with 300 µM thiopental increased FluoZin-3 fluorescence intensity, indicating the presence of [Zn2+]i, both in the presence and absence of extracellular Zn2+. The thiopental-induced elevation of [Zn2+]i was due to an increase in both influx of Zn2+ and intracellular Zn2+ release. Concanavalin A (10 µg/mL) augmented Fluo-3 fluorescence in the presence of an intracellular Zn2+ chelator. The combination of concanavalin A and 100–300 µM thiopental synergistically increased [Ca2+]i. Results suggest that thiopental increases [Ca2+]i in both quiescent and activated lymphocytes, possibly resulting in modulation of immune system function

Divergence of postoperative recovery process and patient QOL based on the surgical site in patients undergoing liver tumor resection

本研究は,肝腫瘍に対する手術創部位によって患者の術後回復過程やQOLに,どのような相違が認められるかを明らかにすることを目的とした.対象は,肝腫瘍切除術を受けた患者17名で,手術創の違いにより開胸+開腹群,開腹群の二群に分けて検討を行った.データ収集の方法は,診療記録と「身体的内容」「心理的内容」「社会的内容」から構成された質問紙調査により行った. その結果,歩行開始時期は開胸+開腹群が開腹群に比べ有意に遅延し,膀胱カテーテル抜去時期やPatient controlled epidural analgesia(PCEA)装着期間,術後～退院までの平均在院日数においても遅延する傾向がみられた.また,創部痛や食欲出現時期においても開胸+開腹群が開腹群に比べ有意に遅延し,術後の生活様式の変化の有無においても有意差を認めた. 従って,医療者は手術創部位によって患者の術後経過に違いが認められることを理解した上で適切なケアや指導を行っていくとともに,患者にとって手術を受けて良かったと思えるような支援を行っていく必要があることが示唆された.The purpose of this study was to clarify the kind of divergence observed in terms of the preoperative recovery process and QOL of patients, depending on the location of the surgical wound for liver tumors. The subjects consisted of 17 patients that underwent resection for liver tumors, and an analysis was carried out by dividing them into two groups, the thoracotomy plus laparotomy group and the laparotomy group, based on the difference in their surgical wounds. Data were collected by browsing through the clinical records and by a questionnaire consisting of "physical content," "psychological content," and "social content." As a result, the period of gait initiation was found to be significantly delayed for the thoracotomy plus laparotomy group compared to the laparotomy group, and a tendency to be delayed was also observed during urethral catheter suture removal, the period of equipping PCEA, and the average hospital days following surgery until discharge. Moreover, wound pain and the recovery of the patient's appetite were significantly delayed in the thoracotomy plus laparotomy group compared to the laparotomy group, and a significant difference was also observed in the presence of postoperative lifestyle change. Therefore, it was suggested that it is necessary for medical staff to carry out appropriate care and guidance with the understanding that there are differences in a patient's postoperative recovery depending on the location of the surgical wound, and along with that, to provide sufficient support to enable the patients to have a positive approach to undergoing surgery

A State-of-the-Art Roadmap for Biomarker-Driven Drug Development in the Era of Personalized Therapies

Advances in biotechnology have enabled us to assay human tissue and cells to a depth and resolution that was never possible before, redefining what we know as the “biomarker”, and how we define a “disease”. This comes along with the shift of focus from a “one-drug-fits-all” to a “personalized approach”, placing the drug development industry in a highly dynamic landscape, having to navigate such disruptive trends. In response to this, innovative clinical trial designs have been key in realizing biomarker-driven drug development. Regulatory approvals of cancer genome sequencing panels and associated targeted therapies has brought personalized medicines to the clinic. Increasing availability of sophisticated biotechnologies such as next-generation sequencing (NGS) has also led to a massive outflux of real-world genomic data. This review summarizes the current state of biomarker-driven drug development and highlights examples showing the utility and importance of the application of real-world data in the process. We also propose that all stakeholders in drug development should (1) be conscious of and efficiently utilize real-world evidence and (2) re-vamp the way the industry approaches drug development in this era of personalized medicines