PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T-ex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the T-ex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T-ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T-ex clonotypes, mainly from TDLNs

Prevalence of and risk factors for post-intensive care syndrome: Multicenter study of patients living at home after treatment in 12 Japanese intensive care units, SMAP-HoPe study

Few studies have examined the epidemiology of post-intensive care syndrome in Japan. This study investigated the mental health and quality of life of patients living at home in Japan after intensive care unit (ICU) discharge. Additionally, we examined whether unplanned admission to the ICU was associated with more severe post-traumatic stress disorder (PTSD), anxiety, and depressive symptoms. An ambidirectional cohort study was conducted at 12 ICUs in Japan. Patients who stayed in the ICU for > 3 nights and were living at home for 1 year afterward were included. One year after ICU discharge, we retrospectively screened patients and performed a mail survey on a monthly basis, including the Impact of Event Scale—Revised (IER-S), the Hospital Anxiety Depression Scale (HADS), and the EuroQOL—5 Dimension (EQ-5D-L) questionnaires. Patients’ characteristics, delirium and coma status, drugs used, and ICU and hospital length of stay were assessed from medical records. Descriptive statistics and multilevel linear regression modeling were used to examine our hypothesis. Among 7,030 discharged patients, 854 patients were surveyed by mail. Of these, 778 patients responded (response rate = 91.1%). The data from 754 patients were analyzed. The median IES-R score was 3 (interquartile range [IQR] = 1‒9), and the prevalence of suspected PTSD was 6.0%. The median HADS anxiety score was 4.00 (IQR = 1.17‒6.00), and the prevalence of anxiety was 16.6%. The median HADS depression score was 5 (IQR = 2‒8), and the prevalence of depression was 28.1%. EQ-5D-L scores were lower in our participants than in the sex- and age-matched Japanese population. Unplanned admission was an independent risk factor for more severe PTSD, anxiety, and depressive symptoms. Approximately one-third of patients in the general ICU population experienced mental health issues one year after ICU discharge. Unplanned admission was an independent predictor for more severe PTSD symptoms

A Comprehensive Resource of Interacting Protein Regions for Refining Human Transcription Factor Networks

Large-scale data sets of protein-protein interactions (PPIs) are a valuable resource for mapping and analysis of the topological and dynamic features of interactome networks. The currently available large-scale PPI data sets only contain information on interaction partners. The data presented in this study also include the sequences involved in the interactions (i.e., the interacting regions, IRs) suggested to correspond to functional and structural domains. Here we present the first large-scale IR data set obtained using mRNA display for 50 human transcription factors (TFs), including 12 transcription-related proteins. The core data set (966 IRs; 943 PPIs) displays a verification rate of 70%. Analysis of the IR data set revealed the existence of IRs that interact with multiple partners. Furthermore, these IRs were preferentially associated with intrinsic disorder. This finding supports the hypothesis that intrinsically disordered regions play a major role in the dynamics and diversity of TF networks through their ability to structurally adapt to and bind with multiple partners. Accordingly, this domain-based interaction resource represents an important step in refining protein interactions and networks at the domain level and in associating network analysis with biological structure and function

Employment status and its associated factors for patients 12 months after intensive care: Secondary analysis of the SMAP-HoPe study

BackgroundReturning to work is a serious issue that affects patients who are discharged from the intensive care unit (ICU). This study aimed to clarify the employment status and the perceived household financial status of ICU patients 12 months following ICU discharge. Additionally, we evaluated whether there exists an association between depressive symptoms and subsequent unemployment status.MethodsThis study was a subgroup analysis of the published Survey of Multicenter Assessment with Postal questionnaire for Post-Intensive Care Syndrome for Home Living Patients (the SMAP-HoPe study) in Japan. Eligible patients were those who were employed before ICU admission, stayed in the ICU for at least three nights between October 2019 and July 2020, and lived at home for 12 months after discharge. We assessed the employment status, subjective cognitive functions, household financial status, Hospital Anxiety and Depression Scale, and EuroQOL-5 dimensions of physical function at 12 months following intensive care.ResultsThis study included 328 patients, with a median age of 64 (interquartile range [IQR], 52–72) years. Of these, 79 (24%) were unemployed 12 months after ICU discharge. The number of patients who reported worsened financial status was significantly higher in the unemployed group (p<0.01) than in the employed group. Multivariable analysis showed that higher age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03–1.08]) and greater severity of depressive symptoms (OR, 1.13 [95% CI, 1.05–1.23]) were independent factors for unemployment status at 12 months after ICU discharge.ConclusionsWe found that 24.1% of our patients who had been employed prior to ICU admission were subsequently unemployed following ICU discharge and that depressive symptoms were associated with unemployment status. The government and the local municipalities should provide medical and financial support to such patients. Additionally, community and workplace support for such patients are warranted

Doubly excited states of molecular hydrogen by scattered electron-ion coincidence measurements

Electron energy-loss spectroscopy and electron-ion coincidence techniques were used to determine the total generalized oscillator strength distribution (GOSD) of molecular hydrogen (H2) under 200 eV incident electron energy at a scattering angle of 6 degree. Ionic GOSDs were obtained for each formed ion at each energy-loss value and were determined by scattered electron-ion coincidence measurements. The total and partial ionic GOSDs of H2 were compared with the OOSDs from the experimental results of both photon and fast-electron impacts. We observed auto-ionization induced by excitation to the optically forbidden Q1 1Σ+g(1) state near 28 eV. Additionally, the non-ionic GOSD, defined as the difference between the total GOSD and the total ionic GOSD, was determined. From the non-ionic GOSD, neutral dissociation from excitation to the forbidden Q1 1Σ+g(1) state near 28 eV and the Q2 series near 35 eV were identified

Microscopic Polyangiitis Initially Presumed to Be Endocarditis

The antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAVs), which include fever of unknown origin (FUO), are rare diseases characterized by necrotizing inflammation of small blood vessels and the presence of ANCAs. Microscopic polyangiitis (MPA) is a subtype of the AAVs. Although the prevalence of AAVs has generally increased over the last 20 years, there have been rare reports from the dental and oral surgery field. In this article, we present a case of MPA suspected to be infective endocarditis (IE) following tooth extraction