A Race between Tumor Immunoescape and Genome Maintenance Selects for Optimum Levels of (epi)genetic Instability

The human immune system functions to provide continuous body-wide surveillance to detect and eliminate foreign agents such as bacteria and viruses as well as the body's own cells that undergo malignant transformation. To counteract this surveillance, tumor cells evolve mechanisms to evade elimination by the immune system; this tumor immunoescape leads to continuous tumor expansion, albeit potentially with a different composition of the tumor cell population (“immunoediting”). Tumor immunoescape and immunoediting are products of an evolutionary process and are hence driven by mutation and selection. Higher mutation rates allow cells to more rapidly acquire new phenotypes that help evade the immune system, but also harbor the risk of an inability to maintain essential genome structure and functions, thereby leading to an error catastrophe. In this paper, we designed a novel mathematical framework, based upon the quasispecies model, to study the effects of tumor immunoediting and the evolution of (epi)genetic instability on the abundance of tumor and immune system cells. We found that there exists an optimum number of tumor variants and an optimum magnitude of mutation rates that maximize tumor progression despite an active immune response. Our findings provide insights into the dynamics of tumorigenesis during immune system attacks and help guide the choice of treatment strategies that best inhibit diverse tumor cell populations

Equation of state in (2+1)-flavor QCD at physical point with improved Wilson fermion action using gradient flow

We study the energy-momentum tensor and the equation of state as well as the chiral condensate in (2+1)-flavor QCD at the physical point applying the method of Makino and Suzuki based on the gradient flow. We adopt a nonperturbatively O(a)-improved Wilson quark action and the renormalization group-improved Iwasaki gauge action. At Lattice 2016, we have presented our preliminary results of our study in (2+1)-flavor QCD at a heavy u, d quark mass point. We now extend the study to the physical point and perform finite-temperature simulations in the range T \simeq 155--544 MeV (Nt = 4--14 including odd Nt's) at a \simeq 0.09 fm. We show our final results of the heavy QCD study and present some preliminary results obtained at the physical point so far.Comment: 8 pages, 15 figures, talk presented at the 35th International Symposium on Lattice Field Theory (LATTICE 2017), 18-24 June 2017, Granada, Spai

L-Qモデルは転移性脳腫瘍の定位放射線照射に適用可能か?

The biologically effective dose (BED) based on the linear-quadratic (LQ) model has been commonly used to evaluate the dose-effect relationships among the different fractionation schedules, but whether the LQ model is appropriate for hypofractionated (HF) high-dose stereotactic irradiation (STI) is uncertain. The validity of the model at high doses per fraction has been critically examined. In this study, STI of metastatic brain tumors was evaluated to suggest the applicability of the LQ model to HF high-dose radiotherapy. No significant difference was found between stereotactic radiosurgery (SRS) and HF stereotactic radiotherapy (SRT) in the analyses of 151 tumors. Furthermore, no significant differences were found among SRS, HF-SRT, and non-HF SRT in 117 metastatic lung adenocarcinomas. The results of this study suggest that BED calculation is a reasonable approach for careful dose-effect evaluation based on the LQ model for HF high-dose radiotherapy for metastatic brain tumors, especially lung adenocarcinomas.博士（医学）・甲第688号・平成30年9月26

Direct Evidence of Abortive Lytic Infection-Mediated Establishment of Epstein-Barr Virus Latency During B-Cell Infection

Viral infection induces dynamic changes in transcriptional profiles. Virus-induced and antiviral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, we infected EBV-negative Akata cells with EBV-EGFP and performed transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprogramming of cell growth by EBV, and a burst of viral lytic gene expression in the early phase of infection. Experimental and mathematical investigations demonstrate that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Fate mapping using recombinant EBV provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency. Furthermore, we find that the BZLF1 protein, which is a key regulator of reactivation, was dispensable for abortive lytic infection in the pre-latent phase, suggesting the divergent regulation of viral gene expressions from a productive lytic infection

A multicenter randomized controlled trial to evaluate the efficacy and safety of nelfinavir in patients with mild COVID-19

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms

Prognostic factors and effect modifiers for personalisation of internet-based cognitive behavioural therapy among university students with subthreshold depression: A secondary analysis of a factorial trial

BACKGROUND: Internet-cognitive behavioural therapy (iCBT) for depression can include multiple components. This study explored depressive symptom improvement prognostic factors (PFs) and effect modifiers (EMs) for five common iCBT components including behavioural activation, cognitive restructuring, problem solving, self-monitoring, and assertion training. METHODS: We used data from a factorial trial of iCBT for subthreshold depression among Japanese university students (N = 1093). The primary outcome was the change in PHQ-9 scores at 8 weeks from baseline. Interactions between each component and various baseline characteristics were estimated using a mixed-effects model for repeated measures. We calculated multiplicity-adjusted p-values at 5 % false discovery rate using the Benjamini-Hochberg procedure. RESULTS: After multiplicity adjustment, the baseline PHQ-9 total score emerged as a PF and exercise habits as an EM for self-monitoring (adjusted p-values <0.05). The higher the PHQ-9 total score at baseline (range: 5-14), the greater the decrease after 8 weeks. For each 5-point increase at baseline, the change from baseline to 8 weeks was bigger by 2.8 points. The more frequent the exercise habits (range: 0-2 points), the less effective the self-monitoring component. The difference in PHQ-9 change scores between presence or absence of self-monitoring was smaller by 0.94 points when the participant exercised one level more frequently. Additionally, the study suggested seven out of 36 PFs and 14 out of 160 EMs examined were candidates for future research. LIMITATIONS: Generalizability is limited to university students with subthreshold depression. CONCLUSIONS: These results provide some helpful information for the future development of individualized iCBT algorithms for depression

Components of smartphone cognitive-behavioural therapy for subthreshold depression among 1093 university students: a factorial trial

BACKGROUND: Internet-based cognitive-behavioural therapy (iCBT) is effective for subthreshold depression. However, which skills provided in iCBT packages are more effective than others is unclear. Such knowledge can inform construction of more effective and efficient iCBT programmes. OBJECTIVE: To examine the efficacy of five components of iCBT for subthreshold depression. METHODS: We conducted an factorial trial using a smartphone app, randomly allocating presence or absence of five iCBT skills including self-monitoring, behavioural activation (BA), cognitive restructuring (CR), assertiveness training (AT) and problem-solving. Participants were university students with subthreshold depression. The primary outcome was the change on the Patient Health Questionnaire-9 (PHQ-9) from baseline to week 8. Secondary outcomes included changes in CBT skills. FINDINGS: We randomised a total of 1093 participants. In all groups, participants had a significant PHQ-9 reduction from baseline to week 8. Depression reduction was not significantly different between presence or absence of any component, with corresponding standardised mean differences (negative values indicate specific efficacy in favour of the component) ranging between -0.04 (95% CI -0.16 to 0.08) for BA and 0.06 (95% CI -0.06 to 0.18) for AT. Specific CBT skill improvements were noted for CR and AT but not for the others. CONCLUSIONS: There was significant reduction in depression for all participants regardless of the presence and absence of the examined iCBT components. CLINICAL IMPLICATION: We cannot yet make evidence-based recommendations for specific iCBT components. We suggest that future iCBT optimisation research should scrutinise the amount and structure of components to examine. TRIAL REGISTRATION NUMBER: UMINCTR-000031307