MAVS-dependent host species range and pathogenicity of human hepatitis A virus

Although hepatotropic viruses are important causes of human disease, the intrahepatic immune response to hepatitis viruses is poorly understood due to a lack of tractable small animal models. Here we describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly results from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver

Enhancing Oral Vaccine Potency by Targeting Intestinal M Cells

The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells

Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations

Abstract Background Compared with standard chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, data comparing the efficacies of different EGFR−TKIs, especially regarding the presence of brain metastasis, are lacking. Methods EGFR-TKI naive patients with recurrent or stage IIIB/IV NSCLC harboring EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively determined progression-free survival (PFS) using the Kaplan−Meier method with log-rank test in patients treated with either gefitinib or erlotinib, cumulative incidence of central nervous system (CNS) progression using the Fine and Gray competing risk regression model, and favorable prognostic factors for CNS progression by multivariate analysis. Results Seventy-seven EGFR-TKI-naive patients were started on either gefitinib (n = 55) or erlotinib (n = 22) in our hospital from April 2010 to April 2016. Among the patients with brain metastasis, PFS tended to be longer in the erlotinib than in the gefitinib group. In the analysis of cumulative incidence, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, in a subgroup analysis of the patients with brain metastasis, there was a significant difference between the erlotinib and gefitinib groups (hazard ratio 0.25; 95% confidence interval, 0.08–0.81; p = 0.021). Of the prognostic factors for CNS progression evaluated, the absence of brain metastasis before EGFR-TKI therapy and receiving erlotinib (vs gefitinib) had a significantly favorable effect on patient prognosis. Conclusion Although this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than gefitinib for treatment of brain metastasis in patients with EGFR-mutant NSCLC

Obsessive-Compulsive Disorder with Psychotic Features: Is It a Clinical Entity?

(1) Background: Even though the comorbidity of obsessive-compulsive disorder (OCD) and a psychotic disorder (PD), such as schizophrenia, is being increasingly recognized, the impact of this comorbidity on the clinical presentation, including insight into obsessive-compulsive symptoms and the functioning of OCD, remains unclear. (2) Methods: To investigate clinical differences between OCD patients with and without PD, 86 Japanese outpatients who met the DSM-IV-TR criteria for OCD were recruited and divided into two groups: 28 OCD patients with PD, and 58 OCD patients without PD. The two groups were cross-sectionally compared in terms of their sociodemographic profiles and clinical characteristics, including the DSM-IV-TR insight specifier and the Global Assessment of Functioning (GAF). (3) Results: The results showed that OCD patients with PD scored lower on both the insight and GAF assessments. (4) Conclusions: The present study suggests that comorbid PD in OCD is a clinical entity

Prospective evaluation of the G8 screening tool for prognostication of survival in elderly patients with lung cancer: A single-institution study.

The G8 questionnaire is a quick and easy-to-use screening tool. Several studies reported that the G8 questionnaire had a high sensitivity for predicting abnormalities in the full comprehensive geriatric assessment and predicted functional decline and survival in elderly cancer patients. The present study aimed to evaluate the role of the G8 questionnaire for predicting clinical outcomes and overall survival (OS) in elderly patients with lung cancer, who received chemotherapy or chemoradiotherapy. The data of 101 lung cancer patients aged ≥70 years, who were hospitalized between September 2011 and August 2014, were analyzed. Of these patients (median age, 77 years), 83 (82%) had impaired G8 scores. The proportion of patients with an impaired G8 score was significantly higher in patients aged ≥80 years than those aged <80 years (p = 0.04). All 18 patients with a normal G8 score possessed an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and none of the patients with a normal G8 score had an ECOG PS of ≥2 (p < 0.0001). An impaired G8 score tended to correlate with a relative dose intensity of <0.65 in patients who received chemotherapy or chemoradiotherapy (p = 0.05, odds ratio = 5.40). In the univariate analysis, an ECOG PS of ≥2 and an impaired G8 score were significantly associated with a poor OS (p = 0.009 and p = 0.003, respectively). Moreover, in the multivariate analysis, an ECOG PS of ≥2 (HR 2.55; 95% CI, 1.23-5.30; p = 0.01) and an impaired G8 score (HR 3.86; 95% CI, 1.44-13.36; p = 0.006) were remained independent prognostic factor for OS. G8 screening tool is useful for the prognostication of elderly lung cancer patients treated with chemotherapy. These finding suggest that the G8 questionnaire could be a useful tool in treatment decision-making to predict prognosis and prevent patients from receiving inappropriate anti-cancer treatment near the end of life

Association of PD‐L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR‐mutated NSCLC

Abstract Background The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) resistance, including osimertinib, and programmed cell death‐ligand 1 (PD‐L1) expression status in EGFR‐mutated non‐small cell lung carcinoma (NSCLC) remains unclear. Patients and Methods We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first‐line treatment. We compared progression‐free survival (PFS) between eligible patients with PD‐L1 tumor proportion scores (TPS) ≥20% and PD‐L1 TPS <20% using the Kaplan–Meier survival plots with a log‐rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. Results The PD‐L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33–86] years; 10 women [45.5%]; 11 current or ex‐smokers [50%]); ECOG performance status (PS) of 0–1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD‐L1 TPS <20% group included 42 patients (median [range] age 73 [43–88] years; 29 women [69%]; 12 current or ex‐smokers [28.6%]); ECOG PS of 0–1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD‐L1 TPS ≥20% and PD‐L1 TPS <20% groups, respectively (log‐rank p = 0.013). Multivariate analysis revealed that PD‐L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09–5.08, p = 0.030). Conclusion PD‐L1 TPS ≥20% in patients with EGFR‐mutated NSCLC may be associated with early resistance to osimertinib

TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions

Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1−/− Ifnar1−/− and Tim4−/− Ifnar1−/− double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1−/− mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1−/−Ifnar1−/− mice compared to Ifnar1−/− mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice

GRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection

Targeting the main protease (Mpro) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.We assessed various newly generated compounds that target the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various previously known compounds reportedly active against SARS-CoV-2, employing RNA quantitative PCR (RNA-qPCR), cytopathicity assays, and immunocytochemistry. Here, we show that two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, exerted potent activity against SARS-CoV-2 in cell-based assays performed using VeroE6 cells and TMPRSS2-overexpressing VeroE6 cells. While GRL-0820 and the nucleotide analog remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred. No significant anti-SARS-CoV-2 activity was found for several compounds reportedly active against SARS-CoV-2 such as lopinavir, nelfinavir, nitazoxanide, favipiravir, and hydroxychroloquine. In contrast, GRL-0920 exerted potent activity against SARS-CoV-2 (50% effective concentration [EC50] = 2.8 μM) and dramatically reduced the infectivity, replication, and cytopathic effect of SARS-CoV-2 without significant toxicity as examined with immunocytochemistry. Structural modeling shows that indole and chloropyridinyl of the derivatives interact with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using high-performance liquid chromatography–mass spectrometry (HPLC/MS), suggesting that the indole moiety is critical for the anti-SARS-CoV-2 activity of the derivatives. GRL-0920 might serve as a potential therapeutic for coronavirus disease 2019 (COVID-19) and might be optimized to generate more-potent anti-SARS-CoV-2 compounds