STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy.

Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)-interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING-IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored.

The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies.

The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs.

Metformin enhances the antitumor activity of oncolytic herpes simplex virus HF10 (canerpaturev) in a pancreatic cell cancer subcutaneous model.

Oncolytic virus (OV) therapy is a promising cancer immunotherapy, especially for cold tumors by inducing the direct lysis of cancer cells and initiation of potent antitumor response. Canerpaturev (C-REV) is an attenuated oncolytic herpes simplex virus-1, which demonstrated a potent antitumor effect in various preclinical models when used either alone or combined. Metformin is a commonly prescribed antidiabetic drug that demonstrated a potent immune modulator effect and antitumor response.

S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model.

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown.

Problem-Based Learning in Child and Adolescent Psychiatry: A Perspective from Japan.

Purpose: Japanese higher education institutions have long been striving for the globalization of medical education. Nagoya University (NU) adopted PBL as a means of enhancing intercultural awareness in globalizing medical education by working with the Norwegian University of Science and Technology (NTNU), Faculty of Medicine and Health Science, under the Trondheim NTNU-Nagoya (TroNa) partnership for mobility and internationalization of child and mental health studies. This study aims to assess students' attitudes towards PBL and to suggest future developments in this form of education by introducing common PBL scenarios experienced at NTNU and NU.

C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells.

Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)-TBK1-IRF3-IFN pathway is known to act as the central cellular host defense against viral infection.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8 PD-1 tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment.

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8 T-cell infiltration. CD8 T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction.

Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth.

The naturally occurring oncolytic herpes simplex virus canerpaturev (C-REV), formerly HF10, proved its therapeutic efficacy and safety in multiple clinical trials against melanoma, pancreatic, breast, and head and neck cancers. Meanwhile, patients with colorectal cancer, which has increased in prevalence in recent decades, continue to have poor prognosis and morbidity. Combination therapy has better response rates than monotherapy.

The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers.

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials.

Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials.

Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of , and latency-associated transcripts, and overexpresses and .

Serbian Language version of the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up: Cross-Cultural Adaptation and Assessment of Reliability.

Early detection of Autism Spectrum Disorder (ASD) has proven to be of high significance, however there is a limited availability of ASD screening tools in Serbian language. In this study we aim to translate, assess reliability and, in part, test the applicability of Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT R/F) in Serbian Healthcare environment. We screened 128 children in three primary healthcare centres and 20 children in a tertiary psychiatric center, using M-CHAT R/F translated into Serbian language, between December 2014 and October 2015.

CD4 virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

It is widely accepted that central and effector memory CD4 T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts.

Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab.

Importance: Immunobullous diseases mediated by IgA are often difficult to manage, but to date no mechanism has been proposed. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated good efficacy in the treatment of refractory mucous membrane pemphigoid. However, not all cases of mucous membrane pemphigoid respond to rituximab.

Multimodal therapy of idiopathic pyoderma gangrenosum.

A 13-year old girl was admitted to the University of California Davis Medical Center for evaluation and treatment of cutaneous bullae and ulcerations over her lower extremities that were refractory to antibiotic therapy and incision and drainage. Her disease continued to worsen with the appearance of multiple new bullae and the progression of old ones into deep ulcers with undermined borders. Biopsy revealed a neutrophilic dermatosis and diagnostic work-up was negative for infectious or autoimmune etiologies.

Lack of CD4⁺CD25⁺FOXP3⁺ regulatory T cells is associated with resistance to intravenous immunoglobulin therapy in patients with Kawasaki disease.

Unlabelled: The aim of this study was to investigate changes in CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) throughout the clinical course of Kawasaki disease (KD) and correlations with response to intravenous immunoglobulin (IVIg) therapy. Participants comprised 18 patients who fulfilled the diagnostic criteria for KD and 20 healthy subjects. Expressions of CD25 and FOXP3 among all CD4(+) T cells in peripheral blood mononuclear cells were analyzed by flow cytometry before and 7 and 30 days after IVIg therapy.

Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation.

We investigated human leukocyte antigen (HLA) expression on leukemic cells derived from patients at diagnosis and relapse after hematopoietic stem cell transplantation (HSCT) using flow cytometry with locus-specific antibodies. Two of 3 patients who relapsed after HLA-haploidentical HSCT demonstrated loss of HLA alleles in leukemic cells at relapse; on the other hand, no loss of HLA alleles was seen in 6 patients who relapsed after HLA-identical HSCT. Single-nucleotide polymorphism array analyses of sorted leukemic cells further revealed the copy number-neutral loss of heterozygosity, namely, acquired uniparental disomy on the short arm of chromosome 6, resulting in the total loss of the mismatched HLA haplotype.

Downregulation of GATA-2 and overexpression of adipogenic gene-PPARgamma in mesenchymal stem cells from patients with aplastic anemia.

Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells and fatty replacement in the bone marrow. Transcriptional factor GATA-2 plays several important roles in both hematopoiesis and adipogenesis. Decreased levels of GATA-2 compromise the proliferation and survival of hematopoietic stem cells.

Plasmacytoid dendritic cell leukemia in children.

CD4/CD56 malignancies are rare hematologic neoplasms, which have recently been shown to represent the malignant counterpart of plasmacytoid dendritic cells (pDC). A 5-year-old boy initially presented with multiple subcutaneous lesions on his upper and lower extremities. Skin biopsy results showed large atypical lymphoid cells in the dermis.

Congenital erythroid and myeloid hypoplasia terminating myelodysplastic syndrome.

We describe a 4-month-old infant girl with congenital erythroid and myeloid hypoplasia who developed myelodysplastic syndrome. Bone marrow examination showed severe erythroid and myeloid hypoplasia without dysplastic morphology. Flow cytometry detected autoantibodies to myeloid cells, indicating a diagnosis of Diamond-Blackfan anemia with autoimmune neutropenia.

Quantification of granulocyte-macrophage colony-stimulating factor hypersensitivity in juvenile myelomonocytic leukemia by 3H-thymidine assay.

Recent molecular studies have revealed that the GM-CSF/RAS signaling pathway plays a central role in the pathogenesis of juvenile myelomonocytic leukemia (JMML). CFU-GM colony assay is an important test for GM-CSF hypersensitivity in patients with JMML, but requires specific skills. We established a simple and easy quantification method to test GM-CSF hypersensitivity, using a (3)H-thymidine assay.

Increased midkine gene expression in childhood B-precursor acute lymphoblastic leukemia.

Midkine (MK) is a heparin-binding growth factor that is overexpressed in a number of solid cancers. However, expression in acute leukemia has not been clarified. We examined MK gene expression using real-time PCR in 94 children with acute leukemia.