Fatal borealpox in an immunosuppressed patient treated with antivirals and vaccinia immunoglobulin - Alaska, 2023.

Background: Borealpox virus (BRPV, formerly known as Alaskapox virus) is a zoonotic member of the Orthopoxvirus genus first identified in a person in 2015. In the six patients with infection previously observed BRPV involved mild, self-limiting illness. We report the first fatal BRPV infection in an immunosuppressed patient.

Silence of FIZZ1 by Short Hairpin RNA Inhibits Atherosclerosis.

Objective: Found in Inflammatory Zone 1 (FIZZ1) protein plays an important enhancive role in inflammation and angiogenesis. This study aims to explore the effects of FIZZ1 on murine atherosclerosis.

Methods: The murine aortic endothelial cells were treated with an adenoviral vector encoding FIZZ1 short hairpin RNA (Ad-shFIZZ1).

Erythropoietic properties of human induced pluripotent stem cells-derived red blood cells in immunodeficient mice.

Transfusion of red blood cells (RBCs) is a life-saving intervention for anemic patients. Human induced pluripotent stem cells (iPSC) have the capability to expand and differentiate into RBCs (iPSC-RBCs). Here we developed a murine model to investigate the in vivo properties of human iPSC-RBCs.

BMI1 enables extensive expansion of functional erythroblasts from human peripheral blood mononuclear cells.

Transfusion of red blood cells (RBCs) from ABO-matched but genetically unrelated donors is commonly used for treating anemia and acute blood loss. Increasing demand and insufficient supply for donor RBCs, especially those of universal blood types or free of known and unknown pathogens, has called for ex vivo generation of functional RBCs by large-scale cell culture. However, generating physiological numbers of transfusable cultured RBCs (cRBCs) ex vivo remains challenging, due to our inability to either extensively expand primary RBC precursors (erythroblasts) or achieve efficient enucleation once erythroblasts have been expanded and induced to differentiation and maturation.

Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice.

This study aimed to explore the interactions among long non-coding RNA H19, transcriptional factor CCCTC-binding factor (CTCF) and polycystic kidney disease 1 (PKD1), and to investigate its potentially regulatory effect on vulnerable plaque formation and angiogenesis of atherosclerosis. We established an atherosclerosis mouse model in ApoE knockout mice, followed by gain- and loss-of-function approaches. H19 was upregulated in aortic tissues of atherosclerosis mice, but silencing of H19 significantly inhibited atherosclerotic vulnerable plaque formation and intraplaque angiogenesis, accompanied by a downregulated expression of MMP-2, VEGF, and p53 and an upregulated expression of TIMP-1.

Erratum: Crim1 suppresses left ventricular hypertrophy.

[This corrects the article DOI: 10.3892/br.2019.

Next-generation sequencing specifies Angiostrongylus eosinophilic meningoencephalitis in infants: Two case reports.

Rationale: Angiostrongylus cantonensis-induced eosinophilic meningoencephalitis (AEM) in infants is a very rare but fatal disease. Utilization of genetic assay to detect the cerebral parasite plays an important role for the treatment of the infection.

Patient Concerns: Two infants (<2 years) presented with cough, intermittent fever, mental fatigue, and poor diet.

Crim1 suppresses left ventricular hypertrophy.

Left ventricular hypertrophy is a leading cause of heart failure and sudden death. Cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1) is expressed at a high level in the heart and has a regulatory role in heart development. The present study aimed to test the hypothesis that Crim1 can have an inhibitory function on ventricular hypertrophy.

Combination of serum lipids and cancer antigens as a novel marker for colon cancer diagnosis.

Background: Colon cancer is a malignancy of the large intestine with high mortality and economic burden. Recent studies reveal a new relationship between blood lipids and the risk of cancer. The presents study aims to investigate the combination of serum lipids with cancer antigens as a novel diagnostic marker for colon cancer.

Monocyte chemotactic protein-induced protein-1 enhances DR5 degradation and negatively regulates DR5 activation-induced apoptosis through its deubiquitinase function.

Monocyte chemotactic protein-induced protein-1 (MCPIP1; also called Regnase-1) encoded by the ZC3H12A gene critically regulates inflammatory responses and immune homeostasis primarily by RNase-dependent and -independent mechanisms. However, the relationship of MCPIP1 with apoptosis and cancer and the underlying mechanisms are largely unclear. The current study has demonstrated a previously uncovered connection between MCPIP1 and the negative regulation of death receptor 5 (DR5; also known as TRAIL-R2 or killer/DR5), a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is produced endogenously by various immune cells such as T cells.

The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5.

b-AP15 and its derivatives block proteasome deubiquitinase (DUB) activity and have been developed and tested in the clinic as potential cancer therapeutic agents. b-AP15 induces apoptosis in cancer cells, but the underlying mechanisms are largely undefined. The current study focuses on studying the modulatory effects of b-AP15 on death receptor 5 (DR5) levels and DR5 activation-induced apoptosis as well as on understanding the underlying mechanisms.

GM-CSF and IL-4 Fusion Cytokine Induces B Cell-Dependent Hematopoietic Regeneration.

Hematopoietic stem cells (HSCs) have the capacity to self-renew and differentiate into hematopoietic cells and have been utilized to replace diseased bone marrow for patients with cancers and blood disorders. Although remarkable progress has been made in developing new tools to manipulate HSCs for clinic use, there is still no effective method to expand HSCs in vivo for quick repopulation of hematopoietic cells following sublethal irradiation. We have recently described a novel synthetic cytokine that is derived from the fusion of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4; named as GIFT4), and we have now discovered that GIFT4 fusokine promotes long-term hematopoietic regeneration in a B cell-dependent manner.

Regulatory B Cells Induce Formation of IL-10-Expressing T Cells in Mice with Autoimmune Neuroinflammation.

Unlabelled: Although B cells are traditionally known for their role in propagating proinflammatory immune responses, their immunosuppressive effects have only recently begun to be appreciated. How these regulatory B cells (B) suppress the immune response remains to be worked out in detail. In this article, we show that B can induce the formation of conventional FoxP3 regulatory T cells (T), as well as a more recently described CD49bCD223 regulatory T-cell subset, known as type 1 regulatory T cells (Tr1s).

Expression of Death Receptor 4 Is Positively Regulated by MEK/ERK/AP-1 Signaling and Suppressed upon MEK Inhibition.

Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism.

Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFβ-Neutralizing Fusion Protein.

The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFβ. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell-stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFβ ligand trap, can overcome immunosuppressive TGFβ to effectively stimulate the proliferation and activation of natural killer (NK) and CD8 T cells with potent antitumor properties. FIST15-treated NK and CD8 T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFβ receptor-Fc fusion protein (sTβRII) in the presence of TGFβ.

Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells.

B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation.

GIFT4 fusokine converts leukemic B cells into immune helper cells.

Background: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL.

Methods: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4).

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy.

Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs.

HIV vaccines should elicit immune responses at both the mucosal portals of entry to block transmission and systemic compartments to clear disseminated viruses. Co-delivery of mucosal adjuvants has been shown to be essential to induce effective mucosal immunity by non-replicating vaccines. A novel cytokine, GIFT4, engineered by fusing GM-CSF and interleukin-4, was previously found to simulate B cell proliferation and effector function.

Blood B Cell and Regulatory Subset Content in Multiple Sclerosis Patients.

Objective: B cell targeted therapies have been effective in slowing multiple sclerosis (MS) disease progression suggesting a direct causal link for this lymphoid subset. A small subset of B cells with regulative properties (Bregs) exists in peripheral blood, and induction of Bregs ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model for MS. Therefore the frequency of B cell subsets and regulatory B cells in particular in peripheral blood of MS patients is of interest.

The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.

Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis.

B cells for cancer immunotherapy.

We have engineered a novel fusion cytokine named GIFT4 derived from GM-CSF and IL-4, and displaying robust gain-of-function immunostimulatory effects on B cells. GIFT4-programmed B cells have a unique identity and potent capacity to elicit a tumoricidal - cell response, thus comprising a novel B cell-based cancer immunotherapeutic approach.

Silence of MCL-1 upstream signaling by shRNA abrogates multiple myeloma growth.

Objectives: Multiple myeloma (MM) is an incurable B-cell cancer with accumulated clonal abnormal plasma cells in bone marrow of patients. MCL-1 (myeloid cell leukemia sequence 1) protein is an anti-apoptotic molecule in MM cells and regulated by pro-inflammatory cytokine IL-6 and downstream signaling molecules STAT3, PI3K and MAPK. The purpose of this study is to investigate the effect of STAT3, PI3K and MAPK gene silence on MCL-1 expression in human MM cells and the consequence of cell survival.