Immunotherapy: rAAV2 expressing interleukin-15 inhibits HeLa cell tumor growth in mice

[[abstract]]Human interleukin-15 (hIL15) has anti-tumor activities, but it is not convenient for tumor treatment because of its short half-life. A gene therapy for mouse lung cancer using an adenovirus vector expressing IL15 has been reported. However, adenovirus vector-mediated gene therapy can provoke cellular toxicity and inflammatory reactions. The recombinant adenovirus-associated vector 2 (rAAV2) is safer due to minimal cellular toxicity and immune response. In order to demonstrate that gene therapy can be used safely and successfully for human cancer treatment, the rAAV2 expressing hIL15 gene (rAAV2-hIL15) is applied for human cervical cancer, HeLa cell, in this study. This study successfully demonstrates that rAAV2-hIL15 can express IL15 with bioactivities in vitro and in vivo. In conclusion, our studies show that human cervical cancers are inhibited on animal model with rAAV2-hIL15 treatment and provide a safer and important reference for human cancer gene therapy

PKC and MEK pathways inhibit caspase-9/-3-mediated cytotoxicity in differentiated cells

[[abstract]]Many studies have indicated that differentiated cells inhibit drug-induced cytotoxicity but undifferentiated cells do not, though the mechanisms are unclear. Currently, HL-60 cells are induced to differentiate into macrophage-like cells with Phor-bol-12-myristate-13-acetate (TPA) treatment (TPA-differentiated cells). Our study shows that caspase-9/-3-mediated cytotoxicity can be induced in undifferentiated HL-60 cells but not in TPA-differentiated HL-60 cells. However, caspase-9/-3-mediated cytotoxicity can be induced in TPA-differentiated cells if they are pretreated with a protein kinase C (PKC) or a mitogen activated protein kinase (MEK) inhibitor. Taken together, this study demonstrates that TPA-differentiated HL-60 cells inhibit caspases-9/-3-mediated cytotoxicity through the PKC and MEK signaling pathways. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved

Immunotherapy: rAAV2 expressing interleukin-15 inhibits HeLa cell tumor growth in mice

Human interleukin-15 (hIL15) has anti-tumor activities, but it is not convenient for tumor treatment because of its short half-life. A gene therapy for mouse lung cancer using an adenovirus vector expressing IL15 has been reported. However, adenovirus vector-mediated gene therapy can provoke cellular toxicity and inflammatory reactions. The recombinant adenovirus-associated vector 2 (rAAV2) is safer due to minimal cellular toxicity and immune response. In order to demonstrate that gene therapy can be used safely and successfully for human cancer treatment, the rAAV2 expressing hIL15 gene (rAAV2-hIL15) is applied for human cervical cancer, HeLa cell, in this study. This study successfully demonstrates that rAAV2-hIL15 can express IL15 with bioactivities in vitro and in vivo. In conclusion, our studies show that human cervical cancers are inhibited on animal model with rAAV2-hIL15 treatment and provide a safer and important reference for human cancer gene therapy

Endoplasmic Reticulum Stress in Elderly Patients with COVID-19: Potential of Melatonin Treatment

Aging processes, including immunosenescence, inflammation, inflammasome formation, genomic instability, telomeric attrition, and altered autophagy, are involved in viral infections and they may contribute to increased pathophysiological responses to the SARS-CoV-2 infection in the elderly; this poses additional risks of accelerated aging, which could be found even after recovery. Aging is associated with oxidative damage. Moreover, SARS-CoV-2 infections may increase the production of reactive oxygen species and such infections will disturb the Ca++ balance via an endoplasmic reticulum (ER) stress-mediated unfolded protein response. Although vaccine development and anti-inflammation therapy lower the severity of COVID-19, the prevalence and mortality rates are still alarming in some countries worldwide. In this review, we describe the involvement of viral proteins in activating ER stress transducers and their downstream signals and in inducing inflammation and inflammasome formation. Furthermore, we propose the potential of melatonin as an ER stress modulator, owing to its antioxidant, anti-inflammatory, and immunoregulatory effects in viral infections. Considering its strong safety profile, we suggest that additive melatonin supplementation in the elderly could be beneficial in treating COVID-19

Acute Retroperitoneal Hemorrhage Induced by Giant Adrenal Myelolipoma Mimicking Renal Colic Pain: A Case Report

Retroperitoneal hemorrhage is a life-threatening clinical entity which is difficult to diagnose due to numerous etiology and unspecific symptoms. Spontaneous severe retroperitoneal hemorrhage, known as Wunderlich’s syndrome presented with Lenk’s triad, includes acute flank pain, flank mass, and hypovolemic shock. Giant adrenal myelolipoma causing Wunderlich’s syndrome is rare. Here, we presented a 59-year-old woman with spontaneous acute onset persistent left flank pain. The kidney, ureter, and bladder (KUB) study revealed left renal stones. The abnormal D-dimer level and progressive symptoms alerted emergency physicians to intervene timely. The computed tomography (CT) scan revealed a giant adrenal mass with retroperitoneal hemorrhage. After hemodynamically controlled and surgical intervention, she recovered and was followed up at the outpatient department (OPD). In this article, we highlight that myelolipoma-induced spontaneous retroperitoneal hemorrhage may cause Wunderlich’s syndrome and lead to hypovolemic shock. It is important for emergency physicians to intervene timely. Early diagnosis and management lead to a better outcome

Klebsiella pneumoniae-Induced Multiple Infections in a Diabetes Mellitus Patient: Pneumonia, Liver Abscess, Endogenous Endophthalmitis, Urinary Tract Infection

Klebsiella pneumoniae-induced endogenous endophthalmitis is a rare but devastating disease, which usually occurs in immunosuppressed patients. Poorly controlled diabetes mellitus is a significant risk factor for this disease. The most common distant infection in patients with K. pneumoniae-induced endogenous endophthalmitis was reported to be liver abscess. Other less commons distant infections were found to be catheter-related bloodstream infection, urinary tract infection, soft tissue infection, renal and psoas abscesses, and endocarditis. Patients with coexisting multiple infection sites are rare according to previous studies. These patients may have a high risk of sepsis and death. Here, we present a case of a 64-year-old male who presented with a progressive visual disturbance with general malaise. A K. pneumoniae-induced endogenous endophthalmitis was suspected. After surveying distant infection sites, pneumonia, liver abscess, and urinary tract infection were reported. This paper also describes the clinical features of endogenous endophthalmitis and highlights K. pneumoniae-induced multiple infections in a diabetes mellitus patient, thus providing information that will be useful for physicians to perform timely interventions and avoid sepsis

The Oxidative Stress and Mitochondrial Dysfunction during the Pathogenesis of Diabetic Retinopathy

Diabetic retinopathy is one of the most serious microvascular complications induced by hyperglycemia via five major pathways, including polyol, hexosamine, protein kinase C, and angiotensin II pathways and the accumulation of advanced glycation end products. The hyperglycemia-induced overproduction of reactive oxygen species (ROS) induces local inflammation, mitochondrial dysfunction, microvascular dysfunction, and cell apoptosis. The accumulation of ROS, local inflammation, and cell death are tightly linked and considerably affect all phases of diabetic retinopathy pathogenesis. Furthermore, microvascular dysfunction induces ischemia and local inflammation, leading to neovascularization, macular edema, and neurodysfunction, ultimately leading to long-term blindness. Therefore, it is crucial to understand and elucidate the detailed mechanisms underlying the development of diabetic retinopathy. In this review, we summarized the existing knowledge about the pathogenesis and current strategies for the treatment of diabetic retinopathy, and we believe this systematization will help and support further research in this area

Epithelial to Mesenchymal Transition and Cell Biology of Molecular Regulation in Endometrial Carcinogenesis

Endometrial carcinogenesis is involved in several signaling pathways and it comprises multiple steps. The four major signaling pathways—PI3K/AKT, Ras/Raf/MEK/ERK, WNT/β-catenin, and vascular endothelial growth factor (VEGF)—are involved in tumor cell metabolism, growth, proliferation, survival, and angiogenesis. The genetic mutation and germline mitochondrial DNA mutations also impair cell proliferation, anti-apoptosis signaling, and epithelial–mesenchymal transition by several transcription factors, leading to endometrial carcinogenesis and distant metastasis. The PI3K/AKT pathway activates the ransforming growth factor beta (TGF-β)-mediated endothelial-to-mesenchymal transition (EMT) and it interacts with downstream signals to upregulate EMT-associated factors. Estrogen and progesterone signaling in EMT also play key roles in the prognosis of endometrial carcinogenesis. In this review article, we summarize the current clinical and basic research efforts regarding the detailed molecular regulation in endometrial carcinogenesis, especially in EMT, to provide novel targets for further anti-carcinogenesis treatment