Novel antigens for targeted radioimmunotherapy in hepatocellular carcinoma.

Liver cancer is the sixth common cancer and forth cause of cancer-related death worldwide. Based on usually advanced stages of hepatocellular carcinoma (HCC) at the time of diagnosis, therapeutic options are limited and, in many cases, not effective, and typically result in the tumor recurrence with a poor prognosis. Radioimmunotherapy (RIT) offers a selective internal radiation therapy approach using beta or alpha emitting radionuclides conjugated with tumor-specific monoclonal antibodies (mAbs), or specific selective peptides. When compared to chemotherapy or radiotherapy, radiolabeled mAbs against cancer-associated antigens could provide a high therapeutic and exclusive radiation dose for cancerous cells while decreasing the exposure-induced side effects to healthy tissues. The recent advances in cancer immunotherapy, such as blockade of immune-checkpoint inhibitors (ICIs), has changed the landscape of cancer therapy, and the efficacy of different classes of immunotherapy has been tested in many clinical trials. Taking into account the use of ICIs in the liver tumor microenvironment, combined therapies with different approaches may enhance the outcome in the future clinical studies. With the development of novel immunotherapy treatment options in the recent years, there has been a great deal of information about combining the diverse treatment modalities to boost the effectiveness of immunomodulatory drugs. In this opinion review, we will discuss the recent advancements in RIT. The current status of immunotherapy and internal radiotherapy will be updated, and we will propose novel approaches for the combination of both techniques. Potential target antigens for radioimmunotherapy in Hepatocellular carcinoma (HCC). HCC radioimmunotherapy target antigens are the most specific and commonly accessible antigens on the surface of HCC cells. CTLA-4 ligand and receptor, TAMs, PD-1/PD-L, TIM-3, specific IEXs/TEXs, ROBO1, and cluster of differentiation antigens CD105, CD147 could all be used in HCC radioimmunotherapy. Abbreviations: TAMs, tumor-associated macrophages; CTLA-4, cytotoxic T-lymphocyte associated antigen-4; PD-1, Programmed cell death protein 1; PD-L, programmed death-ligand1; TIM-3, T-cell immunoglobulin (Ig) and mucin-domain containing protein-3; IEXs, immune cell-derived exosomes; TEXs, tumor-derived exosomes.

3D modeling in cancer studies.

The tumor microenvironment contributes significantly to tumor initiation, progression, and resistance to chemotherapy. Much of our understanding of the tumor and its microenvironment is developed using various methods of cell culture. Throughout the last two decades, research has increasingly shown that 3D cell culture systems can remarkably recapitulate the complexity of tumor architecture and physiology compared to traditional 2D models. Unlike the flat culture system, these novel models enabled more cell-cell and cell-extracellular matrix interactions. By mimicking in vivo microenvironment, 3D culture systems promise to become accurate tools ready to be used in diagnosis, drug screening, and personalized medicine. In this review, we discussed the importance of 3D culture in simulating the tumor microenvironment and focused on the effects of cancer cell-microenvironment interactions on cancer behavior, resistance, proliferation, and metastasis. Finally, we assessed the role of 3D cell culture systems in the contexts of drug screening. 2D culture system is used to study cancer cell growth, progression, behavior, and drug response. It provides contact between cells and supports paracrine crosstalk between host cells and cancer cells. However, this system fails to simulate the architecture and the physiological aspects of in vivo tumor microenvironment due to the absence of cell-cell/ cell-ECM interactions as well as unlimited access to O2 and nutrients, and the absence of tumor heterogeneity. Recently advanced research has led researchers to generate 3D culture system that can better recapitulate the in vivo environment by providing hypoxic medium, facilitating cell-cell and cell-ECM, interactions, and recapitulating heterogeneity of the tumor. Several approaches are used to maintain and expand cancer cells in 3D culture systems such as tumor spheroids (cell aggregate that mimics the in vivo growth of tumor cells), scaffold-based approaches, bioreactors, microfluidic derives, and organoids. 3D systems are currently used for disease modeling and pre-clinical drug testing.

Nicotine and modafinil combination protects against the neurotoxicity induced by 3,4-Methylenedioxymethamphetamine in hippocampal neurons of male rats.

MDMA (3,4-Methylenedioxymethamphetamine) is a common recreational drug of abuse which causes neurodegeneration. Nicotine and modafinil provide antioxidant and neuroprotective properties and may be beneficial in the management of MDMA-induced neurotoxicity. The purpose of this study was to characterize how acute and chronic administration of nicotine and/or modafinil exert protective effects against the MDMA-induced impaired cognitive performance, oxidative stress, and neuronal loss. Adult male rats were divided into three groups, namely control, MDMA and treatment (modafinil and/or nicotine). MDMA (10 mg/kg) was administered intraperitoneally during a three-week schedule (two times/day for two consecutive days/week). The treated-groups were classified based on the acute or chronic status of treatment. In the groups which underwent acute treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected just prior to the MDMA administration (acute nicotine (NA), acute modafinil (MA), and acute nicotine and modafinil (NMA)). In the rats which received chronic treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected every day during the three week-schedule administration of MDMA (chronic nicotine (NC), chronic modafinil (MC), and chronic nicotine and modafinil (NMC)). Learning and memory performance, as well as avoidance response, were assessed by Morris water maze and Shuttle box, respectively. Our findings indicate enhanced learning and memory and avoidance response in the NMC group. By TUNEL test and Cresyl Violet staining we evaluated neuronal loss and apoptosis in the hippocampal CA1 and found increased neuronal viability in the NMC group. On the other hand, chronic administration of modafinil and nicotine significantly down-regulated the caspase 3 and up-regulated both BDNF and TrkB levels in the MDMA-received rats. The serum levels of glutathione peroxidase (GPx) and total antioxidant capacity (TAC) were evaluated and we found that the alterations of serum levels of GPx and TAC were considerably prevented in the NMC group. The overall results indicate that nicotine and modafinil co-administration rescued brain from MDMA-induced neurotoxicity. We suggest that nicotine and modafinil combination therapy could be considered as a possible treatment to reduce the neurological disorders induced by MDMA.

The Interplay of Tau Protein and ß-Amyloid: While Tauopathy Spreads More Profoundly Than Amyloidopathy, Both Processes Are Almost Equally Pathogenic.

Alzheimer's disease (AD) is a neurodegenerative disorder, in which amyloid precursor protein (APP) misprocessing and tau protein hyperphosphorylation are well-established pathogenic cascades. Despite extensive considerations, the central mediator of neuronal cell death upon AD remains under debate. Therefore, we examined the direct interplay between tauopathy and amyloidopathy processes. We employed primary culture neurons and examined pathogenic P-tau and Aß oligomers upon hypoxia treatment by immunofluorescence and immunoblotting. We observed both tauopathy and amyloidopathy processes upon the hypoxia condition. We also applied Aß1-42 or P-tau onto primary cultured neurons. We overexpressed P-tau in SH-SY5Y cells and found Aß accumulation. Furthermore, adult male rats received Aß1-42 or pathogenic P-tau in the dorsal hippocampus and were examined for 8 weeks. Learning and memory performance, as well as anxiety behaviors, were assessed by Morris water maze and elevated plus-maze tests. Both Aß1-42 and pathogenic P-tau significantly induced learning and memory deficits and enhanced anxiety behavior after treatment 2 weeks. Aß administration induced robust tauopathy distribution in the cortex, striatum, and corpus callosum as well as CA1. On the other hand, P-tau treatment developed Aß oligomers in the cortex and CA1 only. Our findings indicate that Aß1-42 and pathogenic P-tau may induce each other and cause almost identical neurotoxicity in a time-dependent manner, while tauopathy seems to be more distributable than amyloidopathy.