Tumor treating fields induced senescence on glioblastoma.

Innovative approaches have given rise to a method for treating newly diagnosed GBM cancer patients within a span of 4.9 months, resulting in improved median overall survival (OS) and minimal side effects during the phase III clinical trial. This approach is referred to as Tumor Treating Fields (TTFields). The objective of this study is to ascertain the potential of TTFields treatment in sensitizing GBM cancer cells by enhancing TTFields-induced senescence. To achieve this, the research employed a multifaceted methodology that encompassed several elements, including the analysis of SA-ß-gal staining, flow cytometry, Western blotting, morphology assessment, Positron Emission Tomography (PET)/Computed Tomography (CT), immunohistochemical staining, and microassay. Over a period of up to 5 days, the number of cells exhibiting senescence-specific morphology and positive SA-ß-Gal activity progressively increased. These findings indicate that p16, p21, p27 and pRB are pivotal regulators of TTFields-induced senescence through NF-κB activation. The outcomes reveal that TTFields treatment effectively promotes TTFields-induced senescence in GBM cells through a mechanism independent of apoptosis. In conclusion, this research underscores the viability of this treatment approach as a reliable protocol to address the limitations associated with the conventional GBM treatment.

Polydeoxyribonucleotide and Shock Wave Therapy Sequence Efficacy in Regenerating Immobilized Rabbit Calf Muscles.

This study primarily aimed to investigate the combined effects of polydeoxyribonucleotide (PDRN) and extracorporeal shock wave therapy (ESWT) sequences on the regenerative processes in atrophied animal muscles. Thirty male New Zealand rabbits, aged 12 weeks, were divided into five groups: normal saline (Group 1), PDRN (Group 2), ESWT (Group 3), PDRN injection before ESWT (Group 4), and PDRN injection after ESWT (Group 5). After 2 weeks of cast immobilization, the respective treatments were administered to the atrophied calf muscles. Radial ESWT was performed twice weekly. Calf circumference, tibial nerve compound muscle action potential (CMAP), and gastrocnemius (GCM) muscle thickness after 2 weeks of treatment were evaluated. Histological and immunohistochemical staining, as well as Western blot analysis, were conducted 2 weeks post-treatment. Staining intensity and extent were assessed using semi-quantitative scores. Groups 4 and 5 demonstrated significantly greater calf muscle circumference, GCM muscle thickness, tibial nerve CMAP, and GCM muscle fiber cross-sectional area (type I, type II, and total) than the remaining three groups (p < 0.05), while they did not differ significantly in these parameters. Groups 2 and 3 showed higher values for all the mentioned parameters than Group 1 (p < 0.05). Group 4 had the greatest ratio of vascular endothelial growth factor (VEGF) to platelet endothelial cell adhesion molecule-1 (PECAM-1) in the GCM muscle fibers compared to the other four groups (p < 0.05). Western blot analysis revealed significantly higher expression of angiogenesis cytokines in Groups 4 and 5 than in the other groups (p < 0.05). The combination of ESWT and PDRN injection demonstrated superior regenerative efficacy for atrophied calf muscle tissue in rabbit models compared to these techniques alone or saline. In particular, administering ESWT after PDRN injection yielded the most favorable outcomes in specific parameters.

Effectiveness of tumor­treating fields to reduce the proliferation and migration of liposarcoma cell lines.

Liposarcoma (LPS) is a rare type of soft tissue sarcoma that constitutes 20% of all sarcoma cases in adults. Effective therapeutic protocols for human LPS are not well-defined. Tumor-treating fields (TTFields) are a novel and upcoming field for antitumor therapy. TTFields combined with chemoradiotherapy have proven to be more effective than TTFields combined with radiotherapy or chemotherapy alone. The present study aimed to assess the effectiveness of TTFields in inhibiting cell proliferation and viability for the anticancer treatment of LPS. The present study used TTFields (frequency, 150 kHz; intensity, 1.0 V/cm) to treat two LPS cell lines (94T778 and SW872) and analyzed the antitumor effects. According to trypan blue and MTT assay results, TTFields markedly reduced the viability and proliferation of LPS cell lines along with the formation of colonies in three-dimensional culture. Based on the Transwell chamber assay, TTFields treatment also markedly reduced the migration of LPS cells. Furthermore, as shown by the higher activation of caspase-3 in the Caspase-3 activity assay and the results of the reactive oxygen species (ROS) assay, TTFields increased the formation of ROS in the cells and enhanced the proportion of apoptotic cells. The present study also investigated the inhibitory effect of TTFields in combination with doxorubicin (DOX) on the migratory capacity of tumor cells. The results demonstrated that TTFields treatment synergistically induced the ROS-induced apoptosis of LPS cancer cell lines and inhibited their migratory behavior. In conclusion, the present study demonstrated the potential of TTFields in improving the sensitivity of LPS cancer cells, which may lay the foundation for future clinical trials of this combination treatment strategy.

Capacitive Electrode-Based Electric Field Treatments on Redox-Toxic Iron Deposits in Transgenic AD Mouse Models: The Electroceutical Targeting of Alzheimer's Disease Feasibility Study.

Iron accumulation in the brain accelerates Alzheimer's disease progression. To cure iron toxicity, we assessed the therapeutic effects of noncontact transcranial electric field stimulation to the brain on toxic iron deposits in either the Aß fibril structure or the Aß plaque in a mouse model of Alzheimer's disease (AD) as a pilot study. A capacitive electrode-based alternating electric field (AEF) was applied to a suspension of magnetite (Fe3O4) to measure field-sensitized reactive oxygen species (ROS) generation. The increase in ROS generation compared to the untreated control was both exposure-time and AEF-frequency dependent. The frequency-specific exposure of AEF to 0.7-1.4 V/cm on a magnetite-bound Aß-fibril or a transgenic Alzheimer's disease (AD) mouse model revealed the degradation of the Aß fibril or the removal of the Aß-plaque burden and ferrous magnetite compared to the untreated control. The results of the behavioral tests show an improvement in impaired cognitive function following AEF treatment on the AD mouse model. Tissue clearing and 3D-imaging analysis revealed no induced damage to the neuronal structures of normal brain tissue following AEF treatment. In conclusion, our results suggest that the effective degradation of magnetite-bound amyloid fibrils or plaques in the AD brain by the electro-Fenton effect from electric field-sensitized magnetite offers a potential electroceutical treatment option for AD.

Emodin coupled with high LET neutron beam-a novel approach to treat on glioblastoma.

The primary motivation of this investigative study is trying to find an alternative treatment that can be used to slow down or treat glioblastoma due to the witnessed toxic side effects of the current drugs coupled with limited effectiveness in overall treatment. Consequently, a Chinese plant extract emodin proves to play a critical role in this investigative study since results from the Western blot and the other accompanying assays for anti-cancer effects indicate that it cannot work a lot to suppress cell migration and possible invasion, but rather emodin can be combined with radiation to give desired outcomes. Our result shows that the kind of radiation which acts well with emodin is neutron radiation rather than gamma radiation. Emodin significantly enhanced the radiosensitivity of LN18 and LN428 cells to γ-rays through MTT assay and cell counting. Accordingly, exposure to neutron radiation in the presence of emodin induced apoptotic cell death and autophagic cell death to a significantly higher extent, and suppressed cell migration and invasiveness more robustly. These effects are presumably due to the ability of emodin to amplify the effective dose from neutron radiation more efficiently. Thus, the study below is one such trial towards new interventional discovery and development in relation to glioblastoma treatment.

Effects of gold nanoparticles on normal hepatocytes in radiation therapy.

Background: Gold nanoparticles (GNP, AuNPs) have received much attention as a tool to improve the therapeutic index of radiation therapy. This study aimed to evaluate the normal in vitro toxicity of AuNPs at kilovoltage energies on hepatocytes to provide scientific support for using AuNPs with radiotherapy. Methods: Using the same treatment protocol applied to tumor cell lines, hepatocytes were exposed to AuNPs and/or radiation at various time points. Results: The combination of X-ray irradiation and AuNPs did not have any significant effect on cell survival and apoptosis in normal hepatocytes. Furthermore, the combination treatment resulted in no or little change in the level of gamma-H2A histone family member X (γ-H2AX), a marker for DNA double-strand breaks (DSB), nor on the proportion of cells in the G2/M phase. Additionally, interleukin-8 (IL-8) secretion was measured using an enzyme-linked immunosorbent assay (ELISA) to assess its role in tumor progression and angiogenesis. The combination of irradiation and AuNP treatment revealed no significant reduction in hepatocyte viability, proliferation, or secretory capacity compared to cells receiving either treatment alone. According to this study, AuNPs in combination with radiation do have potentially in the treatment of hepatocellular carcinoma (HCC) with no critical cytotoxicity on normal tissue. Conclusions: Therefore, it is postulated that radiation and AuNPs are an effective combination therapy against HCC with no little cytotoxic effects on normal tissue, a hypothesis which warrants further investigation in in vivo, as well as in in vitro.

Tumor-treating fields in combination with sorafenib curtails the growth of colorectal carcinoma by inactivating AKT/STAT3 signaling.

Background: Tumor-treating fields (TTFields) have been extensively used to treat various cancers as well as glioblastoma multiforme (GBM), owing to their antimitotic effects. Furthermore, sorafenib is also extensively used to treat hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) and is under phase II/III clinical trials for other solid tumors. Hence, this investigation aimed to assess the efficacy of combination therapy with TTFields and sorafenib for colorectal carcinoma (CRC). Methods: Human CRC HCT116 and SW480 cells were subjected to cell viability assay, followed by the assessment of their cell death using fluorescence-activated cell sorting (FACS) analysis. Furthermore, the expression of proteins involved in AKT/STAT3 signaling and apoptosis was assessed via western blotting. Results: Combination treatment inhibited cell proliferation and induced apoptosis via Reactive oxygen species (ROS) generation, evident from caspase-3 cleavage in CRC cells and suppressed the AKT/STAT3 signaling pathway, as evident from downregulation of BCL-2 after post-treatment. The present results indicate that combination treatment with TTFields and sorafenib inactivates AKT/STAT3 signaling pathway, thus altering the expression of BCL-2, thus inducing apoptosis and inhibiting the growth of CRC cells. Conclusions: Thus, combination treatment with TTFields and sorafenib is clinically applicable for treating metastatic CRC, although safety examination in patients with CRC will required to be achieved before this protocol can be implemented clinically for TTFields-sensitizer.

Tumor-treating fields in combination with sorafenib restrain the proliferation of liver cancer in vitro.

Liver cancer is a common malignancy worldwide, with a poor prognosis and a high recurrence rate despite the available treatment methodologies. Tumor-treating fields (TTFields) have shown good preclinical and clinical results for improving the prognosis of patients with glioblastoma and malignant pleural mesothelioma. However, there is minimal evidence for the effect of TTFields on other cancer types. Thus, the present study aimed to investigate the therapeutic efficacy of TTFields in an in vitro model, and to further elucidate the underlying mechanisms. In the present study, two hepatocellular carcinoma (HCC) cell lines (Hep3B and HepG2) were treated with TTFields (intensity, 1.0 V/cm; frequency, 150 kHz) in order to determine the potential antitumor effects of this approach. TTFields significantly inhibited the proliferation and viability of HCC cell lines, as measured using Trypan blue and MTT assays, as well as colony formation in three-dimensional cultures. The TTFields also significantly inhibited the migration and invasion of HCC cells in Transwell chamber and wound-healing assays. Moreover, TTFields enhanced the production of reactive oxygen species in the cells and increased the proportion of apoptotic cells, as evidenced by increased caspase-3 activity, as well as PARP cleavage in western blotting experiments. All of these effects were increased following the application of TTFields in combination with the multi-kinase inhibitor sorafenib, which demonstrated a synergistic effect. Thus, to the best of our knowledge, these results demonstrate for the first time the potential of TTFields in improving the sensitivity of HCC cells to sorafenib, which may lay the foundation for future clinical trials for this combination treatment strategy.

Combination therapy of Doxorubicin with TTFields and radiation: newer approaches to combat lung cancer.

BACKGROUND: Tumor-treating fields (TTFields) have been used singly or with chemoradiation for treating glioblastoma and mesothelioma but not yet for lung cancer. Survival rates in lung cancer remain abysmal despite advances in early diagnosis and targeted therapies. AIMS AND OBJECTIVES: We aimed to investigate the effectiveness of TTFields in inhibiting lung cancer growth and metastasis, as well as the therapeutic effectiveness of TTFields alongside radiation and chemosensitivity-enhancing agents in an in vitro model. METHODS: We generated TTFields yielding 0-800 V sine-wave signals, 0.9 V/cm applied electric field intensity, and 150 kHz frequency. The human lung cancer cell lines A549 and H460 were used in this study. Cell viability, colony formation, cell death detection, and cell invasion assays were performed to assess the therapeutic effectiveness of TTFields; sensitization of lung cancer cells to TTFields by doxorubicin (DOX); and the combined effect of TTFields, DOX, and irradiation (IR). RESULTS: Lung cancer cells showed a nearly 20% decrease in cell viability at 1 V/cm and 150 kHz. In A549 and H460 cells, TTFields increased apoptosis through increased cleaved caspase3, hindered cell migration and invasion, and improved chemosensitivity to DOX. The combination of DOX and TTFields showed better antitumor results than those of each individually. However, the DOX/TTFields/IR combination was most effective in reducing the viability and migration of lung cancer cells. CONCLUSION: TTFields as an adjuvant therapy offers probability for improving lung cancer patient outcomes.

Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects.

Glioblastoma is a deadly cancer tumor in the brain and has a survival rate of about 15 months. Despite the high mortality rate, temozolomide has proven to increase the survival rate of patients when combined with radiotherapy. However, its effects may be limited because some patients develop therapeutic resistance. Curcumin has proven to be a cancer treatment due to its broad anticancer spectrum, high efficiency and low toxic level. Additionally, curcumin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, curcumin increased the cell population in the sub-G1 phase and the reactive oxygen species (ROS) level, ultimately increasing GBM cellular apoptosis. The radiosensitizing effects of curcumin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Curcumin plus neutron combination significantly inhibited cell invasion compared with that of single treatment or curcumin combined γ-ray treatment. Curcumin enhances the radiosensitivity of Glioblastoma (GBM), suggesting it may have clinical utility in combination cancer treatment with neutron high-LET radiation.

CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer. MATERIALS AND METHODS: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied. RESULTS: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone. CONCLUSION: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer.

Enhanced proton treatment with a LDLR-ligand peptide-conjugated gold nanoparticles targeting the tumor microenvironment in an infiltrative brain tumor model.

The tumor microenvironment (TME) of glioblastoma malforms (GBMs) contains tumor invasiveness factors, microvascular proliferation, migratory cancer stem cells and infiltrative tumor cells, which leads to tumor recurrence in the absence of effective drug delivery in a Blood Brain Barrier (BBB)-intact TME and radiological invisibility. Low-density lipoprotein receptor (LDLR) is abundant in the blood brain barrier and overexpressed in malignant glioma cells. This study aimed to treat the TME with transmitted proton sensitization of LDLR ligand-functionalized gold nanoparticles (ApoB@AuNPs) in an infiltrative F98 glioma rat model. BBB-crossing ApoB@AuNPs were selectively taken up in microvascular endothelial cells proliferation and pericyte invasion, which are therapeutic targets in the glioma TME. Proton sensitization treated the TME and bulk tumor volume with enhanced therapeutic efficacy by 67-75% compared to that with protons alone. Immunohistochemistry demonstrated efficient treatment of endothelial cell proliferation and migratory tumor cells of invasive microvessels in the TME with saving normal tissues. Taken together, these data indicate that the use of LDLR ligand-functionalized gold nanoparticles is a promising strategy to treat infiltrative malignant glioma while overcoming BBB crossing.

Tumor-treating fields as a proton beam-sensitizer for glioblastoma therapy.

Few advances in GBM treatment have been made since the initiation of the Stupp trials in 2005. Experimental studies on immunotherapy drugs, molecular inhibitors, radiation dosage escalation and vascular growth factor blockers have all failed to provide satisfactory outcomes. TTFields therapy, on the other hand, have emerged as a viable substitute to therapies like radiation in GBM patients having a highly immunosuppressive tumor microenvironment. To enhance the biofunctional impacts, we explored the combination events with TTFields and proton treatment in this study. We conducted a cell viability test, a cell death detection evaluation, a ROS analysis, a three-dimensional (3D) culture system, and a migration assay. The combination of proton radiation and TTFields therapy laid a substantial anticancer impact on the F98 and U373 as compared to the consequences of either of these therapies used separately. The combination proton beam therapy used by TTFields was very successful in curbing GBM from migrating. GBM cell metastasis is restricted by TTFields combined proton by downregulating the MAPK, NF-κB, and PI3K/AKT indicating pathways, caused by reduced EMT marker expression. These findings furnish biological proof for the molecular grounds of TTFields in combination with proton used for GBM therapy.

Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response.

High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth.

Tumor treating fields can effectively overcome trastuzumab resistant breast cancer multiplication.

The Human Epidermal Growth Receptor 2, or the HER2 is one of the highest expressed negative receptor that constitutes approximately 15-20% of malevolent breast cancerous tumors among women. The prevalence of HER2 has untimely and unfavorable consequences on breast cancer, and its underlying carcinomous cell processes, structures, and growth. Trastuzumab (TRZ), a humanized antibody that is rooted in relatively recent foundations, has been found operational in its construction of treatments against HER2-positive breast cancer. This drug is combined with radiotherapy or chemotherapy to deregulate HER2 genes in the body. However, patients who suffer from evolved tumors in advanced stages of cancer exhibit a good amount of tolerance towards singularly used TRZ treatment. Inversely, the factorization of Tumor Testing Fields (TTFields or TTFs) into cancer therapy revives the functions of a TRZ treatment plan, by sensitizing the HER2 genes to the drug. In turn, this facilitates TRZ to continue limiting cancerous cell multiplication and toxicity levels within the treatment. This research evaluates the aspects and effects of this pairing, both in vivo and in vitro through BT474 cells. The TTFields conduct an electromagnetic boundary, which generates sine-wave radiations to manipulate the HER2 gene structure. The methods followed in the research also examines the gene cell cultures and their viability through solutions like Tryptophan blue, or the Crystal violet which may or may not deliver certain testmants to the experiment. The Western Blot Test and the IHC confirm the presence of antibodies and negative receptors in the BT474 cells. These procedures contribute to the formulation of a treatment plan that overcomes the TRZ-resistant nature of the tumor, which is essentially the aim of the research. Thus, the paper substantiates that a healthy combination of TTF's with TRZ can enhance the penetration of TRZ after inducing apoptosis due to TTFields therapy. The success of a TTField in undertaking this pursuit makes room for more utilization of it in future cancerous treatment ventures.

Carbon-Ion Beam Irradiation and the miR-200c Mimic Effectively Eradicate Pancreatic Cancer Stem Cells Under in vitro and in vivo Conditions.

PURPOSE: The study investigated the molecular mechanisms that killed pancreatic cancer cells, including cancer stem cells (CSCs), by carbon ion beam irradiation alone or in combination with miRNA-200c under in vitro and in vivo conditions. METHODS: Human pancreatic cancer (PC) cells, PANC1 and PK45, were treated with carbon-ion beam irradiation alone or in combination with microRNA-200c (miR-200c) mimic. Cell viability assay, colony and spheroid formation assay, quantitative real-time PCR analysis of apoptosis-, autophagy-, and angiogenesis-related gene expression, xenograft tumor control and histopathological analyses were performed. RESULTS: The cell viability assay showed that transfection of the miRNA-200c (10 nM) mimic into pancreatic CSC (CD44+/ESA+) and non-CSC (CD44-/ESA-) significantly suppressed proliferation of both types of cell populations described above. Combining carbon-ion beam irradiation with the miRNA-200c mimic significantly reduced the colony as well as spheroid formation abilities compared to that observed with the treatment of carbon-ion beam alone or X-ray irradiation combined with the miRNA-200c mimic. Moreover, the combination of carbon ion beam irradiation and miRNA-200c mimic increased the expression of apoptosis-related gene BAX, autophagy-related genes Beclin-1 and p62, addition of gemcitabine (GEM) further enhanced the expression of these genes. In vivo data showed that carbon-ion beam irradiation in combination with the miRNA-200c mimic effectively suppressed xenograft tumor growth and significantly induced tumor necrosis and cavitation. CONCLUSION: The combination of miRNA-200c mimic and carbon ion beam irradiation may be powerful radiotherapy that significantly kills pancreatic cancer cells containing CSCs and enhances the effect of carbon-ion beam irradiation compared to carbon-ion beam irradiation alone.

Mutation SVCT2 promotes cell proliferation, invasion and migration in colorectal cancer.

The sodium-dependent vitamin C transporter 2 (SVCT2) surface glycoprotein regulates ascorbate accumulation in the plasma, often resulting in the induction of cancer cell death. Therefore, high expression of this gene associates with increased overall survival in several cancers. However, in colorectal cancer (CRC), high (likely mutated) SVCT2 expression relates to poor overall survival, and its functional significance has not been studied. Thus, we hypothesize that mutant SVCT2 expression could affect CRC patient survival. According to biological databases, SVCT2 has been found to be mutated frequently, and SVCT2 E264K has a particularly high pathogenic score (0.98), compared to other SVCT2 mutant sites, in CRC patients. Interestingly, our results reveal expression of SVCT2 E264K in many CRC tissues and cells. Also, we found wild-type SVCT2 expression to be largely localized to the cytoplasm and membrane, while SVCT2 E264K was restricted to the cytoplasm. We further found that SVCT2 E264K overexpression increases cell growth. By contrast, SVCT2 E264K knockdown significantly reduced cell proliferation and promoted cell apoptosis, resulting in inhibition of cell invasion and migration. Taken together, SVCT2 E264K plays a critical role in proliferation in CRC. Our results suggest that SVCT2 E264K could be a promising novel therapeutic target in CRC.

Signal Enhancement of Low Magnetic Field Magnetic Resonance Image Using a Conventional- and Cyclic-Generative Adversarial Network Models With Unpaired Image Sets.

In this study, the signal enhancement ratio of low-field magnetic resonance (MR) images was investigated using a deep learning-based algorithm. Unpaired image sets (0.06 Tesla and 1.5 Tesla MR images for different patients) were used in this study following three steps workflow. In the first step, the deformable registration of a 1.5 Tesla MR image into a 0.06 Tesla MR image was performed to ensure that the shapes of the unpaired set matched. In the second step, a cyclic-generative adversarial network (GAN) was used to generate a synthetic MR image of the original 0.06 Tesla MR image based on the deformed or original 1.5 Tesla MR image. Finally, an enhanced 0.06 Tesla MR image could be generated using the conventional-GAN with the deformed or synthetic MR image. The results from the optimized flow and enhanced MR images showed significant signal enhancement of the anatomical view, especially in the nasal septum, inferior nasal choncha, nasopharyngeal fossa, and eye lens. The signal enhancement ratio, signal-to-noise ratio (SNR) and correlation factor between the original and enhanced MR images were analyzed for the evaluation of the image quality. A combined method using conventional- and cyclic-GANs is a promising approach for generating enhanced MR images from low-magnetic-field MR.

Role of p53 in transcriptional repression of SVCT2.

SVCT2, Sodium-dependent Vitamin C Transporter 2, uniquely transports ascorbic acid (also known as vitamin C and ascorbate) into all types of cells. Vitamin C is an essential nutrient that must be obtained through the diet and plasma levels are tightly regulated by transporter activity. Vitamin C plays an important role in antioxidant defenses and is a cofactor for many enzymes that enable hormone synthesis, oxygen sensing, collagen synthesis and epigenetic pathways. Although SVCT2 has various functions, regulation of its expression/activity remains poorly understood. We found a p53-binding site, within the SVCT2 promoter, using a transcription factor binding-site prediction tool. In this study, we show that p53 can directly repress SVCT2 transcription by binding a proximal- (~-185 to -171 bp) and a distal- (~-1800 to -1787 bp) p53-responsive element (PRE), Chromatin immunoprecipitation assays showed that PRE-bound p53 interacts with the corepressor-histone deacetylase 3 (HDAC3), resulting in deacetylation of histones Ac-H4, at the proximal promoter, resulting in transcriptional silencing of SVCT2. Overall, our data suggests that p53 is a potent transcriptional repressor of SVCT2, a critical transporter of diet-derived ascorbic acid, across the plasma membranes of numerous essential tissue cell types.

CXCR4 uses STAT3-mediated slug expression to maintain radioresistance of non-small cell lung cancer cells: emerges as a potential prognostic biomarker for lung cancer.

Lung cancer is one of the most common reasons for cancer-induced mortality across the globe, despite major advancements in the treatment strategies including radiotherapy and chemotherapy. Existing reports suggest that CXCR4 is frequently expressed by malignant tumor and is imperative for vascularization, tumor growth, cell migration, and metastasis pertaining to poor prognosis. In this study, we infer that CXCR4 confers resistance to ionizing radiation (IR) in nonsmall cell lung cancer (NSCLC) cells. Further, on the basis of colony forming ability, one finds that drug-resistant A549/GR cells with improved CXCR4 expression exhibited more resistance to IR than A549 cells evidenced along with a reduction in the formation of γ-H2AX foci after IR. Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR. Conversely, the overexpression of CXCR4 in A549 and H460 cell lines was found to improve clonogenic survival, and reduce the formation of γ-H2AX foci after IR. CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.