Thymidine kinase 1 (TK1) is a proliferation biomarker
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Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignan... - 0 views
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TK1 LI was found to be a more reliable prognostic marker for 5-year survival than pathological stages, FIGO stages and Ki-67,
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nuclear TK1 expression is a reliable prognostic factor in CIN patients, a group of cervical lesion patients that respond positively to treatment
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low TK1 expression in the tumors in these patients might indicate that these tumors have a lower proliferation rate
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TK1 is a key kinase in the one-step salvage pathway by which thymidine is introduced into DNA via the salvage pathway
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TK1 participates in DNA synthesis and is therefore closely related to the S-phase of the cell cycle, and is correlated with proliferation
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TK1 intensity (TK1 synthesis rate) increases from CIN grade I to CIN grade III, but does not further increase in invasive cervical carcinomas.
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TK1 intensity seems to be a prognostic factor particularly when pre-malignant cervical lesions progress to malignancy
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Vitamin C increases DNA breaks and suppresses DNA damage-independent activation of ATM ... - 0 views
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Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer - 0 views
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Previous studies from our laboratory have demonstrated that pharmacological ascorbate is cytotoxic to pancreatic cancer cells while normal cells are resistant
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Ascorbate-induced cytotoxicity is mediated by the formation of H2O2 during the oxidation of ascorbate
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Under steady-state conditions, intracellular GSH is maintained at millimolar concentrations, which keeps cells in a reduced environment and serves as the principal intracellular redox buffer when cells are subjected to an oxidative stressor including H2O2 (26). Glutathione peroxidase (GPx) activity catalyzes the reduction of H2O2 to water with the conversion of GSH to glutathione disulfide (GSSG). Under steady-state conditions, GSSG is recycled back to GSH by glutathione disulfide reductase using reducing equivalents from NADPH. However, under conditions of increased H2O2 flux, this recycling mechanism may become overwhelmed leading to a depletion of intracellular GSH (27, 28).
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ascorbate radiosensitization can create an overwhelming oxidative stress to pancreatic cancer cells resulting in oxidation/depletion of the GSH intracellular redox buffer, resulting in cell death.
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Treatment with the combination of ascorbate + IR significantly delayed tumor growth compared to controls or ascorbate alone
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Ascorbate + IR also significantly increased overall survival compared to controls, IR alone or ascorbate alone
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Glutathione is a measurable marker indicative of the oxidation state of the thiol redox buffer in cells. In severe systemic oxidative stress, the GSSG/2GSH couple may become oxidized, i.e. the concentration of GSH decreases and GSSG may increase because the capacity to recycle GSSG to GSH becomes rate-limiting
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This suggests that the very high levels of pharmacological ascorbate in these experiments may have a pro-oxidant toward red blood cells as seen by a decrease in the capacity of the intracellular redox buffer
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These data support the hypothesis that ascorbate radiosensitization does not cause an increase in oxidative damage from lipid-derived aldehydes to other organs.
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Our current study demonstrates the potential for pharmacological ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
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pharmacological ascorbate enhances IR-induced cell killing and DNA fragmentation leading to induction of apoptosis in HL60 leukemia cells
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pharmacological ascorbate significantly decreases clonogenic survival and inhibits the growth of all pancreatic cancer cell lines as a single agent, as well as sensitizes cancer cells to IR
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Hurst et al. demonstrated that pharmacological ascorbate combined with IR leads to increased numbers of double-strand DNA breaks and cell cycle arrest when compared to either treatment alone
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The combination of ascorbate and IR provide two distinct mechanisms of action: ascorbate-induced toxicity due to extracellular production of H2O2 that then diffuses into cells and causes damage to DNA, protein, and lipids; and radiation-induced toxicity as a result of ROS-induced damage to DNA. In addition, redox metal metals like Fe2+ may play an important role in ascorbate-induced cytotoxicity. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of H2O2; labile iron can also react with H2O2. Recently our group has demonstrated that pharmacological ascorbate and IR increase the labile iron in tumor homogenates from this murine model of pancreatic cancer
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we demonstrated that ascorbate or IR alone decreased tumor growth, but the combination treatment further inhibited tumor growth, indicating that pharmacological ascorbate is an effective radiosensitizer in vivo
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data suggest that pharmacological ascorbate may protect the gut locally by decreasing IR-induced damage to the crypt cells, and systemically, by ameliorating increases in TNF-α
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Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde... - 0 views
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Hydroxyl radicals cause oxidative damage to cells because they unspecifically attack biomolecules [22] located less than a few nanometres from its site of generation and are involved in cellular disorders such as neurodegeneration [23, 24], cardiovascular disease [25], and cancer [26, 27].
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It is generally assumed that in biological systems is formed through redox cycling by Fenton reaction, where free iron (Fe2+) reacts with hydrogen peroxide (H2O2) and the Haber-Weiss reaction that results in the production of Fe2+ when superoxide reacts with ferric iron (Fe3+)
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Lipid peroxidation can be described generally as a process under which oxidants such as free radicals or nonradical species attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs) that involve hydrogen abstraction from a carbon, with oxygen insertion resulting in lipid peroxyl radicals and hydroperoxides as described previously
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under medium or high lipid peroxidation rates (toxic conditions) the extent of oxidative damage overwhelms repair capacity, and the cells induce apoptosis or necrosis programmed cell death
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The overall process of lipid peroxidation consists of three steps: initiation, propagation, and termination
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Once lipid peroxidation is initiated, a propagation of chain reactions will take place until termination products are produced.
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Among the many different aldehydes which can be formed as secondary products during lipid peroxidation, malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal (4-HNE) have been extensively studied
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MDA has been widely used for many years as a convenient biomarker for lipid peroxidation of omega-3 and omega-6 fatty acids because of its facile reaction with thiobarbituric acid (TBA)
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MDA is one of the most popular and reliable markers that determine oxidative stress in clinical situations [53], and due to MDA’s high reactivity and toxicity underlying the fact that this molecule is very relevant to biomedical research community
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4-HNE is considered as “second toxic messengers of free radicals,” and also as “one of the most physiologically active lipid peroxides,” “one of major generators of oxidative stress,” “a chemotactic aldehydic end-product of lipid peroxidation,” and a “major lipid peroxidation product”
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Identifying in vivo MDA production and its role in biology is important as indicated by the extensive literature on the compound (over 15 800 articles in the PubMed database using the keyword “malondialdehyde lipid peroxidation” in December 2013)
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MAA adducts are shown to be highly immunogenic [177–181]. MDA adducts are biologically important because they can participate in secondary deleterious reactions (e.g., crosslinking) by promoting intramolecular or intermolecular protein/DNA crosslinking that may induce profound alteration in the biochemical properties of biomolecules and accumulate during aging and in chronic diseases
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Dietary intake of certain antioxidants such as vitamins was associated with reduced levels of markers of DNA oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells of healthy subjects, which could contribute to the protective role of vitamins on cancer risk
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Therapeutic hyperthermia: The old, the new, and the upcoming - Critical Reviews in Onco... - 1 views
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not well understood, but it is felt to be a combination of both heat-induced necrosis and of protein inactivation (e.g., repair enzymes) as opposed to DNA damage
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alterations in tumor cytoskeletal and membrane structures, which disrupt cell motility and intracellular signal transduction
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A common explanation for HT-enhancement of RT and CT involves inhibition of homologous recombination repair of double-strand DNA breaks, preventing cells from repairing sub-lethal damage
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it does appear to inhibit rejoining of RT-induced DNA breaks more than is commonly observed after RT alone
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HT damages cells and enhances RT and CT sensitivity as a function of both temperature and duration of treatment
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Cancer cells are particularly vulnerable to heating; in vivo studies have shown that temperatures in the range of 40–44 °C cause more selective damage to tumor cells
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selective cytotoxic effect on tumor cells include inhibition of key cancer cell-signaling pathways such as AKT, inducing apoptosis, suppression of cancer stem cell proliferation, and others
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increase in immunological attacks against tumors after HT, which were believed to be achieved through activation of HSPs and subsequent modulation of the innate and adaptive immune responses against tumor cells
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HT does lead to activation of the immune system and HSP-induced cell death through modification of the tumor cell surface
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These HSPs and tumor antigens are taken up by dendritic cells and macrophages and go on to induce specific anti-tumor immunity
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In vivo studies demonstrate HT-enhancement of NK cell activity, and HT has been shown to increase neutrophilic granulocytes with anti-tumor activity
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it has become increasingly clear that HT results in immune stimulation, through both direct heat-mediated cell killing as well as innate and adaptive immune system modulation
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The term hyperthermia is used in this review to refer to heating within the clinically accepted range of 40–45 °C
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temperatures above 42.5–43 °C the exposure time can be halved with each 1 °C increase while maintaining equivalent cell killing
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Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer ... - 0 views
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daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature
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chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks
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long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness
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both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds
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CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces
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the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis
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TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA
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HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells
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In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks
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Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy
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Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.
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daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD
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shared by Nathan Goodyear on 07 Feb 11
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Mitochondrial DNA damage and repair in neurodegene... [DNA Repair (Amst). 2008] - PubMe... - 0 views
www.ncbi.nlm.nih.gov/...18463003
mitochondria aging neurodegenerative disease Alzheimer's Parkinson's Huntington's ALS
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Natural inhibitors of poly(ADP-ribose) polymerase-1 - PubMed - 0 views
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Hyperthermia and Chemotherapy - Holland-Frei Cancer Medicine - NCBI Bookshelf - 0 views
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Brief review from book on severe hyperthermia and chemotherapy: The mechanisms that underlie the synergy may include (1) increased cellular uptake of drug, (2) increased oxygen radical production, and (3) increased DNA damage and inhibition of repair; potential use of HT with many drugs is its ability to reverse, at least partially, drug resistance
53BP1: Pro Choice in DNA Repair - 0 views
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shared by Nathan Goodyear on 14 Oct 13
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Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women - 0 views
www.ncbi.nlm.nih.gov/...PMC3283536
estrogen metabolism estrogen metabolism breast cancer breast cancer
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The ratio of the 2-hydroxylation pathway to parent estrogens was associated with a statistically significantly decreased risk of breast cancer
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In this study, this ratio was more strongly associated with the risk of breast cancer compared with the ratio of 2-hydroxylation pathway to 16-hydroxylation pathway or unconjugated estradiol alone
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2-hydroxylation pathway catechols have relatively low affinities for estrogen receptors (4) and are rapidly cleared from circulation
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In this study, the ratio of the 2-hydroxylation pathway to the 16-hydroxylation pathway was associated with a non-statistically significantly decreased risk of breast cancer
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In this study, the ratio of catechols to methylated catechols in the 4-hydroxylation pathway was associated with statistically significantly increased risk of breast cancer.
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This result is consistent with the hypothesis that mutagenic quinones derived from 4-hydroxylation pathway catechols contribute to pathogenesis of postmenopausal breast cancer.
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Catechols in both the 2- and 4-hydroxylation pathways can be oxidized to form quinones; these reactive electrophiles can then react with DNA to form a variety of adducts
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the most common DNA adducts derived from 4-hydroxylation pathway catechols are depurinating and highly mutagenic (7,40), most of those derived from 2-hydroxylation pathway catechols are stable and can be repaired with little error
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Thymidine Kinase 1 Upregulation Is an Early Event in Breast Tumor Formation - 0 views
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Adenoid cystic carcinoma: current therapy and potential therapeutic advances based on g... - 0 views
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Cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and cyclophosphamide) regimens can be used for combination chemotherapy
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patients with advanced salivary gland malignancy treated with the CAP regimen achieved partial response (PR) or stable disease (SD) rates of 67% (8 out of 12 patients)
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Agents commonly given as monotherapy for treating ACC are cisplatin, mitoxantrone, epirubicin, vinorelbine, paclitaxel, and gemcitabine. However, few of these agents have shown efficacy
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ACC is subdivided into 3 histological groups based on solid components of the tumor including cribriform, tubular, and solid
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Cribriform and tubular ACCs usually exhibit a more indolent course, whereas the solid subtype is associated with worse prognosis
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ACC consists of two different cell types: inner luminal epithelial cells and outer myoepithelial cells
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a balanced translocation of the v-myb avian myeloblastosis viral oncogene homolog-nuclear factor I/B (MYB-NFIB) is considered to be a signature molecular event of ACC oncogenesis
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As a transcription factor, MYB is known to modulate multiple genetic downstream targets involved in oncogenesis, such as cox-2, c-kit, Bcl-2 and BclX
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Various signaling cascades are essential for cancer cells to survive and grow. The PI3K/Akt/mTOR pathway is one of them
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Mutations in genes associated with DNA repair are frequently found in familial cancer syndromes, such as hereditary breast-ovarian cancer syndrome (HBOC), hereditary non-polyposis colorectal cancer (HNPCC, also called Lynch syndrome) and Li-Fraumeni syndrome [30, 31]. These mutations were also reported in non-hereditary cancers
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70% of ACC samples (58 of 84) were found to have genetic alterations in the MYB/MYC pathway, indicating that changes in this pathway are crucial in ACC pathogenesis
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The second most frequently mutated pathway was involved in chromatin remodeling (epigenetic modification), a pathway that includes multiple histone related proteins, and was altered in 44% of samples
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VEGF, iNOS and NF-κB were noted to be highly expressed in ACC cells as compared to normal salivary gland cells
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FABP7 (Fatty acid binding protein 7) and AQP1 (Aquaporin 1) tend to be overexpressed in ACC cell lines
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the study with cetuximab and concurrent chemoradiation or chemotherapy showed the highest ORR (total 43%, 9.5% CR and 33% PR), but this regimen was only given to the EGFR positive patients
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Cancer immunotherapy can be classified into 3 major groups. Active immunization using anti-tumor vaccines to induce and recruit T cells, passive immunization based on monoclonal antibodies, and adoptive cell transfer to expand tumor-reactive autologous T cells ex vivo and then reintroduce these cells into the same individual
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cytokine-induced cell apoptosis and the cytotoxic effect of the LAK cells contributed to tumor regression
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molecular finding of the MYB-NFIB fusion gene has the greatest potential to target what appears to be a fundamental event in disease pathogenesis
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Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil... - 0 views
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tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure.
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surgery results in a serious wound that disrupts the structural barrier preventing the outspreading of cancer cells, change the properties of the cancer cells and stromal cells remaining in the tumor microenvironment, or impairs the host defense systems against cancers
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After the primary tumor is surgically removed, the metastases can start to grow vigorously via neoangiogenesis because the circulating inhibitors disappear
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infection and inflammation during the postoperative period have been reported to increase the risk of cancer recurrence in patients
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Surgeons have long suspected that surgery, even if it is a necessary step in cancer treatment, facilitates cancer metastasis
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Even externally palpitating tumors for diagnosis could increase the numbers of CTCs in skin cancer and breast cancer
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In addition to glucocorticoids, during stimulation of the HPA axis, the catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla
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NK cell suppression may be attributed to increased levels of catecholamines as well as glucocorticoids
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In mice bearing a primary tumor, it was observed that the removal of the primary tumor facilitated the growth of highly vascularized metastases
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second phase of tumor recurrence and metastasis, which are newly acquired events, rather than just outcomes of incomplete treatment.
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formation of neutrophil extracellular traps (NETs), which are large extracellular complexes composed of chromatin and cytoplasmic/granular proteins1
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Once activated, neutrophils produce intracellular precursors by using DNA, histones, and granular and cytoplasmic proteins and then spread the mature form of NETs out around themselves
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neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, lactoferrin, gelatinase, lysozyme C, calprotectin, neutrophil defensins, and cathelicidins
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NETs are present in a variety of cancers, such as lung cancer, colon cancer, ovarian cancer, and leukemia
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the proliferative cytokines TGFβ and IL-10 and the angiogenic factor VEGF are representative of neutrophil-derived tissue repair proteins.
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when neutrophils are excessively stimulated, they produce excess NETs, thereby leading to pathological consequences
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local invasion, intravasation into the blood or lymphatic vessels, escape from the immune system, anchoring to capillaries in target organs, extravasation into the organs, transformation from dormant cells to proliferating cells, colonization to micrometastases, and growth to macrometastases
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NETs and platelets wrap CTCs, which protects them from attack by immune cells and shearing force by blood flow
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After metastasizing to distant tissues, tumor cells are often found to remain dormant for a period of time and unexpectedly regrow late
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NET-associated proteases NE and MMP-9 were found to be responsible for the reactivation of dormant cancer cells
Combinatorial Therapy of High Dose Vitamin C and PARP Inhibitors in DNA Repair Deficien... - 0 views
journals.sagepub.com/...1534735420969812
tumor microenvironment Fe TME iron metabolism labile iron pool cancer iron
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