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1
Del Pinto, Rita, and Claudio Ferri. "Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives." International Journal of Molecular Sciences 19, no. 12 (November 22, 2018): 3701. http://dx.doi.org/10.3390/ijms19123701.
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Low-grade chronic inflammation is a common denominator in atherogenesis and related diseases. Solid evidence supports the occurrence of an impairment in the innate and adaptive immune system with senescence, favoring the development of acute and chronic age-related diseases. Cardiovascular (CV) diseases (CVD), in particular, are a leading cause of death even at older ages. Inflammation-associated mechanisms that contribute to CVD development include dysregulated redox and metabolic pathways, genetic modifications, and infections/dysbiosis. In this review, we will recapitulate the determinants and consequences of the immune system dysfunction at older age, with particular focus on the CV system. We will examine the currently available and potential future strategies to counteract accelerated CV aging, i.e., nutraceuticals, probiotics, caloric restriction, physical activity, smoking and alcohol cessation, control of low-grade inflammation sources, senolytic and senescence-modulating drugs, and DNA-targeting drugs.
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Nie, Lulingxiao, Peng Zhang, Qian Wang, Xinyi Zhou, and Qi Wang. "lncRNA-Triggered Macrophage Inflammaging Deteriorates Age-Related Diseases." Mediators of Inflammation 2019 (December 21, 2019): 1–12. http://dx.doi.org/10.1155/2019/4260309.
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Aging and age-related diseases (ARDs) share basic mechanisms largely involving inflammation. A chronic, low-grade, subclinical inflammation called inflammaging occurs during aging. Autophagy defects, oxidative stresses, senescence-associated secretory phenotypes (SASPs), and DNA damage generally contribute to inflammaging and are largely regulated by numerous lncRNA through two-level vicious cycles disrupting cellular homeostasis: (1) inflammaging and the cellular senescence cascade and (2) autophagy defects, oxidative stress, and the SASP cascade. SASPs and inflammasomes simultaneously cause inflammaging. This review discusses the involvement of macrophage inflammaging in various ARDs and its regulation via lncRNA. Among macrophages, this phenomenon potentially impairs its immunosurveillance and phagocytosis mechanisms, leading to decreased recognition and clearance of malignant and senescent cells. Moreover, SASPs extracellularly manifest to induce paracrine senescence. Macrophage senescence escalates to organ level malfunction, and the organism is more prone to ARDs. By targeting genes and proteins or functioning as competing endogenous RNA (ceRNA), lncRNA regulates different phenomena including inflammaging and ARDs. The detailed mechanism warrants further elucidation to obtain pathological evidence of ARDs and potential treatment approaches.
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Hoey, Christianne, Jessica Ray, Xiaoyong Huang, Jouhyun Jeon, Paul Christopher Boutros, and Stanley K. Liu. "Overcoming miR-106a induced radioresistance in prostate cancer: Targeting senescence with KU-55933." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 77. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.77.
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77 Background: Prostate cancer is a leading cause of cancer related death in men worldwide, with recurrence being a major clinical problem after radiotherapy. There is an unmet need to better characterize radioresistant tumors and identify biomarkers to improve patient outcomes. Methods: We identified that miR-106a was overexpressed in radiation resistant cell lines compared to parental cells. We analyzed The Cancer Genome Atlas dataset to assess miR-106a expression in normal prostate, and low- to high-grade prostate tumors. To assess the functional role of miR-106a, we performed in vitro and in vivo assays for radiation response, including clonogenic survival, proliferation, senescence, and tumor xenograft growth after radiation. We performed gene array and pathway analyses to identify downstream effectors of miR-106a. Results: MiR-106a expression was significantly higher in prostate tumors with Gleason score > 7 compared to Gleason ≤ 7, suggesting miR-106a is involved in high grade disease. MiR-106a overexpression confers radioresistance in vitro and in vivo, by targeting LITAF. We now extend miR-106a’s effects to upregulation of ATM at the promoter level, thereby increasing ATM transcript and protein in the cell. Unexpectedly, we found that miR-106a’s mechanism of radioresistance through ATM upregulation does not alter DNA damage repair. ATM upregulation affects clonogenic survival through reduced senescence. KU-55933, a specific ATM kinase inhibitor, resensitizes miR-106a overexpressing cells to radiation by inducing senescence, a predominant mode of cell death in prostate cancer. Conclusions: Our research challenges the current paradigm of ATM and DNA damage repair by outlining another mechanism of radioresistance through alteration of senescence. Our findings suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer. In addition, we have identified a therapeutic intervention for miR-106a induced radioresistance. Improvements in bioavailability of KU-55933 may lead to its clinical use in combination with radiation therapy to radiosensitize miR-106a induced radioresistant prostate cancer.
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Chen, Ruping, Kexiong Zhang, Hao Chen, Xiaoyin Zhao, Jianqiu Wang, Li Li, Yusheng Cong, et al. "Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs." Journal of Biological Chemistry 290, no. 52 (October 30, 2015): 30813–29. http://dx.doi.org/10.1074/jbc.m115.681619.
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Mas-Bargues, Cristina, Consuelo Borrás, and Jose Viña. "Bcl-xL as a Modulator of Senescence and Aging." International Journal of Molecular Sciences 22, no. 4 (February 3, 2021): 1527. http://dx.doi.org/10.3390/ijms22041527.
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Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.
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Serino, Alexa, and Gloria Salazar. "Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease." Nutrients 11, no. 1 (December 28, 2018): 53. http://dx.doi.org/10.3390/nu11010053.
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Aging is a major risk factor in the development of chronic diseases affecting various tissues including the cardiovascular system, muscle and bones. Age-related diseases are a consequence of the accumulation of cellular damage and reduced activity of protective stress response pathways leading to low-grade systemic inflammation and oxidative stress. Both inflammation and oxidative stress are major contributors to cellular senescence, a process in which cells stop proliferating and become dysfunctional by secreting inflammatory molecules, reactive oxygen species (ROS) and extracellular matrix components that cause inflammation and senescence in the surrounding tissue. This process is known as the senescence associated secretory phenotype (SASP). Thus, accumulation of senescent cells over time promotes the development of age-related diseases, in part through the SASP. Polyphenols, rich in fruits and vegetables, possess antioxidant and anti-inflammatory activities associated with protective effects against major chronic diseases, such as cardiovascular disease (CVD). In this review, we discuss molecular mechanisms by which polyphenols improve anti-oxidant capacity, mitochondrial function and autophagy, while reducing oxidative stress, inflammation and cellular senescence in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). We also discuss the therapeutic potential of polyphenols in reducing the effects of the SASP and the incidence of CVD.
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Roxburgh, Campbell SD, Colin H. Richards, Arfon Powell, Donald C. Mcmillan, Joanne E. Edwards, Paul G. Horgan, and Paul G. Shiels. "The in situ local immune response, tumour senescence, and proliferation in colorectal cancer." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 412. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.412.
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412 Background: Immune cell infiltrates play a key role in determining colorectal cancer outcome. It is unclear whether they are tumour or host specific. Increased immunogenicity may relate to senescence or proliferation. Senescence, a state of cell-cycle arrest, slows tumour progression. In animal models, senescence associated regression is mediated by upregulated antitumour immune responses. High proliferation may provoke immune responses. Relationships between senescence, proliferation and immune cell infiltrates have not previously been studied. We explore whether p16ink4a associated senescence relates to T cell infiltrates in colorectal tumours and whether p16ink4a expression, proliferation and T cell infiltrates confer similar survival relationships. Methods: Immunostaining of nuclear p16inka and Ki67 was performed using a tissue microarray. Nuclear p16inkaand Ki67 were scored as high or low expression. (T cell markers CD3/CD45RO/CD8/FOXP3) were scored high/low grade on corresponding full sections (margin/stroma/ cancer cell nest). Results: 230 Stage I-III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki67 >15% ) in 61%. P16ink4a expression related to reduced margin, stroma and cancer cell nest (CCN) CD45RO cells (P=0.054, P=0.062, P=0.025) and reduced margin CD8 cells (P=0.016). High Ki67 labeling related to increased margin, and CCN CD3 cells (P=0.017, P<0.001), increased margin and CCN CD45RO cells (P=0.023, P<0.001), increased margin, stroma and CCN FOXP3 cells (P<0.001, P=0.001, P<0.001) and increased margin and CCN CD8 cells (P=0.026, P=0.001). On multivariate analysis, TNM stage (P<0.001), low margin CD3 (P=0.014), low margin CD8 (P=0.037), low proliferation (Ki67) (P=0.013) and low senescence (P16ink4a) (P=0.002) conferred poorer cancer survival. Conclusions: p16ink4a expression, proliferation and immune cell infiltrates are independent prognostic factors in colorectal cancer. Proliferation relates to increasing T cell infiltrates but independently influences survival. P16ink4a associated senescence does not appear to mediate improved outcome by upregulating T cell responses. Relationships observed here suggest the opposite.
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Romagosa, C., S. Simonetti, L. López-Vicente, A. Mazo, M. E. Lleonart, J. Castellvi, and S. Ramon y Cajal. "p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors." Oncogene 30, no. 18 (February 7, 2011): 2087–97. http://dx.doi.org/10.1038/onc.2010.614.
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Nangami, Gladys N., Amos M. Sakwe, Michael G. Izban, Tanu Rana, Philip E. Lammers, Portia Thomas, Zhenbang Chen, and Josiah Ochieng. "Fetuin-A (alpha 2HS glycoprotein) modulates growth, motility, invasion, and senescence in high-grade astrocytomas." Cancer Medicine 5, no. 12 (November 23, 2016): 3532–43. http://dx.doi.org/10.1002/cam4.940.
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Taylor, Z. G., L. R. Fisher, and D. L. Jordan. "Peanut (Arachis hypogaea L.) Response to the Ethylene Binding Inhibitor 1-Methylcyclopropene." Peanut Science 37, no. 1 (January 1, 2010): 20–25. http://dx.doi.org/10.3146/ps09-002.1.
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Abstract Senescence and abscission of mature peanut pods is controlled by the ethylene cascade. Reducing senescence and abscission could involve inhibiting the ethylene cascade and allow greater harvest flexibility in peanut. Application of 1-methylcyclopropene (1-MCP), the ethylene binding inhibitor, may reduce senescence and abscission of mature peanut pods. Research was conducted from 2005 through 2008 in North Carolina to determine the effects of 1-MCP on pod yield and percentages of sound mature kernels (%SMK), sound splits (%SS), total sound mature kernels (%TSMK), other kernels (%OK), extra large kernels (%ELK), fancy pods (%FP), and pod retention. Treatments of 1-MCP were applied at 26 g ai/ha plus a crop oil concentrate at 7, 10, or 14 d prior to digging peanut at the projected optimum digging date. Peanut was dug at the projected optimum digging date or at 7 or 20 d after projected optimum digging date. The cultivars NC-V 11 (2005 and 2007), Phillips (2006 and 2007), and Perry (2008) were evaluated in separate experiments. Pod yield, %SMK, %TSMK, %SS, %OK, %ELK, and %FP were not affected by 1-MCP regardless of application timing when NC-V 11 and Phillips were evaluated. Only %SMK and %TSMK were affected by 1-MCP when applied to the cultivar Perry. Digging date affected pod yield and market grade characteristics. When digging of Phillips and Perry was delayed by 7 or 20 d past the optimum digging date, %SMK and %TSMK increased. Pod retention, determined by comparing the number and mass of pods/plant following digging, was affected by digging date and location but not 1-MCP treatment. These data suggest that 1-MCP will have little activity on peanut pod yield, market grade characteristics, or pod retention.
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Giuliani, Angelica, Francesco Prattichizzo, Luigina Micolucci, Antonio Ceriello, Antonio Domenico Procopio, and Maria Rita Rippo. "Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?" Mediators of Inflammation 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/2309034.
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A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondria activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells. We discuss the potential role of several of SA-mitomiRs (i.e., let-7b, miR-1, miR-130a-3p, miR-133a, miR-146a-5p, miR-181c-5p, and miR-378-5p), using miR-146a as a proof-of-principle model. Finally, we propose a comprehensive, metabolic, and epigenetic view of the senescence process, in order to amplify the range of possible approaches to target inflammaging, with the ultimate goal of decelerating the aging rate, postponing or blunting the development of age-related diseases.
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Tarte, Karin, Julien Gaillard, Jean-Jacques Lataillade, Loic Fouillard, Martine Becker, Hossein Mossafa, Andrei Tchirkov, et al. "Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation." Blood 115, no. 8 (February 25, 2010): 1549–53. http://dx.doi.org/10.1182/blood-2009-05-219907.
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Abstract Clinical-grade human mesenchymal stromal cells (MSCs) have been expanded in vitro for tissue engineering or immunoregulatory purposes without standardized culture conditions or release criteria. Although human MSCs show poor susceptibility for oncogenic transformation, 2 recent studies described their capacity to accumulate chromosomal instability and to give rise to carcinoma in immunocompromised mice after long-term culture. We thus investigated the immunologic and genetic features of MSCs expanded with fetal calf serum and fibroblast growth factor or with platelet lysate in 4 cell-therapy facilities during 2 multicenter clinical trials. Cultured MSCs showed a moderate expression of human leukocyte antigen-DR without alteration of their low immunogenicity or their immunomodulatory capacity. Moreover, some transient and donor-dependent recurring aneuploidy was detected in vitro, independently of the culture process. However, MSCs with or without chromosomal alterations showed progressive growth arrest and entered senescence without evidence of transformation either in vitro or in vivo.
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Arnold, Antje, Ming Yuan, Antionette Price, Lauren Harris, Charles G. Eberhart, and Eric H. Raabe. "Synergistic activity of mTORC1/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity." Neuro-Oncology 22, no. 4 (December 16, 2019): 563–74. http://dx.doi.org/10.1093/neuonc/noz230.
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Abstract Background Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Many patients with unresectable or recurrent/refractory tumors have significant lifelong disability. The majority of pLGG have mutations increasing the activity of the Ras/mitogen-activated protein kinase (MAPK) pathway. Activation of mammalian target of rapamycin (mTOR) is also a hallmark of pLGG. We therefore hypothesized that the dual target of rapamycin complexes 1 and 2 (TORC1/2) kinase inhibitor TAK228 would synergize with the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in pLGG. Methods We tested TAK228 and trametinib in patient-derived pLGG cell lines harboring drivers of pLGG including BRAFV600E and neurofibromatosis type 1 loss. We measured cell proliferation, pathway inhibition, cell death, and senescence. Synergy was analyzed via MTS assay using the Chou–Talalay method. In vivo, we tested for overall survival and pathway inhibition and performed immunohistochemistry for proliferation and vascularization. We performed a scratch assay and measured angiogenesis protein activation in human umbilical vein endothelial cells (HUVECs). Results TAK228 synergized with trametinib in pLGG at clinically relevant doses in all tested cell lines, suppressing proliferation, inducing apoptosis, and causing senescence in a cell line–dependent manner. Combination treatment increased median survival by 70% and reduced tumor volume compared with monotreatment and control cohorts. Vascularization of tumors decreased as measured by CD31 and CD34. Combination treatment blocked activation of focal adhesion kinase (FAK) and sarcoma proto-oncogene non-receptor tyrosine kinase (SRC) in HUVEC cells and reduced HUVEC migration compared with each drug alone. Conclusions The combination of TAK228 and trametinib synergized to suppress the growth of pLGG. These agents synergized to reduce tumor vascularity and endothelial cell growth and migration by blocking activation of FAK and SRC.
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Andrade, Francisco, and Manuel Loor Bermúdez. "Colección y caracterización de variedades tradicionales de arroz." Investigación, Tecnología e Innovación 2, no. 2 (December 30, 2010): 107–18. http://dx.doi.org/10.53591/iti.v2i2.130.
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La Investigación realizada tuvo la finalidad de colectar y caracterizar variedades tradicionales de arroz. Este trabajo pretende evitar la erosión genética producida por la introducción y siembra de material mejorado, utilizar sus características de productividad, calidad de grano, buena adaptación y otras, sembrándolas directamente en zonas recomendadas o cruzándolas con otros materiales que permitan obtener suficiente variabilidad genética para la selección de genotipos superiores. La investigación se estableció en la EELS3 del lNIAP3 y Samborondón, desde agosto del 2007 a enero del 2009. Las variables que se evaluaron fueron: ciclo vegetativo, altura de planta, número de panículas/m2, excerción de panículas, desgrane, senescencia de las hojas, acame de plantas, resistencia a enfermedades, longitud de panículas, número de granos por panícula, porcentaje de esterilidad, rendimiento, peso de mil granos, longitud de grano, centro blanco, índice de pilada. Para el análisis estadístico se utilizó el Diseño de Bloques Completos al Azar, Prueba de Tuckey y correlaciones. Las conclusiones fueron as siguientes: a) Se colectaron 55 variedades tradicionales. b) Se caracterizaron 45 variedades tradicionales. e) Se ha contribuido a la conformación de un Banco de Variedades Tradicionales caracterizadas. d) Se difundieron los resultados.
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Zhao, Jianxin, Yoshitomo Honda, Tomonari Tanaka, Yoshiya Hashimoto, and Naoyuki Matsumoto. "Releasing Behavior of Lipopolysaccharide from Gelatin Modulates Inflammation, Cellular Senescence, and Bone Formation in Critical-Sized Bone Defects in Rat Calvaria." Materials 13, no. 1 (December 23, 2019): 95. http://dx.doi.org/10.3390/ma13010095.
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Lipopolysaccharide (LPS) is a well-known strong inducer of inflammation. However, there is little information regarding how LPS-release behavior affects cellular senescence at the affected area. In this paper, we demonstrate that a vacuum-heating technique (dehydrothermal treatment) can be utilized to prepare an LPS sustained-release gelatin sponge (LS-G). LPS sustained release from gelatin leads to the long-term existence of senescent cells in critical-sized bone defects in rat calvaria. Three types of gelatin sponges were prepared in this study: a medical-grade gelatin sponge with extremely low LPS levels (MG), LS-G, and a LPS rapid-release gelatin sponge (LR-G). Histological (H-E) and immunohistochemical (COX-2, p16, and p21) staining were utilized to evaluate inflammatory reactions and cellular senescence one to three weeks after surgery. Soft X-ray imaging was utilized to estimate new bone formation in the defects. The LR-G led to stronger swelling and COX-2 expression in defects compared to the MG and LS-G at 1 week. Despite a small inflammatory reaction, LS-G implantation led to the long-term existence of senescent cells and hampered bone formation compared to the MG and LR-G. These results suggest that vacuum heating is a viable technique for preparing different types of materials for releasing bacterial components, which is helpful for developing disease models for elucidating cellular senescence and bone regeneration.
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Guiho, Romain, Florian Selt, Thomas Stone, Thomas Jacques, Darren Hargrave, Jesús Gil, Olaf Witt, Till Milde, and Juan Pedro Martinez Barbera. "LGG-09. SENOLYTIC AGENT NAVITOCLAX TARGETS VINBLASTINE- AND MAPK INHIBITORS-INDUCED SENESCENT TUMOUR CELLS IN PAEDIATRIC LOW GRADE GLIOMAS." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i33. http://dx.doi.org/10.1093/neuonc/noab090.133.
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Abstract Pilocytic astrocytoma (PA, WHO grade I), the most common paediatric brain tumour, is characterized by constitutive activation of the MAPK pathway. PA tumours show a slow growth, without tendency to progress to high-grade malignancies. However, a significant group of patients for whom a total resection is not feasible require additional therapy. The typical proliferative index of a PA, measured by Ki-67 staining, is 1–2%, whereas a large part of the tumour is Ki-67 negative and expresses markers of oncogene-induced senescence (OIS) such as SA-β-Gal positivity and the cell cycle inhibitors p16INK4a (CDKN2A) and p21Cip1 (CDKN1A). Conventional treatments (i.e. chemotherapy) tend to target only proliferative cells and the effect of new molecularly targeted therapies (e.g., MAPK pathway inhibitors) on senescent cells remains unclear. Here, we discuss the opportunities to combine these therapies with new compounds targeting the senescent cells, referred to as senolytics, using three different PA models. (1) Ex vivo culture of human PA tumours (2) Two cell lines: the DKFZ-BT66 PA human cell line, carrying the oncogenic driver KIAA1549:BRAF-fusion, used as a model of OIS; and the proliferative BT40 cell line harbouring the BRAFV600E mutation; (3) In vivo xenograft model induced by orthotopic transplantation of BT40 cells. We have previously shown that OIS cells exhibit an increased sensitivity to senolytic compounds, such as navitoclax, a clinically approved BCL2/XL inhibitor, relative to proliferative controls (Buhl et al, Clin Cancer Res. 2019). Our current research demonstrates that treatments with low doses of chemotherapy (e.g., vinblastine) or MAPK inhibitors (e.g., dabrafenib or trametinib) triggers a therapy-induced senescence response in proliferative cells (e.g., abolished proliferation, SA-β-Gal positivity, SASP production), making these senescent cells sensitive to senolytic compounds, including navitoclax. Together, our research provides a strong rationale supporting the combined use of senolytics with current conventional and targeted therapies against human PA.
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Sigaud, Romain, Florian Selt, Thomas Hielscher, Nina Overbeck, Diren Usta, Marc Remke, Daniel Picard, et al. "LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii368. http://dx.doi.org/10.1093/neuonc/noaa222.396.
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Abstract Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.
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Xu, Ming, Tamara Tchkonia, Husheng Ding, Mikolaj Ogrodnik, Ellen R. Lubbers, Tamar Pirtskhalava, Thomas A. White, et al. "JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age." Proceedings of the National Academy of Sciences 112, no. 46 (November 2, 2015): E6301—E6310. http://dx.doi.org/10.1073/pnas.1515386112.
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Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
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Prattichizzo, Francesco, Valeria De Nigris, Lucia La Sala, Antonio Domenico Procopio, Fabiola Olivieri, and Antonio Ceriello. "“Inflammaging” as a Druggable Target: A Senescence-Associated Secretory Phenotype—Centered View of Type 2 Diabetes." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/1810327.
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Aging is a complex phenomenon driven by a variety of molecular alterations. A relevant feature of aging is chronic low-grade inflammation, termed “inflammaging.” In type 2 diabetes mellitus (T2DM), many elements of aging appear earlier or are overrepresented, including consistent inflammaging. T2DM patients have an increased death rate, associated with an incremented inflammatory score. The source of this inflammation is debated. Recently, the senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammaging in both aging and T2DM. Different pathogenic mechanisms linked to T2DM progression and complications development have been linked to senescence and SASP, that is, oxidative stress and endoplasmic reticulum (ER) stress. Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current medical practice is insufficient to completely suppress the increased death rate of diabetic patients, we propose a SASP-centered view of T2DM as a futuristic therapeutic option, possibly opening new prospects by moving the attention from one-organ studies of diabetes complications to a wider targeting of the aging process.
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Ham, Seok Won, Hee-Young Jeon, and Hyunggee Kim. "Verapamil augments carmustine- and irradiation-induced senescence in glioma cells by reducing intracellular reactive oxygen species and calcium ion levels." Tumor Biology 39, no. 5 (May 2017): 101042831769224. http://dx.doi.org/10.1177/1010428317692244.
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Resistance to conventional therapies and frequent recurrence are the major obstacles to the treatment of high-grade gliomas, including glioblastoma. Thus, the development of new therapeutic strategies to overcome these obstacles is necessary to improve the treatment outcomes. In this study, we found that verapamil, a pan–adenosine triphosphate–binding cassette transporter and L-type voltage-dependent calcium channel inhibitor, sensitized U87MG glioma cells to carmustine- and irradiation-induced senescence. Furthermore, our results indicated that verapamil treatment, in combination with carmustine and irradiation, rendered U87MG glioma cells and several patient-derived glioma stem cells more sensitive to therapy-induced senescence than individual or dual-combination treatments. When investigating the underlying mechanism, we found that verapamil treatment markedly decreased intracellular reactive oxygen species and calcium ion levels. Reactive oxygen species reduction with N-acetylcysteine, a reactive oxygen species scavenger, rendered U87MG glioma cells more sensitive to carmustine and irradiation whereas the protein kinase C agonist, phorbol 12-myristate 13-acetate, mitigated the effects of carmustine and irradiation. Taken together, our results indicate that verapamil may be a potent therapeutic sensitizer for increasing the effectiveness of glioblastoma treatment.
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Reich, Thomas R., Christian Schwarzenbach, Juliana Brandstetter Vilar, Sven Unger, Fabian Mühlhäusler, Teodora Nikolova, Alicia Poplawski, et al. "Localization matters: nuclear-trapped Survivin sensitizes glioblastoma cells to temozolomide by elevating cellular senescence and impairing homologous recombination." Cellular and Molecular Life Sciences 78, no. 14 (June 8, 2021): 5587–604. http://dx.doi.org/10.1007/s00018-021-03864-0.
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AbstractTo clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.
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Gnanavel, Mutharasu, Akshaya Murugesan, Saravanan Konda Mani, Olli Yli-Harja, and Meenakshisundaram Kandhavelu. "Identifying the miRNA Signature Association with Aging-Related Senescence in Glioblastoma." International Journal of Molecular Sciences 22, no. 2 (January 6, 2021): 517. http://dx.doi.org/10.3390/ijms22020517.
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Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein–protein, protein–ncRNA, and protein–peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from 574 samples to explore the role of non-coding RNAs in the disease progression and unique signaling communication in GBM. A series of computational methods involving miRNA expression, gene ontology (GO) based gene enrichment, pathway mapping, and annotation from metabolic pathways databases, and network analysis were used for the analysis. Our study revealed the physiological roles of many known and novel miRNAs in cancer signaling, especially concerning signaling in cancer progression and proliferation. Overall, the results revealed a strong connection with stress induced senescence, significant miRNA targets for cell cycle arrest, and many common signaling pathways to GBM in the network.
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Arnold, Antje, Lauren Harris, Ming Yuan, Fausto Rodriguez, Charles Eberhart, and Eric Raabe. "PDTM-18. COMBINED SUPPRESSION OF THE mTOR AND MAPK PATHWAYS INHIBITS GROWTH, DECREASES VASCULARITY AND INDUCES APOPTOSIS OR SENESCENCE IN PEDIATRIC LOW GRADE GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi191. http://dx.doi.org/10.1093/neuonc/noz175.794.
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Abstract Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in four patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1(NF1mut), BT40(BRAFV600E), Res186(PTEN-/-) and Res259(CDKN2A-/-). Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). The combination of TAK228 and trametinib increased apoptosis by up to 127% (p< 0.001 by 1-way ANOVA) in Res186 and Res259 cells as measured by cleaved caspase 3 immunocytochemistry. Trametinib and combination treatment induces senescence in JHH_NF1_PA1 cell line verified through increase in p27 protein expression (Western Blot) and positive b-galactosidase staining. Mono-treatment with TAK228 or vehicle showed no signs of senescence. We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived cell line in immunodeficient mice. The combination treatment showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p< 0.01). Combination treatment strikingly reduced the vascularization in the tumor tissue after combination treatment analyzed by CD31 and CD34 protein expression (Western Blot), compared to vehicle and mono-treatment. Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide the first strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.
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Mariscal-Amaro, Luis A., Héctor E. Villaseñor-Mir, Ernesto Solís-Moya, René Hortelano-Santa Rosa, and Eliel Martínez-Cruz. "EFECTO DE FUNGICIDAS SOBRE CARACTERES AGRONÓMICOS, RENDIMIENTO Y TIZONES FOLIARES EN TRIGO DE TEMPORAL EN MÉXICO." Revista Fitotecnia Mexicana 43, no. 1 (March 29, 2020): 71. http://dx.doi.org/10.35196/rfm.2020.1.71.
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El trigo (Triticum aestivum L.) sembrado bajo condiciones de temporal en México hospeda hongos causantes de manchas y tizones foliares que reducen el rendimiento hasta en 60 %. Ante la falta de materiales resistentes a estas enfermedades y las pérdidas de rendimiento que ocasionan en las variedades actuales sembradas bajo estas condiciones se recurre al control químico como alternativa complementaria en este cereal. Actualmente existe poca información del efecto de fungicidas con diferentes ingredientes activos sobre la severidad de estas enfermedades y otros rasgos agronómicos. El objetivo de este estudio fue probar la efectividad de fungicidas foliares sobre la severidad de la enfermedad medida como el área foliar dañada y observar su efecto sobre los caracteres agronómicos y de rendimiento. El estudio se llevó a cabo en tres localidades de Valles Altos del centro de México, donde se probaron ocho fungicidas sistémicos y tres de contacto. Los fungicidas sólo tuvieron efecto altamente significativo en los días a madurez, donde la azoxistrobina + propiconazole retrasó la madurez de la planta hasta en 8 d comparado con el testigo. Todos los fungicidas redujeron el área foliar dañada hasta en 63.3 % y aumentaron el rendimiento de grano hasta en 56 %. Los fungicidas a base de azoxistrobina y los de la familia de los triazoles indujeron el efecto stay-green (demora en la senescencia foliar) y mejoraron la sanidad de las plantas. Se observó una correlación positiva entre días a madurez y rendimiento de grano, y negativa entre el porcentaje de área foliar dañada y rendimiento de grano. La aplicación de fungicidas foliares para el manejo de manchas y tizones foliares en trigo se recomienda como una alternativa para proteger el cultivo y aumentar el rendimiento en trigo.
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Machado, Marcel Cerqueira Cesar, Ana Maria Mendonça Coelho, Luiz Augusto Carneiro D’Albuquerque, and Sonia Jancar. "Effect of Ageing on Systemic Inflammatory Response in Acute Pancreatitis." International Journal of Inflammation 2012 (2012): 1–4. http://dx.doi.org/10.1155/2012/270319.
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Elderly patients show increased incidence of multiple organ dysfunction in acute pancreatitis possibly due to bacterial translocation. This is associated with increased susceptibility to infections in older people. Several reports have related this increased susceptibility to a proinflammatory status calledinflammaging, which decreases the capacity of the immunological system to respond to antigens. Cellular senescence also contributes to this low-grade chronic inflammation in older subjects. We discuss here the effect of ageing on systemic inflammation, focusing on that induced by acute pancreatitis and some of the mechanisms involved. It is important to understand the immunological changes in the elderly to adjust treatment strategies in order to reduce the morbidity and mortality associated with acute pancreatitis and other conditions that lead to systemic inflammation.
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Loisel, Séverine, Joëlle Dulong, Cédric Ménard, Marie-Laure Renoud, Nadine Meziere, Bezier Isabelle, Maëlle Latour, et al. "Brief Report: Proteasomal Indoleamine 2,3-Dioxygenase Degradation Reduces the Immunosuppressive Potential of Clinical Grade-Mesenchymal Stromal Cells Undergoing Replicative Senescence." STEM CELLS 35, no. 5 (February 23, 2017): 1431–36. http://dx.doi.org/10.1002/stem.2580.
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Minguzzi, Manuela, Silvia Cetrullo, Stefania D’Adamo, Ylenia Silvestri, Flavio Flamigni, and Rosa Maria Borzì. "Emerging Players at the Intersection of Chondrocyte Loss of Maturational Arrest, Oxidative Stress, Senescence and Low-Grade Inflammation in Osteoarthritis." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–17. http://dx.doi.org/10.1155/2018/3075293.
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The prevalence of Osteoarthritis (OA) is increasing because of the progressive aging and unhealthy lifestyle. These risk factors trigger OA by removing constraints that keep the tightly regulated low turnover of the extracellular matrix (ECM) of articular cartilage, the correct chondrocyte phenotype, and the functionality of major homeostatic mechanisms, such as mitophagy, that allows for the clearance of dysfunctional mitochondria, preventing increased production of reactive oxygen species, oxidative stress, and senescence. After OA onset, the presence of ECM degradation products is perceived as a “danger” signal by the chondrocytes and the synovial macrophages that release alarmins with autocrine/paracrine effects on the same cells. Alarmins trigger innate immunity in the joint, with important systemic crosstalks that explain the beneficial effects of dietary interventions and improved lifestyle. Alarmins also boost low-grade inflammation: the release of inflammatory molecules and chemokines sustained by continuous triggering of NF-κB within an altered cellular setting that allows its higher transcriptional activity. Chemokines exert pleiotropic functions in OA, including the recruitment of inflammatory cells and the induction of ECM remodeling. Some chemokines have been successfully targeted to attenuate structural damage or pain in OA animal models. This represents a promising strategy for the future management of human OA.
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Penfield, Joshua D., Cadman L. Leggett, Marlys Anderson, Lori S. Lutzke, Tsung-Teh Wu, Alan R. Zinsmeister, Prasad G. Iyer, and Kenneth K. Wang. "Mo1925 Cellular Senescence and P16ink4a Immunohistochemistry Predicts Response to Radiofrequency Ablation (RFA) for Barrett's Esophagus (BE) With High-grade Dysplasia (HGD)." Gastroenterology 144, no. 5 (May 2013): S—696. http://dx.doi.org/10.1016/s0016-5085(13)62577-9.
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He, Yang, and Bernd Kaina. "Are There Thresholds in Glioblastoma Cell Death Responses Triggered by Temozolomide?" International Journal of Molecular Sciences 20, no. 7 (March 28, 2019): 1562. http://dx.doi.org/10.3390/ijms20071562.
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Temozolomide (TMZ) is an alkylating agent used in the treatment of high-grade malignant glioma, notably glioblastoma multiforme, the most aggressive form of brain cancer. The drug induces a dozen DNA methylation adducts, including O6-methylguanine (O6MeG), which is the most toxic primary DNA lesion as it causes the formation of DNA double-strand breaks (DSBs) that trigger apoptosis. In p53 wild-type cells, TMZ activates p-p53ser15 and p-p53ser46, which have opposing dual functions regulating survival and death, respectively. Since the use of TMZ in a therapeutic setting is limited because of its side effects, the question arises as to the existence of threshold doses that activate the death pathway and start apoptosis. To determine whether there is a threshold for the TMZ-induced DNA damage response and exploring the factors regulating the switch between p53 dependent survival and death, the glioblastoma lines LN-229 (deficient in MGMT) and LN-229MGMT (stably transfected with MGMT) were exposed to different doses of TMZ. p53 protein expression and phosphorylation levels of p-p53ser15 and p-p53ser46 were determined by Western blotting. Also, apoptosis, senescence and autophagy levels were checked after different doses of TMZ. The results show that pro-survival p-p53ser15 and pro-death p-p53ser46 were induced by O6MeG in a specific dose- and time-dependent manner. p-p53ser15 was an early response while p-p53ser46 was activated at later times following treatment. Unexpectedly, the dose-response curves for total p53, p-p53ser15 and p-p53ser46 were linear, without an obvious threshold. O6MeG induces apoptosis late after treatment as a linear function of TMZ dose. This was observed for both p53 proficient LN-229 and p53 lacking LN-308 cells. A linear dose-response after TMZ was also observed for senescence and autophagy as well as γH2AX, an indicator of DSBs that are considered to be the downstream trigger of apoptosis, senescence and autophagy. LN-229MGMT cells were highly resistant to all measured endpoints because of repair of the critical primary lesion. Although LN-308 were less responsive than LN-229 to TMZ, they displayed the same TMZ-induced DSB level. The observed linear dose-responses are not compatible with the view that low DNA damage level evokes survival while high damage level activates death functions. The data bear important therapeutic implications as they indicate that even low doses of TMZ may elicit a cytotoxic response. However, since O6MeG triggers apoptosis, senescence and autophagy in the same dose range, it is likely that the accumulation of senescent cells in the population counteracts the killing effect of the anticancer drug.
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Häussinger, Dieter, Markus Butz, Alfons Schnitzler, and Boris Görg. "Pathomechanisms in hepatic encephalopathy." Biological Chemistry 402, no. 9 (May 31, 2021): 1087–102. http://dx.doi.org/10.1515/hsz-2021-0168.
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Abstract Hepatic encephalopathy (HE) is a frequent neuropsychiatric complication in patients with acute or chronic liver failure. Symptoms of HE in particular include disturbances of sensory and motor functions and cognition. HE is triggered by heterogeneous factors such as ammonia being a main toxin, benzodiazepines, proinflammatory cytokines and hyponatremia. HE in patients with liver cirrhosis is triggered by a low-grade cerebral edema and cerebral oxidative/nitrosative stress which bring about a number of functionally relevant alterations including posttranslational protein modifications, oxidation of RNA, gene expression changes and senescence. These alterations are suggested to impair astrocyte/neuronal functions and communication. On the system level, a global slowing of oscillatory brain activity and networks can be observed paralleling behavioral perceptual and motor impairments. Moreover, these changes are related to increased cerebral ammonia, alterations in neurometabolite and neurotransmitter concentrations and cortical excitability in HE patients.
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Haemmig, Stefan, Dafeng Yang, Xinghui Sun, Debapria Das, Siavash Ghaffari, Roberto Molinaro, Lei Chen, et al. "Long noncoding RNA SNHG12 integrates a DNA-PK–mediated DNA damage response and vascular senescence." Science Translational Medicine 12, no. 531 (February 19, 2020): eaaw1868. http://dx.doi.org/10.1126/scitranslmed.aaw1868.
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Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr−/− mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr−/− mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.
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Baranowska-Bik, Agnieszka, and Wojciech Bik. "Vascular Dysfunction and Insulin Resistance in Aging." Current Vascular Pharmacology 17, no. 5 (August 1, 2019): 465–75. http://dx.doi.org/10.2174/1570161117666181129113611.
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: Insulin was discovered in 1922 by Banting and Best. Since that time, extensive research on the mechanisms of insulin activity and action has continued. Currently, it is known that the role of insulin is much greater than simply regulating carbohydrate metabolism. Insulin in physiological concentration is also necessary to maintain normal vascular function. : Insulin resistance is defined as a pathological condition characterized by reduced sensitivity of skeletal muscles, liver, and adipose tissue, to insulin and its downstream metabolic effects under normal serum glucose concentrations. There are also selective forms of insulin resistance with unique features, including vascular insulin resistance. Insulin resistance, both classical and vascular, contributes to vascular impairment resulting in increased risk of cardiovascular disease. Furthermore, in the elderly population, additional factors including redistribution of fat concentrations, low-grade inflammation, and decreased self-repair capacity [or cell senescence] amplify the vascular abnormalities related to insulin resistance.
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Ebert, Thomas, Sven-Christian Pawelzik, Anna Witasp, Samsul Arefin, Sam Hobson, Karolina Kublickiene, Paul G. Shiels, Magnus Bäck, and Peter Stenvinkel. "Inflammation and Premature Ageing in Chronic Kidney Disease." Toxins 12, no. 4 (April 4, 2020): 227. http://dx.doi.org/10.3390/toxins12040227.
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Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.
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Shirinsky, V. S., and I. V. Shirinsky. "Polymorbidity, ageing of immune system and low-grade systemic inflammation: a challenge for modern medicine." Medical Immunology (Russia) 22, no. 4 (August 7, 2020): 609–24. http://dx.doi.org/10.15789/1563-0625-pao-2042.
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The review article considers the data from literature that concern polymorbidity aspects, its interrelations with ageing of immune system and lo-grade immune ageing, mechanisms of genesis, approaches to its prevention and treatment. Evolution of “comorbidity” and “polymorbidity” terms is traced, an updated definition of polymorbidity is proposed. The world-wide incidence of polymorbidity is increased and now it reaches 23-25% in general population, and up to 98%, in elderly people (> 65 years old). The risk factors of polymorbidity are considered, like as its social burden due to high costs for healthcare, high mortality rates, excessive treatment provided by multidisciplinary specialists. We present evidence for common molecular and cellular mechanisms involved in ageing and polymorbidity, being unified by the term “inflammaging” which represents a low-grade chronic systemic inflammation associated with ageing. The data are presented that concern the “inflammaging” development with involvement of ageing cells from innate and adaptive immunity systems, different pro and anti-inflammatory mediators, lifelong antigenic load. The data are analyzed concerning functional and structural changes in the inborn and adaptive immune system in ageing, role of these changes in “inflammaging” persistence and development of polymorbid conditions. There are complex interactions shown between the bodily senescence and immune ageing, with similar underlying mechanisms in some cases, however, being quite different in other instances. With age, upon existing risk factors, the changed adaptive immunity in most people is not able to full-scale coping with chronic antigenic load, thus increasing the risk of diseases. Moreover, in many elderly people these changes are compensated by steady activation of the innate immunity cells. It is noted that the aging events and development of disease (polymorbidity) cannot be considered distinct entities, since they can interact, being, however, basically different in their nature. In future, one should concentrate our efforts on elucidation of molecular and cellular mechanisms of these interactions, solution of the tasks oriented for development of such interventions that could be able to reduce harmful consequences of ageing and to use useful effects for health maintenance and reaching maximal longevity.
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Dickson, Mark Andrew, Mary Louise Keohan, William D. Tap, Cristina Antonescu, Jonathan Landa, Li-Xuan Qin, Eric Gerard Dohrenwend, et al. "Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10002. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10002.
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10002 Background: CDK4 is amplified in approximately 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6 inhibitor PD0332991 (PD) inhibits growth and induces senescence in liposarcoma cell lines and xenografts. In a phase I trial of PD, several patients with progressive WD/DDLS had prolonged stable disease for several years. To determine the safety and efficacy of PD, a phase II study was performed. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age≥18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥1+). Pts received oral PD 200mg daily for 14 consecutive days in 21-day cycles. The primary endpoint was progression-free survival (PFS) at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD would be considered to have activity in WD/DDLS. Results: Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB+), 29 were enrolled and 27 were evaluable for the primary endpoint. Median age was 65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%), and the median number of prior regimens was 1 (range 1-5). PFS at 12 weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study significantly exceeded its primary endpoint. At the data cutoff, the median PFS was 18 weeks. Seven patients remain on study with stable disease at 18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3, 14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia (grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions were required in 24% of patients. Conclusions: Among patients with WD/DDLS with CDK4 amplification and RB expression who had actively progressing disease despite prior systemic therapy, treatment with the CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized phase 3 trial is planned.
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Dickson, Mark Andrew, William D. Tap, Mary Louise Keohan, Sandra P. D'Angelo, Mrinal M. Gounder, Ping Chi, Cristina R. Antonescu, et al. "Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10512. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10512.
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10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.
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Condurat, Alexandra-Larisa, Annika Wefers, Elizabeth Gonzalez, Jeyna Doshi, Prasidda Khadka, Selin Jessa, Jessica Tsai, et al. "LGG-35. FUNCTIONAL GENOMIC APPROACHES TO IDENTIFY THERAPEUTIC TARGETS IN MYB AND MYBL1 EXPRESSING PEDIATRIC LOW-GRADE GLIOMAS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii373. http://dx.doi.org/10.1093/neuonc/noaa222.417.
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Abstract AIM Recurrent structural variants involving MYB and MYBL1 transcription factors were recently identified in pediatric low-grade gliomas (pLGGs), such as the MYB-QKI rearrangement in Angiocentric Gliomas and truncations of MYBL1 (MYBL1tr) in Diffuse Astrocytomas. However, therapeutic dependencies induced by these alterations remain unexplored. METHODOLOGY We have generated in vitro pLGG mouse neural stem cell (NSCs) models engineered to harbor distinct MYB/MYBL1 genomic alterations. We used single cell RNA sequencing approaches to determine the transcriptional profile and dissect the central regulatory networks of our in vitro pLGG models over time. To identify specific genetic dependencies associated with MYB/MYBL1 mutations, we employed the Brie genome-wide mouse CRISPR lentiviral knockout pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS MYB/MYBL1 expression in neural stem cells induced activation of cell-cycle related, glioma-related and senescence-related pathways that are involved in normal development, including activation of MAPK and mTOR signaling which are also activated in human pLGG samples. Genome-scale CRISPR-cas9 screens in isogenic NSCs expressing MYB-QKI or MYBL1tr identified differential genetic dependencies relative to GFP controls. These included regulators of cell-cycle progression and several modulators of the ubiquitin-proteasome degradation pathway. Analysis of RNA-sequencing data from human tumors revealed several of these dependencies identified in the cell line model to be differentially expressed in MYB-altered pLGG tumors relative to normal brain. CONCLUSION Expression of MYB family alterations induces expression of key developmental and oncogenic pathways and genetic dependencies that represent potential therapeutic targets for MYB or MYBL1 rearranged pLGGs.
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Rezuș, Elena, Anca Cardoneanu, Alexandra Burlui, Andrei Luca, Cătălin Codreanu, Bogdan Tamba, Gabriela-Dumitrița Stanciu, Nicoleta Dima, Codruța Bădescu, and Ciprian Rezuș. "The Link Between Inflammaging and Degenerative Joint Diseases." International Journal of Molecular Sciences 20, no. 3 (January 31, 2019): 614. http://dx.doi.org/10.3390/ijms20030614.
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Aging is an inevitable process in the human body that is associated with a multitude of systemic and localized changes. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade proinflammatory status. Inflammaging refers to all the processes that contribute to the occurrence of various diseases associated with aging such as frailty, atherosclerosis, Alzheimer’s disease, sarcopenia, type 2 diabetes, or osteoarthritis. Inflammaging is systemic, chronic, and asymptomatic. Osteoarthritis and many age-related degenerative joint diseases are correlated with aging mechanisms such as the presence of an inflammatory microenvironment and the impaired link between inflammasomes and autophagy. There is a close relationship between chondrocyte activity and local articular environment changes due to cell senescence, followed by secretion of inflammatory mediators. In addition, systemic inflammaging can lead to cartilage destruction, pain, disability, and an impaired quality of life. The purpose of this review is to summarize the main mechanisms implicated in inflammaging and the connection it has with degenerative joint diseases.
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Bienfait, Lucie, Nicky D’Haene, Xavier Catteau, and Jean-Christophe Noël. "PIK3CA and p53 Mutations by Next Generation Sequencing in Lymphoepithelioma-Like Carcinoma of the Endometrium." Case Reports in Pathology 2018 (2018): 1–5. http://dx.doi.org/10.1155/2018/5894589.
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Lymphoepithelioma-like carcinoma of the endometrium is a very rare variant of endometrial carcinoma characterized by syncytial nests of pleomorphic epithelial cells and heavy infiltration of the stroma by lymphocytes (in particular CD8 cytotoxic T-lymphocytes) and plasma cells. Until now, only five cases have been characterized in this location. This report describes the clinicopathological and the molecular features of this unusual tumor. In particular, using the next generation sequencing (NGS) technique, we have demonstrated that this tumor could be associated with PIK3CA and p53 gene mutations. These data have not been reported to date and suggest that lymphoepithelioma-like carcinoma of the endometrium shares common molecular features with high grade endometrioid and serous-like endometrial carcinoma which are associated with poor outcome. Nevertheless, in endometrial lymphoepithelioma-like carcinoma, the alterations on cell cycle, apoptosis, and/or senescence secondary to p53 mutations could potentially be counterbalanced by the antitumoral response induced by CD8 cytotoxic T-lymphocytes numerous in these tumors.
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Zhou, Yi-Ting, Lin Zhu, Yunyun Yuan, Shuang Ling, and Jin-Wen Xu. "Effects and Mechanisms of Five Psoralea Prenylflavonoids on Aging-Related Diseases." Oxidative Medicine and Cellular Longevity 2020 (June 18, 2020): 1–21. http://dx.doi.org/10.1155/2020/2128513.
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During the aging process, senescent cells gradually accumulate in the organs; they secrete proinflammatory cytokines and other factors, collectively known as the senescence-associated secretory phenotype (SASP). SASP secretions contribute to “inflammaging,” which is a state of chronic, systemic, sterility, low-grade inflammatory microenvironment and a key risk factor in the development of aging-related diseases. Fructus psoraleae is a traditional Chinese medical herb best known for delaying aging and treating osteoporosis. Prenylflavonoids from fructus psoraleae are the main bioactive compounds responsible for its pharmacological applications, such as beaching, bavachinin, bavachalcone, isobavachalcone, and neobavaisoflavone. In previous decades, there have been some promising studies on the pharmacology of fructus psoraleae. Here, we focus on the anti-inflammatory and antiaging diseases of five psoralea prenylflavonoids, such as cardiovascular protection, diabetes and obesity intervention, neuroprotection, and osteoporosis, and discuss the mechanism of these active ingredients for better understanding the material basis and drug application of fructus psoraleae in Chinese medicine.
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Xu, Jin-Wen, Shuang Ling, and Jun Liu. "Higher-Order Chromatin Regulation of Inflammatory Gene Expression." Mediators of Inflammation 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/7848591.
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Whether it is caused by viruses and bacteria infection, or low-grade chronic inflammation of atherosclerosis and cellular senescence, the transcription factor (TF) NF-κB plays a central role in the inducible expression of inflammatory genes. Accumulated evidence has indicated that the chromatin environment is the main determinant of TF binding in gene expression regulation, including the stimulus-responsive NF-κB. Dynamic changes in intra- and interchromosomes are the key regulatory mechanisms promoting the binding of TFs. When an inflammatory process is triggered, NF-κB binds to enhancers or superenhancers, triggering the transcription of enhancer RNA (eRNA), driving the chromatin of the NF-κB-binding gene locus to construct transcriptional factories, and forming intra- or interchromosomal contacts. These processes reveal a mechanism in which intrachromosomal contacts appear to be cis-control enhancer-promoter communications, whereas interchromosomal regulatory elements construct trans-form relationships with genes on other chromosomes. This article will review emerging evidence on the genome organization hierarchy underlying the inflammatory response.
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Singareeka Raghavendra, Akshara, Danielle Kwiatkowski, Senthil Damodaran, Nicole M. Kettner, David Luis Ramirez, Dan S. Gombos, Kelly Hunt, Yu Shen, Khandan Keyomarsi, and Debu Tripathy. "Phase I safety and efficacy study of autophagy inhibition with hydroxychloroquine to augment the antiproliferative and biological effects of preoperative palbociclib plus letrozole for estrogen receptor-positive, HER2-negative metastatic breast cancer (MBC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 1067. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.1067.
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1067 Background: Endocrine therapy with a CDK4/6 inhibitor is standard of care for patients (pts) with estrogen-receptor-positive (ER+), HER2-negative MBC, yet resistance ultimately develops. We have shown that low doses of palbociclib activates autophagy, which reverses initial G1 cell cycle arrest. High concentrations of palbociclib induce senescence, but these are off target effects of the drug. The autophagy inhibitor hydroxychloroquine (HCQ) induces senescence at a lower (i.e. on-target) continuous dosing of palbociclib, in in vitro and in vivo models. This strategy is being tested in a phase I/II trial (NCT03774472). Results from the phase I portion are reported here. Methods: The phase I part of this study uses a dose escalation 3+3 design testing HCQ, 400, 600 and 800 mg daily (6 pts at 800 mg) with continuously dosed palbociclib at 75 mg and letrozole 2.5 mg daily. Dose limiting toxicity (DLT) includes any study drug-related grade ≥ 3 nonhematological (lab) toxicity. Responding pts may continue on therapy beyond 8 weeks for up to 52 weeks. Primary objective is to determine safety, tolerability and the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives are overall tumor response and time to progression. Eligible pts are ≥18 years of age, postmenopausal (ovarian suppression allowed) with ER+/HER2-negative MBC, ECOG performance status score of ≤1 and with adequate renal, hepatic, and hematologic function. Response is assessed per RECIST v1.1. Results: Between 9/24/18 and 12/15/20, 14 pts were evaluable for safety. Median age was 41 with Asian (1, 7.1%), Black (2, 14.3%) White (11, 78.6%) patients enrolled. No DLTs were observed. One pt progressed during the DLT period and 2 withdrew consent (one during the DLT period); two pts were replaced for DLT assessment. Reasons for coming off study were grade 3 skin toxicity (1), per protocol at 8 weeks (non-measurable or pt/physician preference, 9), and (2) full duration treatment at 50 and 52 weeks. Adverse events (AEs) of grade ≥3 were hematologic (29), metabolism/nutrition (2), musculoskeletal/ connective tissue (1), and skin/subcutaneous tissue (3), with no serious AEs reported. The percent of palbociclib doses held per pt due to neutrophil level ranged from 0-37.5% with no apparent relation to HCQ dose. Best response was partial (2) stable (11); and progression (1). For measurable disease, tumor decreases of 11%, 12%, 21%, 26%, 30%, 55% and increase in 1 pt by 55% were seen. Conclusions: This phase I study showed acceptable safety and no HCQ dose-toxicity relationship. The RP2D of HCQ is 800 mg/day with continuous dosing palbociclib at 75 mg/day and letrozole at 2.5 mg/day. The phase 2 trial will proceed in the neoadjuvant setting, with Ki67 proliferative index response as the primary endpoint. Clinical trial information: NCT03774472 .
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Jia, Yali, Ning Cao, Jinglei Zhai, Quan Zeng, Pei Zheng, Ruyu Su, Tuling Liao, et al. "HGF Mediates Clinical‐Grade Human Umbilical Cord‐Derived Mesenchymal Stem Cells Improved Functional Recovery in a Senescence‐Accelerated Mouse Model of Alzheimer's Disease." Advanced Science 7, no. 17 (July 6, 2020): 1903809. http://dx.doi.org/10.1002/advs.201903809.
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Houben, Amelie Pia, Anja Buchheiser, Murat Aktas, Johannes Fischer, Peter Wernet, and Gesine Koegler. "Age-Related Differences Between Unrestricted Somatic Stem Cells from Cord Blood and Bone Marrow Derived Mesenchymal Stroma Cells." Blood 112, no. 11 (November 16, 2008): 1335. http://dx.doi.org/10.1182/blood.v112.11.1335.1335.
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Abstract During the past years haematopoietic stem cells from unrelated umbilical cord blood have been increasingly used for treatment of leukaemia and genetic diseases. Human cord blood also contains a non-haematopoietic, adherently growing, CD45 negative, Oct4, nanog and Sox2 negative cell population with intrinsic multipotent differentiation potential, described as Unrestricted Somatic Stem Cells (USSC) (Kögler et al. 2004, Kögler et al. 2005, Kögler et al. 2006, Sensken et al. 2007, Liedtke et al. 2007, Liedtke et al.2008, Greschat et al. 2008, Ghodsizad A et al. 2008, Trapp et al. 2008). USSC can be cultivated GMP-grade reaching 1×109 cells in Passage 4–5 (correlating to 26,5 – 28 cumulative population doublings) without losing multipotency. To better understand and characterise USSC, we carried out in vitro studies concerning age-related changes in USSC-lines from human cord blood and in mesenchymal stroma cells derived from human bone marrow (BM-MSC). Telomerase activity and telomeres are involved in cell proliferation as well as the regulation of cell senescence (Lansdorp 2008). In this study 7 USSC-lines and 9 BM-MSC were analyzed for proliferation and senescence at different population doublings (PD). In vitro USSC have a higher proliferation capacity and accordingly a comparably more extended lifespan than BM-MSC. They undergo about 35 to 45 CPD whereas mean level of CPD from BM-MSC reaches 25. Telomere length of 12 USSC, 5 BM-MSC and 5 clonal populations of USSC were calculated after several PD and telomerase activity was measured. Mean terminal restriction fragment’s (TRF’s) length calculated from USSC after 31 CPD averages 9.7 kbp whereas mean telomere length from BM-MSC decreases already after 20 CPD to 7.9 kbp. After 47 CPD in clonal USSC populations mean TRF’s length is 6.1 kbp. Telomerase activity was analysed with RT-PCR and real time PCR. In contrast to previous publications telomerase activity was detected neither in BM-MSC (Parsch et al.) 2003 nor in USSCs (Manca et al. 2008). The percentage of senescent cells after the same number of CPD is significantly higher in BM-MSC than in USSC. About 80% of senescence was observed in BM-MSC but only 10% senescence in USSCs after 26 CPD. Wnt signalling is mandatory for self-renewal, cell proliferation and differentiation of haematopoietic stem cells (Reya et al. 2003). In primitive MSC populations Wnt signalling regulates mesenchymal lineage specification (Etheridge et al. 2004). For analysing the role of Wnt pathway in USSC development quantitative PCR Arrays have been carried out profiling the expression of 84 genes related to Wnt-mediated signal transduction. 8 different USSC populations have been analysed. In all USSCs factors essential for canonical and also non-canonical Wnt-signalling are present. Poor proliferating USSC with high adipogenic differentiation potential show a stronger expression of Wnt-signalling inhibitors like SFRP1, DKK1 and CXXC4. Based on age-related characteristics, USSC from cord blood are a much better source for regeneration compared to their adult MSC counterpart from bone marrow.
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Wellenhofer, Alfred, and Hermann Brustmann. "Expression of Human Telomerase Reverse Transcriptase in Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma: An Immunohistochemical Study With Survivin and p53." Archives of Pathology & Laboratory Medicine 136, no. 11 (November 1, 2012): 1359–65. http://dx.doi.org/10.5858/arpa.2011-0440-oa.
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Context.—Human telomerase reverse transcriptase (hTERT), an enzyme that enables cells to overcome replicative senescence and to divide indefinitely, is overexpressed in many cancers and their precursor lesions. Objective.—To test whether hTERT expression is related to neoplastic progression and resistance to apoptosis in vulvar epithelia. Design.—Immunoexpression of hTERT was evaluated in 101 formalin-fixed, paraffin-embedded archival vulvar epithelia consisting of normal squamous vulvar epithelia (n = 25), lichen sclerosus (n = 10), high-grade classic vulvar intraepithelial neoplasia (n = 16), differentiated vulvar intraepithelial neoplasia (n = 18), and vulvar invasive keratinizing squamous cell carcinoma (n = 32) and related to survivin and p53 expression. Immunostaining for all factors was scored for moderate and strong intensities with regard to quantity to determine upregulation and overexpression (score 0, 0% immunoreactive cells; score 1+, <5% immunoreactive cells; score 2+, 5% to 50% immunoreactive cells; score 3+, >50% immunoreactive cells). Score 3+ was considered as overexpression. Results.—Nuclear hTERT immunoexpression was closely related to survivin reactivity, increased from normal vulvar squamous epithelia to lichen sclerosus and to high-grade classic vulvar intraepithelial neoplasia, differentiated vulvar intraepithelial neoplasia, and invasive keratinizing squamous cell carcinoma (P < .001), and followed the morphologic distribution of atypical squamous epithelial cells. Overexpression of hTERT was comparable to that seen for p53 in invasive keratinizing squamous cell carcinoma (P = .62); significant differences were calculated for differentiated vulvar intraepithelial neoplasia (P = .003) and high-grade classic vulvar intraepithelial neoplasia (P = .001). Conclusion.—Human telomerase reverse transcriptase is upregulated in vulvar intraepithelial neoplasia and invasive keratinizing squamous cell carcinoma compared with nonneoplastic squamous epithelia of the vulva as an apparently early and preinvasive event in the neoplastic transformation, with development of cellular longevity and resistance to apoptosis by survivin activation as associated features, independent of the etiology of vulvar intraepithelial neoplasia.
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Cavezzi, Attilio, Lorenzo Ambrosini, Roberto Colucci, Giuseppe D. Ionna, and Simone Urg Urso. "Aging in the Perspective of Integrative Medicine, Psychoneuroendocrineimmunology and Hormesis." Current Aging Science 13, no. 2 (December 29, 2020): 82–91. http://dx.doi.org/10.2174/1874609812666191129095417.
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: Aging has been considered a progressive decrease of a living organism’s homeodynamics, which indicates a reduction of psycho-biological resilience. This narrative review provides an overview of the available literature related to the holistic approach of integrative medicine, Psychoneuroendocrineimmunology (PNEI) and hormesis in the aging process. On the basis of Pathophysiology of cell senescence and of chronic degenerative diseases, possible preventive/therapeutic pathways have been examined. Chronic low grade cellular inflammation and chronic stress have been shown as the general interlinked factors inducing aging, on the basis of complex biochemical, cell and multi-organ derangements. The main cell degenerative processes which have been related to aging are: altered mitochondria DNA/metabolism, excessive oxidative stress, glycation, alteration of autophagy and proteasome, and genome alterations. Literature about longevity-targeting interventions, beyond conventional medicine, describes a spectrum of possible measures to improve psycho-biological resilience, based on the PNEI paradigm, on hormesis and upon mitochondriatargeted interventions. Calorie restriction, exercising, fasting, nutraceuticals, sleep regulation, specific breathing, meditation and psychotherapy are discussed, among others.
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Schallmoser, Katharina, Nicole A. Hofmann, Andreas Reinisch, Anna Ortner, Claudia Url, Nathalie Etchart, Sylvia Joussen, Wolfgang Wagner, and Dirk Strunk. "Maintenance of Osteogenic Differentiation Capacity of MSPC Despite Amplified Proliferation Under Elevated Oxgen Conditions." Blood 120, no. 21 (November 16, 2012): 1916. http://dx.doi.org/10.1182/blood.v120.21.1916.1916.
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Abstract Abstract 1916 Clinical trials are underway to test the safety and efficacy of mesenchymal stem/progenitor cells (MSPCs) in various diseases. Due to their low frequency in situ, MSPC expansion is the prerequisite for dose finding studies as well as for most applications in adult patients. Notably, cultured MSPCs are a mixture of heterogeneous cells in various stages of cell cycle, proliferation and differentiation activity. A major safety concern for MSPC propagation is the risk of malignant transformation or premature senescence hampering MSPC function. The in vitro and consequently in vivo cellular characteristics may be influenced by factors as tissue source, age of the donor, materials and media, growth factors and oxygen pressure, arguing for standardized culture procedures at least in clinical trials. Defining the optimal conditions for efficient expansion of clinical grade cell therapeutics is still a challenge. We have previously shown that long-term expanded human bone marrow-derived MSPCs acquired senescence-related gene expression changes independent of culture conditions (Haematologica 2010). It has been speculated that elevated oxygen (20% air O2) contributes to genomic instability and malignant transformation in vitro. We therefore analyzed the influence of different oxygen conditions during long-term expansion on MSPC behavior focussing osteogenic differentiation. A gene panel previously defined as senescence markers was tested for differential expression after varying culture conditions. Bone marrow-derived MSPCs were expanded in α-MEM supplemented with 10% human platelet lysate replacing fetal bovine serum under physiologic conditions (5% O2) or air oxygen (20% O2) until spontaneous cessation of proliferation. Osteogenic induction was analyzed by Alizarin red. RNA was isolated from corresponding early and late passages and analyzed by qRT-PCR for p16ink4a, PARG1, CDKN2B, PTN and MCM6. In total, MSPCs could be cultured for 5 passages at 30 cells/cm2 and for 10 passages at 3,000 cells/cm2 for up to 85 days resulting in more cumulative population doublings (PDs) of MSPCs at air O2 compared to 5% O2 and in cultures with low compared to standard seeding density. Long-term cultured MSPCs after 40 PDs (air O2) and 35 PDs (5% O2) retained their osteogenic differentiation capacity. Compared to early passages, RT-PCR in late passages revealed an up-regulation of p16ink4a, PARG1 and CDKN2B without specific influence of culture conditions. PTN and MCM6 were significantly down-regulated, mainly in air O2 cultures with high seeding density correlating with diminished cell proliferation compared to low density cultures. There was no evidence of immortalization or malignant transformation. The capacity for in vivo bone formation of long term cultured MSPCs is currently tested in a novel humanized mouse model for bone and marrow niche formation (Blood 2012). Long term expansion of MSPCs under animal serum-free air oxygen conditions was safe and most efficient at low seeding density. Even in late passages (>30 PDs) MSPCs preserved their potential for osteogenic differentiation in vitro. At air oxygen delayed replicative senescence was observed, mainly at low seeding density. There was no evidence for immortalization or transformation indicating applicability of standardized ambient air culture conditions for pre-clinical cell expansion. Disclosures: No relevant conflicts of interest to declare.
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Rogers, IA, BW Philp, and TK Twigden. "Daminozide reduces mean weight of potato tubers but fails to increase uniformity." Australian Journal of Experimental Agriculture 28, no. 3 (1988): 385. http://dx.doi.org/10.1071/ea9880385.
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At 3 sites in South Australia daminozide reduced mean potato tuber weight by 9-13% (P<0.05). Total yield of potatoes was reduced by 6-11%, although the effect was significant (P< 0.01) at only 1 site (Purnong Landing, reduction 11%). There were no effects of daminozide on tuber number, uniformity of tuber weight, specific gravity of tubers (at 1 site) or yield of ware grade tubers (80-350 g fresh weight). However, daminozide increased yield of grades (90-130 g) by 40% and decreased yield of grades (260-350 g) by 32% (P<0.05). In achieving these results, rates of 0.85, 1.7, 3.4 and 6.8 kg a.i. ha-l of daminozide were about equally effective. We conclude that, unless there is a market requirement for tubers of 90-130 g in weight, daminozide should not be used for the cultivars Sebago, Exton and Coliban if haulms are killed by herbicide or disease from 15 to 30 days before natural plant senescence. Stem length and leaf area index were reduced early in the season by daminozide, but late in the season leaf area index was increased.
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Tava, Aldo, and Luciano Pecetti. "Chemical Investigation of Saponins from Twelve Annual Medicago Species and their Bioassay with the Brine Shrimp Artemia salina." Natural Product Communications 7, no. 7 (July 2012): 1934578X1200700. http://dx.doi.org/10.1177/1934578x1200700708.
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The saponin and sapogenin composition of the aerial growth of 12 annual Medicago species sampled at full senescence were investigated. Saponins were extracted from the plant material and obtained in a highly pure grade by reverse-phase chromatography, with a yield ranging from 0.38 ± 0.04% to 1.35 ± 0.08% dry matter, depending on the species. Sapogenins were then obtained after acid hydrolysis of saponins, and evaluated by GC/FID and GC/MS methods. Different compositions of the aglycone moieties were observed in the 12 Medicago species. Medicagenic acid was the dominant aglycone in M. × blancheana, M. doliata, M. littoralis, M. rotata, M. rugosa, M. scutellata, M. tornata and M. truncatula, bayogenin and hederagenin in M. arabica and M. rigidula, echinocystic acid in M. polymorpha, and soyasapogenol B in M. aculeata. The purified saponin mixtures, characterized by different chemical compositions, were then used in a toxicity test using the brine shrimp Artemia salina. The most active compounds were the saponins from M. arabica and M. rigidula with LD50 values of 10.1 and 4.6 μg/mL, respectively. A structure-activity relationship for the tested saponin mixtures was observed.
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Lowenthal, David T., Zebulon V. Kendrick, Joseph W. Starnes, and Eli Carmeli. "Effects of Caloric Restriction and Exercise Training on Skeletal Muscle Histochemistry in Aging Fischer 344 Rats." Scientific World JOURNAL 6 (2006): 1339–49. http://dx.doi.org/10.1100/tsw.2006.183.
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The purpose of this study was to determine the effects of calorie restriction and exercise on hindlimb histochemistry and fiber type in Fischer 344 rats as they advanced from adulthood through senescence. At 10 months of age, animals were divided into sedentary fedad libitum, exercise (18 m/min, 8% grade, 20 min/day, 5 days/week) fedad libitum, and calorie restricted by alternate days of feeding. Succinic dehydrogenase, myosin adenosine triphosphatase (mATPase at pH 9.4), nicotine adenonine dinucleotide reductase, and Periodic Acid Shiff histochemical stains were performed on plantaris and soleus muscles. The results indicated that aging resulted in a progressive decline in plantaris Type I muscle fiber in sedentary animals, while exercise resulted in maintenance of these fibers. The percent of plantaris Type II fibers increased between 10 and 24 months of age. Exercise also resulted in a small, but significant, increase in the percentage of plantaris Type IIa fibers at 24 months of age. The soleus fiber distribution for Type I fibers was unaffected by increasing age in all groups of animals. The implications of these results suggest the implementation of exercise as a lifestyle modification as early as possible.