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1
Inami, K. "MCP-PMT development for Belle-II TOP counter." Physics Procedia 37 (2012): 683–90. http://dx.doi.org/10.1016/j.phpro.2012.02.417.
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Inami, K., N. Kishimoto, Y. Enari, M. Nagamine, and T. Ohshima. "A 5 ps TOF-counter with an MCP–PMT." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 560, no. 2 (May 2006): 303–8. http://dx.doi.org/10.1016/j.nima.2006.01.027.
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Jung, Seok-Kyu, and Jung-Myung Lee. "(32) Effects of 1-MCP Treatments on Several Major Apple Cultivars Grown in Korea." HortScience 40, no. 4 (July 2005): 1004D—1004. http://dx.doi.org/10.21273/hortsci.40.4.1004d.
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Fruits of `Tsugaru' (an early maturing cultivar), `Hongro' (mid-season cultivar), and `Fuji' (late cultivar), were harvested at different times of the year, depending upon their maturity, and treated with 1-MCP at 0.0, 0.5, 1.0, and 2.0 ppm for 8-24 hours. Fruits were also treated with 1-MCP at different times after harvest. Portions of 1-MCP-treated apples were also treated with ethylene in order to study the interaction between 1-MCP and ethylene. In other experiments, fruits were treated with ethylene first and then treated again with 1-MCP. Major results are as follows. Treatment of 1-MCP greatly retarded the senescence of `Tsugaru' apple stored at room temperatures as compared with the control. The sooner the time of 1-MCP treatment after harvest of fruit, the greater was the 1-MCP effect. In contrast to the time of 1-MCP treatment, the concentration of 1-MCP and duration of 1-MCP infiltration in a closed chamber exhibited only a minor effect. Ethylene treatment immediately before and/or after the 1-MCP treatment showed only the 1-MCP effect, thus clearly showing that 1-MCP treatment could completely reverse or counter the ethylene effect in `Fuji' apples. Repeated treatments of 1-MCP after a certain period of low temperature storage of `Fuji' apples were more effective than a single treatment. Parameters related with fruit quality will be discussed in detail.
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Gruss, H. J., M. A. Brach, R. R. Schumann, and F. Herrmann. "Regulation of MCP-1/JE gene expression during monocytic differentiation." Journal of Immunology 153, no. 11 (December 1, 1994): 4907–14. http://dx.doi.org/10.4049/jimmunol.153.11.4907.
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Abstract We examined the expression of the MCP-1/JE gene in freshly prepared human monocytes and again after either in vitro or in vivo maturation of these cells. We show that previously unstimulated blood monocytes of healthy individuals prepared by adherence procedures display high levels of MCP-1/JE mRNA and protein. Monocytes that were not previously exposed to activational plastic surfaces but were separated from other blood cells by counter-flow centrifugal elutriation expressed severalfold lower MCP-1/JE transcript and protein levels. Treatment of these cells with endotoxin was associated with the down-regulation of MCP-1/JE mRNA and protein levels. In contrast, exposure to IFN-gamma resulted in increased MCP-1/JE gene expression. During the process of in vitro maturation of monocytes into macrophages, a gradual decrease of MCP-1/JE mRNA and protein expression was noted. Both mature (day 8) blood monocyte-derived culture macrophages and peritoneal macrophages completely failed to express the MCP-1/JE gene, which could be restored after exposure to IFN-gamma and cross-linking of macrophage Fc gamma R with murine solid phase IgG2a mAbs; however, endotoxin failed to induce MCP-1/JE expression in these cells.
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Calvi, M., S. Capelli, P. Carniti, C. Gotti, and G. Pessina. "Single photon counting performance of the Auratek-Square MCP-PMT." Journal of Instrumentation 17, no. 11 (November 1, 2022): P11009. http://dx.doi.org/10.1088/1748-0221/17/11/p11009.
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Abstract This paper reports on the time resolution of the Auratek-Square MCP-PMT, a multi-anode microchannel plate photomultiplier produced by Photek. When operating as single photon counter at low photon rate and with a single pixel illuminated it shows a transit time spread (jitter) of ∼100 ps FWHM, saturating at high rate, above ∼100 kHz/mm2. The worsening of the timing performance depends on the bias voltage between the photocathode and the MCP input and between the MCP slabs. The charge sharing between neighbouring pixels can become a major crosstalk source if not accounted for, degrading the time resolution to ∼170 ps FWHM when the entire pixel area is illuminated.
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Wierzbicki, Jarosław, Artur Lipiński, Iwona Bednarz-Misa, Łukasz Lewandowski, Katarzyna Neubauer, Paulina Lewandowska, and Małgorzata Krzystek-Korpacka. "Monocyte Chemotactic Proteins (MCP) in Colorectal Adenomas Are Differently Expressed at the Transcriptional and Protein Levels: Implications for Colorectal Cancer Prevention." Journal of Clinical Medicine 10, no. 23 (November 26, 2021): 5559. http://dx.doi.org/10.3390/jcm10235559.
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The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression.
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Nagaraju, Raju, Apurva Kumar R. Joshi, Sowmya Giriyapura Vamadeva, and Rajini Padmanabhan Sharda. "Plasma paraoxonase1 activity in rats treated with monocrotophos: a study of the effect of duration of exposure." Interdisciplinary Toxicology 12, no. 3 (November 1, 2019): 129–35. http://dx.doi.org/10.2478/intox-2019-0015.
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Abstract We have earlier demonstrated the potential of monocrotophos (MCP), a highly toxic organophosphorus insecticide (OPI), to elicit insulin resistance in rats after chronic exposure. Given the understanding of role of paraoxonase1 (PON1) in OPI toxicity and diabetes pathology, this study was envisaged to understand the effect of duration of exposure to MCP on plasma PON1 activity in rats. Rats were administered MCP per os at 1/20 and 1/10th LD50 as daily doses for 180 days. Interim blood samples were collected at 15, 30, 45, 90 and 180 d for analysis of plasma parameters. Exposure to MCP for 45 resulted in persistent trend of hyperinsulinemia, while significant increase in fasting glucose levels was observed after 180 days. MCP caused suppression of plasma cholinesterase activity though the study period, albeit extent of inhibition was more severe during the early phase of the study. Exposure to MCP for 180 d resulted in hypertriglyceridemia and marginal decrease in HDL-C levels. MCP failed to modulate PON1 activity in plasma during the early phase of the study (up to 45 d). However, prolonged exposure resulted in significant increase in the plasma PON1 activity. This suggests that manifestation of insulin resistance in rats subjected to chronic exposure to MCP is associated with increase in PON1 activity. Our work provides rationale for studying whether the increase in PON1 activity observed in the present study serves to counter the deleterious effect of long term exposure to organophosphorus insecticides on metabolic homeostasis.
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Akiyoshi, Takashi, Zhe Wang, Tomoko Kaneyasu, Osamu Gotoh, Norio Tanaka, Sayuri Amino, Noriko Yamamoto, et al. "Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer." JAMA Network Open 6, no. 1 (January 20, 2023): e2252140. http://dx.doi.org/10.1001/jamanetworkopen.2022.52140.
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ImportanceNeoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, estimating response to CRT remains an unmet clinical challenge.ObjectiveTo investigate and better understand the transcriptomic factors associated with response to neoadjuvant CRT and survival in patients with advanced rectal cancer.Design, Setting, and ParticipantsA single-center, retrospective, case series was conducted at a comprehensive cancer center. Pretreatment biopsies from 298 patients with rectal cancer who were later treated with neoadjuvant CRT between April 1, 2004, and September 30, 2020, were analyzed by RNA sequencing. Data analysis was performed from July 1, 2021, to May 31, 2022.ExposuresChemoradiotherapy followed by total mesorectal excision or watch-and-wait management.Main Outcomes and MeasuresTranscriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using microenvironment cell populations-counter (MCP-counter) scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade 3 to 4 or whose care was managed by the watch-and-wait approach for more than 3 years were defined as good responders.ResultsOf the 298 patients in the study, 205 patients (68.8%) were men, and the median age was 61 (IQR, 52-67) years. Patients classified as CMS1 (6.4%) had a significantly higher rate of good response, albeit survival was comparable among the 4 subtypes. Good responders exhibited an enrichment in various immune-related pathways, as determined by ssGSEA. Microenvironment cell populations-counter scores for cytotoxic lymphocytes were significantly higher for good responders than nonresponders (median, 0.76 [IQR, 0.53-1.01] vs 0.58 [IQR, 0.43-0.83]; P < .001). Cytotoxic lymphocyte MCP-counter score was independently associated with response to CRT, as determined in the multivariable analysis (odds ratio, 3.81; 95% CI, 1.82-7.97; P < .001). Multivariable Cox proportional hazards regression analysis, including postoperative pathologic factors, revealed the cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (hazard ratio [HR], 0.38; 95% CI, 0.16-0.92; P = .03) and overall survival (HR, 0.16; 95% CI, 0.03-0.83; P = .03).Conclusions and RelevanceIn this case series of patients with rectal cancer treated with neoadjuvant CRT, the cytotoxic lymphocyte score in pretreatment biopsy samples, as computed by RNA sequencing, was associated with response to CRT and survival. This finding suggests that the cytotoxic lymphocyte score might serve as a biomarker in personalized multimodal rectal cancer treatment.
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Matsuoka, K. "Development and production of the MCP-PMT for the Belle II TOP counter." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 766 (December 2014): 148–51. http://dx.doi.org/10.1016/j.nima.2014.05.003.
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White, Kieron, Maxime Meylan, Antoine Bougoüin, Kate Connor, Manuela Salvucci, Franck Bielle, Jochen H. M. Prehn, et al. "TAMI-51. IDENTIFYING NEW TUMOR MICROENVIRONMENT (TME) CONTEXTS OF VULNERABILITY IN GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii224. http://dx.doi.org/10.1093/neuonc/noaa215.938.
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Abstract Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor with 85% of patients dying within two years. New effective precision medicine therapies are urgently required, especially for isocitrate dehydrogenase wild-type (IDHwt) disease. Despite efforts to subtype patients based on molecular profiles, this approach has yet failed to direct treatment strategies. Further interrogation of the tumor microenvironment (TME) across molecular subtypes and identification of new TME specific subtypes may guide new directions for future therapies. Here, we analysed transcriptomic data from selected GLIOTRAIN(www.gliotrain.eu)(n=120) and TCGA(n=69) IDHwt patients. Firstly, the microenvironment cell population (MCP)-counter method (a gene-expression-based TME deconvolution tool) was validated for use in the brain tumor setting using quantitative multiplex immunohistochemistry. In this context, immune markers (CD20/CD3/CD68/CD8) were significantly correlated with MCP-counter scores. We are currently optimizing and validating a vessel-density and microglial RNA-signature to provide a more robust representation of brain TME. Next, using MCP-counter, the TME composition of IDHwt tumors was assessed within proneural (24%), classical (38%) and mesenchymal (38%) subtypes. We initially classified the GLIOTRAIN cohort into 3 novel clusters characterised by differences in TME composition and validated our findings in the TCGA cohort. A TME-high group (37%) is characterized by elevated presence of lymphocytes and myeloid cells, and presents a high level of immune checkpoint genes: PDCD1(PD1) and CTLA4. In addition, the presence of tertiary lymphoid structures (TLS) is a feature of TMEhigh/mesenchymal+ patients. This finding has been validated by IHC and RNA-signature. TME-med (38%) displayed heterogenous immune populations and the TME-low (25%) represented an ‘immune-desert’ group. There was no significant difference in OS based on these TME subtypes(p=0.50). We hypothesise that PD1/CTLA4 blockade might be an effective treatment strategy in TME-high patients. These hypotheses will be tested (in the adjuvant setting) using appropriate syngeneic disease models which incorporate surgical resection.
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WHITE, NICHOLAS J. "Capitalism and Counter-insurgency? Business and Government in the Malayan Emergency, 1948-57." Modern Asian Studies 32, no. 1 (February 1998): 149–77. http://dx.doi.org/10.1017/s0026749x98002996.
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Contemporary critics argued that counter-insurgency in Malaya represented more than the defeat of militant communism. Britain's campaign against the Malayan Communist Party (MCP) was seen as resulting from British government collaboration with British capitalists to maintain profits at the expense of the legitimate aspirations of Malayan workers. More recently, it has been argued that the declaration of the emergency in June 1948 was a pre-emptive strike intended to ‘resolve the problem of political control’ and prevent the ‘radical nationalist forces organized around the MCP’ from gaining a nation-wide following. According to this view, government strategy was to ‘manage nationalism’ and ‘control’ decolonization so as to preserve the position of British capital in Malaya. For marxists, the emergency is seen as part of the process of establishing ‘neo-colonialism’. Even for less determinist models, the general complicity between British government and British business in colonial counter-insurgency campaigns is apparently clear. In primary-producing territories like Malaya, the harmony of interests between ‘gentlemanly capitalist’ officials and unofficials (centred on the City of London) ensured that after 1945 ‘coercion tended to be the first resort of policy’. The majority of scholarly output on the emergency has focused on official and guerrilla strategies leaving aside the role of business interests. As a result, the relationship between British business and British government has not been explored in depth. The present article seeks to fill this historiographical gap by reassessing official and commercial interaction in politically disturbed Malaya.
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Hirose, S. "Performance of the MCP-PMT for the Belle II TOP counter in a magnetic field." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 766 (December 2014): 163–66. http://dx.doi.org/10.1016/j.nima.2014.05.012.
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Olko, Pavel, Maciej Budzanowski, Pavel Bilski, Snezana Milosevic, Barbara Obryk, Eva Ochab, Miroslav Simic, Peter Stegnar, Michael Waligorski, and Zora Zunic. "Application of MCP-N (Lif: Mg, Cu, P) TL detectors in monitoring environmental radiation." Nuclear Technology and Radiation Protection 19, no. 1 (2004): 20–25. http://dx.doi.org/10.2298/ntrp0401020o.
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Thermoluminescent MCP-N detectors based on LiF:Mg,Cu,P are by about 2 orders of magnitude more sensitive than TLD-100 detectors based on conventional LiF:Mg,Ti, which makes it possible to use them in short-term monitoring of ionizing radiation in the environment (e. g., over a two-week period, rather than over 3-12 months). We describe the properties of MCP-N detectors and methods of their application in environmental monitoring. The system was tested in short and long-term exposure periods at 100 sites around Krakow region. MCP-N detectors were then applied to measure variation of radiation dose rate at four selected villages in Serbia, where depleted uranium ammunition was deployed in 1999. Together with short-term thermoluminescent dosimetry, in situ measurements using proportional counters were per formed in order to assess the range of variation of natural radiation background in these villages. The mean terrestrial kerma dose rate in these villages was found to vary between 85 and 116 nGyh?1 and the average ambient dose equivalent rate H*(10) determined by thermoluminescent detectors and by proportional counter measurements was 160 nSvh?1. These values of natural radiation back ground dose rates can be applied as reference levels for field measurements around other sites where depleted uranium ammunition was deployed.
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Sidorenko, V. P., O. I. Radkevich, Yu V. Prokofiev, Yu V. Tayakin, and T. M. Virozub. "VLSI for a new generation of microelectronic coordinate-sensitive etectors with an extended field of analysis for use in mass spectrometry." Технология и конструирование в электронной аппаратуре, no. 1 (2018): 13–20. http://dx.doi.org/10.15222/tkea2018.1.13.
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The authors have developed a custom VLSI chip for the new generation of MCSD devices — multichip detectors with an extended analysis field and higher technical characteristics, which can be used in elemental analysis devices to simultaneously determine the elements that make up the material with high sensitivity and accuracy in real time. VLSI chip contains 384 channels with a spatial resolution of 25 microns has been integrated onto a single chip, each channel has a metal anode to collect the electrons as they emerge from the microchannel plate electron multiplier (MCP); a charge sensitive amplifier to produce a digital signal in response to the electron pulse and a 16-bit counter associated with it to accumulate the counts as they arrive and circuitry to read out the data sequentially from all channels in the microcircuit. The VLSI chip is designed according to the design rules standard 1,0 µm CMOS process. The speed of the microcircuit in the counting mode is at least 15 MHz, in the mode of reading information from the counters — more than 10 MHz. The output from the 16-bit counters on the detectors is presented via an 8-bit port and is read into the control electronics sequentially from each counter in turn in low-byte, high-byte order. The circuit has been designed in such a way that an arbitrary number of detector chips may be abutted together on a substrate behind the MCP, allowing for long focal plane detectors to be built, limited only by the size of MCPs available.
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Wawrzeniak, Keith, Gauri Gaur, Eva Sapi, and Alireza G. Senejani. "Effect of Borrelia burgdorferi Outer Membrane Vesicles on Host Oxidative Stress Response." Antibiotics 9, no. 5 (May 25, 2020): 275. http://dx.doi.org/10.3390/antibiotics9050275.
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Outer membrane vesicles (OMVs) are spherical bodies containing proteins and nucleic acids that are released by Gram-negative bacteria, including Borrelia burgdorferi, the causative agent of Lyme disease. The functional relationship between B. burgdorferi OMVs and host neuron homeostasis is not well understood. The objective of this study was to examine how B. burgdorferi OMVs impact the host cell environment. First, an in vitro model was established by co-culturing human BE2C neuroblastoma cells with B. burgdorferi B31. B. burgdorferi was able to invade BE2C cells within 24 h. Despite internalization, BE2C cell viability and levels of apoptosis remained unchanged, but resulted in dramatically increased production of MCP-1 and MCP-2 cytokines. Elevated secretion of MCP-1 has previously been associated with changes in oxidative stress. BE2C cell mitochondrial superoxides were reduced as early as 30 min after exposure to B. burgdorferi and OMVs. To rule out whether BE2C cell antioxidant response is the cause of decline in superoxides, superoxide dismutase 2 (SOD2) gene expression was assessed. SOD2 expression was reduced upon exposure to B. burgdorferi, suggesting that B. burgdorferi might be responsible for superoxide reduction. These results suggest that B. burgdorferi modulates cell antioxidant defense and immune system reaction in response to the bacterial infection. In summary, these results show that B. burgdorferi OMVs serve to directly counter superoxide production in BE2C neurons, thereby ‘priming’ the host environment to support B. burgdorferi colonization.
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Bradley, Linda M., Valérie C. Asensio, Li-Karine Schioetz, Judith Harbertson, Troy Krahl, Gail Patstone, Nigel Woolf, Iain L. Campbell, and Nora Sarvetnick. "Islet-Specific Th1, But Not Th2, Cells Secrete Multiple Chemokines and Promote Rapid Induction of Autoimmune Diabetes." Journal of Immunology 162, no. 5 (March 1, 1999): 2511–20. http://dx.doi.org/10.4049/jimmunol.162.5.2511.
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Abstract Migration of CD4 cells into the pancreas represents a hallmark event in the development of insulin-dependent diabetes mellitus. Th1, but not Th2, cells are associated with pathogenesis leading to destruction of islet β-cells and disease onset. Lymphocyte extravasation from blood into tissue is regulated by multiple adhesion receptor/counter-receptor pairs and chemokines. To identify events that regulate entry of CD4 cells into the pancreas, we transferred Th1 or Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells into immunodeficient (NOD.scid) recipients. Although both subsets infiltrated the pancreas and elicited multiple adhesion receptors (peripheral lymph node addressin, mucosal addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on vascular endothelium, entry/accumulation of Th1 cells was more rapid than that of Th2 cells, and only Th1 cells induced diabetes. In vitro, Th1 cells were also distinguished from Th2 cells by the capacity to synthesize several chemokines that included lymphotactin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1α, whereas both subsets produced macrophage inflammatory protein-1β. Some of these chemokines as well as RANTES, MCP-3, MCP-5, and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10 (IP-10) were associated with Th1, but not Th2, pancreatic infiltrates. The data demonstrate polarization of chemokine expression by Th1 vs Th2 cells, which, within the microenvironment of the pancreas, accounts for distinctive inflammatory infiltrates that determine whether insulin-producing β-cells are protected or destroyed.
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Toriuchi, Kohki, Toshie Kihara, Hiromasa Aoki, Hiroki Kakita, Satoru Takeshita, Hiroko Ueda, Yasumichi Inoue, et al. "Monocyte-Derived miRNA-1914-5p Attenuates IL-1β–Induced Monocyte Adhesion and Transmigration." International Journal of Molecular Sciences 24, no. 3 (February 1, 2023): 2829. http://dx.doi.org/10.3390/ijms24032829.
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Atherosclerosis can lead to cardiovascular and cerebrovascular diseases. Atherosclerotic plaque formation is promoted by the accumulation of inflammatory cells. Therefore, modulating monocyte recruitment represents a potential therapeutic strategy. In an inflammatory state, the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) is upregulated in endothelial cells. We previously reported that miR-1914-5p in endothelial cells suppresses interleukin (IL)-1β–induced ICAM-1 expression and monocyte adhesion to endothelial cells. However, whether monocyte miR-1914-5p affects monocyte recruitment is unclear. In this study, IL-1β decreased miR-1914-5p expression in a human monocyte cell line. Moreover, miR-1914-5p inhibition enhanced adhesion to endothelial cells with the upregulation of macrophage-1 antigen (Mac-1), a counter-ligand to ICAM-1. Transmigration through the endothelial layer was also promoted with the upregulation of monocyte chemotactic protein-1 (MCP-1). Furthermore, a miR-1914-5p mimic suppressed IL-1β–induced monocyte adhesion and transmigration in monocytes with Mac-1 and MCP-1 downregulation. Further investigation of miR-1914-5p in monocytes could lead to the development of novel diagnostic markers and therapeutic strategies for atherosclerosis.
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Zhang, Haofuzi, Yutao Huang, Erwan Yang, Xiangyu Gao, Peng Zou, Jidong Sun, Zhicheng Tian, et al. "Identification of a Fibroblast-Related Prognostic Model in Glioma Based on Bioinformatics Methods." Biomolecules 12, no. 11 (October 30, 2022): 1598. http://dx.doi.org/10.3390/biom12111598.
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Background: Glioma is the most common primary tumor of the central nervous system with a high lethality rate. This study aims to mine fibroblast-related genes with prognostic value and construct a corresponding prognostic model. Methods: A glioma-related TCGA (The Cancer Genome Atlas) cohort and a CGGA (Chinese Glioma Genome Atlas) cohort were incorporated into this study. Variance expression profiling was executed via the “limma” R package. The “clusterProfiler” R package was applied to perform a GO (Gene Ontology) analysis. The Kaplan–Meier (K–M) curve, LASSO regression analysis, and Cox analyses were implemented to determine the prognostic genes. A fibroblast-related risk model was created and affirmed by independent cohorts. We derived enriched pathways between the fibroblast-related high- and low-risk subgroups using gene set variation analysis (GSEA). The immune infiltration cell and the stromal cell were calculated using the microenvironment cell populations-counter (MCP-counter) method, and the immunotherapy response was assessed with the SubMap algorithm. The chemotherapy sensitivity was estimated using the “pRRophetic” R package. Results: A total of 93 differentially expressed fibroblast-related genes (DEFRGs) were uncovered in glioma. Seven prognostic genes were filtered out to create a fibroblast-related gene signature in the TCGA-glioma cohort training set. We then affirmed the fibroblast-related risk model via TCGA-glioma cohort and CGGA-glioma cohort testing sets. The Cox regression analysis proved that the fibroblast-related risk score was an independent prognostic predictor in prediction of the overall survival of glioma patients. The fibroblast-related gene signature revealed by the GSEA was applicable to the immune-relevant pathways. The MCP-counter algorithm results pointed to significant distinctions in the tumor microenvironment between fibroblast-related high- and low-risk subgroups. The SubMap analysis proved that the fibroblast-related risk score could predict the clinical sensitivity of immunotherapy. The chemotherapy sensitivity analysis indicated that low-risk patients were more sensitive to multiple chemotherapeutic drugs. Conclusion: Our study identified prognostic fibroblast-related genes and generated a novel risk signature that could evaluate the prognosis of glioma and offer a theoretical basis for clinical glioma therapy.
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Hummel, Justin, Yuanyuan Shen, Iiulia Innokenteva, Christos Papageorgiou, Chi-Ren Shyu, and Jonathan B. Mitchem. "Network analysis to reveal BTK as a link between myeloid and T cells in TLR signaling in colorectal cancer." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 30. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.30.
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30 Background: Colorectal cancer (CRC) is the second-leading cause of cancer mortality in the US today. Recent advances in immunotherapy have only been shown to benefit a limited subgroup of patients with CRC. In other malignancies, activation of Toll-like receptors (TLRs) has been shown to overcome resistance to immunotherapy, such as immune checkpoint inhibition (ICI). In this study, using publicly available data and informatics-based analysis, we identified BTK as a critical link between TLR signaling and T cells in the CRC tumor microenvironment. Methods: Using RNA-seq data from The Cancer Genome Atlas (TCGA) and the Microenvironment Cell Populations (MCP)-Counter, abundance scores were generated for the tumor microenvironment of each patient. A curated TLR gene panel was generated using Reactome and GO. Pearson analysis was used to evaluate each pairwise combination of genes and cell-types. Significance was determined by the correlation coefficient, r ≥ | 0.7 | with a p-value < 0.05. Network analysis was performed using the Girvan–Newman algorithm to establish critical connections across these features. Results: After establishing a 453 gene TLR panel and creating MCP-Counter scores, correlation analysis demonstrated strong correlations between 54 different genes and 7 cell-types. As expected the most genes were associated with monocytic lineage cells' (30) and 'myeloid dendritic cells' (7). Only 5 genes were significantly associated with 'T cells'. Genes and cell-types that were highly correlated were then further analyzed for network association. From this analysis, BTK was identified as a critical edge acting as the primary link between ‘myeloid cells’ and ‘T cells’. Conclusions: Developing novel strategies for the treatment of CRC is critical and immunotherapy represents an area ripe for advancement. Informatics based analysis combined with publicly available data provides us with an opportunity to shape pre-clinical and translational studies. Using this approach, we have identified BTK as a critical link between myeloid cells and T cells in the tumor microenvironment in CRC. Further studies in our laboratory will focus confirming these findings for translation into patients.
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Malouf, Gabriel G., Anthony Dohan, Hui Yao, Roger Mouawad, Raphael Carapito, Seiamak Bahram, INSTITUT CANCEROLOGIE Meyer KHAYAT, Jean-Emannuel Kurtz, Xiaoping Su, and Marc Pocard. "Comprehensive characterization of pseudomyxoma peritonei." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15701-e15701. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15701.
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e15701 Background: Pseudomyxoma peritonei (PMP) is a rare malignant tumor characterized by the infiltration of the peritoneum by mucus-secreting tumor cells. The genetic landscape of these tumors and correlation with clinico-pathological tumor features is unclear to date. Methods: We performed whole-exome sequencing (WES) on 8 PMPs and matched normal. We then validated our finding using ultra-deep sequencing of hotspot mutations (~82.270 x) in 45 clinically annotated samples. In addition, bulk RNAseq was performed on 10 samples and MCP-counter was used to infer absolute abundance of eight immune and two stromal cell populations. Results: Overall, 323 somatic mutations were identified through WES with most frequent mutations involving GNAS (R186H) (50%), KRAS (G12D) (50%), AHNAK2 (25%) and ATXN1 (25%). Furthermore, ultra-deep sequencing uncovered KRAS, GNAS and IDH1/2 hotspots mutations in 16 (35.5%), 11 (24.4%) and 2 (4.4%) PMPs, respectively. Strikingly, KRAS mutations were enriched in females (79% vs 39%, p = 0.03) while GNAS in males (67% vs 28%, p = 0.04). No other significant associations were identified between mutations and other clinico-pathological features. Using MCP-counter, fibroblasts, endothelial cells and moncoytic cells were the most frequent inferred cells. Unsupervised clustering using expression of most variable cells identified two PMP clusters, namely C1 (n = 4) and C2 (n = 6). C2 cluster displayed higher T cells as compared to C1 (p < 0.0001), consistent with increased cytotoxic lymphocytes (p = 0.04). Notably, C2 was enriched for tumors with higher grade as compared to C1 (80% vs 0%; p = 0.04). Conclusions: Our study represents the largest study to data exploring genetic and immune alterations in PMPs. We uncovered puzzling associations between genetic landscape of PMPs and patients gender, which deserve further validation in an independent cohort. The association of high-grade tumors with increased tumor infiltrating lymphocytes suggests the existence of an immunogenic microenvironment; PD-1/PD-L1 blockade might represent a therapeutic option for these patients.
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White, Kieron, Kate Connor, Maxime Meylan, Antoine Bougoüin, Manuela Salvucci, Franck Bielle, Alice O’Farrell, et al. "TMIC-10. IDENTIFICATION, VALIDATION AND BIOLOGICAL CHARACTERIZATION OF NOVEL GLIOBLASTOMA TUMOUR MICROENVIRONMENT SUBTYPES: IMPLICATIONS FOR PRECISION IMMUNOTHERAPY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii273. http://dx.doi.org/10.1093/neuonc/noac209.1054.
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Abstract New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles, have failed to direct treatment strategies. We hypothesized that interrogation of the GBM tumor microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision treatment strategies. To this end, a refined and validated microenvironment cell population (MCP)-counter method was applied to > 800 GBM patient tumours and validated by multiplex-immunohistochemistry. The MCP-counter deconvolution method interrogates the TME composition from transcriptomic data. Using this refined method, we classified the GLIOTRAIN(www.gliotrain.eu) IDHwt GBM cohort (n=123) into 3 novel clusters characterised by differences in TME composition and subsequently validated findings in the TCGA (n=69), CGGA (n=72) and DUKE (unpublished)(n=162) cohorts. TMEHigh tumours (30%) displayed elevated immune populations, functional orientation markers, immune checkpoint genes, and upregulated immunoregulatory pathways. Moreover, tertiary lymphoid structures were a feature of TMEHigh/mesenchymal+ patients. TMEMed (46%) tumours displayed heterogeneous immune populations and upregulated neuronal signalling pathways. TMELow (24%) tumours represented an ‘immune-desert’ group, high EGFR mutation frequency and upregulated EGFR signalling pathways. Longitudinal analysis of the GLASS cohort revealed TME-subtype transitions upon recurrence, influenced by TME composition changes. Finally, assessment of three GBM immunotherapy clinical trial cohorts revealed that TMEHigh patients treated with neo-adjuvant anti-PD1 have a significantly improved survival (P=0.04). Moreover, TMEHigh patients treated with anti-PD1 and an oncolytic virus (PVSRIPO) in the adjuvant setting, showed a trend towards improved survival (P=0.15 and P=0.056 respectively). Overall, we have established a novel TME-based classification system for application in intracranial malignancies. This system may be used to better inform a precision targeting approach in the brain tumour setting. For example, we hypothesise that patients bearing TMELow tumours may be amenable to neoadjuvant anti-TIM3 + EGFR inhibitor, TMEMed to anti-angiogenic immunotherapy, and TMEHigh patients to neoadjuvant anti-PD1 + anti-CTLA4.
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Carpi, Sara, Stefano Quarta, Stefano Doccini, Anella Saviano, Noemi Marigliano, Beatrice Polini, Marika Massaro, et al. "Tanshinone IIA and Cryptotanshinone Counteract Inflammation by Regulating Gene and miRNA Expression in Human SGBS Adipocytes." Biomolecules 13, no. 7 (June 23, 2023): 1029. http://dx.doi.org/10.3390/biom13071029.
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Inflammation of the adipose tissue contributes to the onset and progression of several chronic obesity-related diseases. The two most important lipophilic diterpenoid compounds found in the root of Salvia milthorrhiza Bunge (also called Danshen), tanshinone IIA (TIIA) and cryptotanshinone (CRY), have many favorable pharmacological effects. However, their roles in obesity-associated adipocyte inflammation and related sub-networks have not been fully elucidated. In the present study, we investigated the gene, miRNAs and protein expression profile of prototypical obesity-associated dysfunction markers in inflamed human adipocytes treated with TIIA and CRY. The results showed that TIIA and CRY prevented tumor necrosis factor (TNF)-α induced inflammatory response in adipocytes, by counter-regulating the pattern of secreted cytokines/chemokines associated with adipocyte inflammation (CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, IL-6, IL-8, MIF and PAI-1/Serpin E1) via the modulation of gene expression (as demonstrated for CCL2/MCP-1, CXCL10/IP-10, CCL5/RANTES, CXCL1/GRO-α, and IL-8), as well as related miRNA expression (miR-126-3p, miR-223-3p, miR-124-3p, miR-155-5p, and miR-132-3p), and by attenuating monocyte recruitment. This is the first demonstration of a beneficial effect by TIIA and CRY on adipocyte dysfunction associated with obesity development and complications, offering a new outlook for the prevention and/or treatment of metabolic diseases.
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Semba, Takashi, Yiling Tong, Feng Wei, Atsuko Yonemura, Tadahito Yasuda, Tomoyuki Uchihara, Huaito Wang, Hideo Baba, and Takatsugu Ishimoto. "Abstract 5861: Tumor cell-intrinsic factors promoting fibrotic tumor microenvironment in gastric cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5861. http://dx.doi.org/10.1158/1538-7445.am2023-5861.
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Abstract Background: Gastric cancer (GC) is one of the leading causes of death in the world. Evidence has shown over the past decade that cancer-associated fibroblasts (CAFs) play essential roles in various types of cancers, including GC, such as tumorigenesis, therapy resistance, and immunosuppression, which contribute to the progress of tumors. Although GC tumors are known to be enriched with stroma, the molecular mechanisms of how GC tumors foster the fibrotic milieu is still largely unknown. Here we analyzed a large-scale genomic and transcriptomic dataset of GC to identify GC tumor cell-intrinsic factors for developing fibroblast-rich microenvironments. Methods: We analyzed GC patient samples with gene expression data and copy number variation profiles from the Asian Cancer Research Group (ACRG) (N = 271). The microenvironment cell populations-counter (MCP-counter) method was used for transcriptome deconvolution to estimate the population of fibroblasts and immune cells in GC tumors. Genes with q value < 0.05 and fold change > 1.5 were defined as differentially expressed genes (DEGs) and identified using the Subio Platform. The copy number amplified genes found in more than 3% of the samples were selected as amplified genes. Pathway and process enrichment analysis and protein-protein interaction analysis were performed using Metascape. Results: We analyzed MCP-counter outputs and observed a fibroblast-enriched population with few infiltrations of anti-tumor immune cells, such as CD8 T cells and cytotoxic T cells in GC patients, suggesting the immunosuppressive role of CAFs in the GC tumor. By analyzing 933 DEGs upregulated in fibroblast-high patients, we found 96 genes with frequent copy number amplification that were not listed on the curated stroma and extracellular matrix-related genes and thus potentially tumor cell-intrinsic genes correlated with the abundance of the stroma. Pathway and protein-interaction analyses revealed that G protein-coupled receptor (GPCR) signaling pathway was enriched in these genes, including HTR2A, AGTR1, FZD1, CALCRL, and NBEA with strong correlations between fibroblast score (Spearman's r > 0.55), implying that these signaling in GC tumor cells contribute to promoting fibroblast-enriched microenvironment. Conclusions: Bioinformatic analyses of a publicly available genomic and transcriptomic dataset revealed a fibroblast-rich and immune-excluded population in GC patients. Several GPCR signaling in tumor cells were strongly correlated with fibroblast abundance in tumors, and these signaling pathways have potential roles in promoting the stroma-rich GC microenvironment. Citation Format: Takashi Semba, Yiling Tong, Feng Wei, Atsuko Yonemura, Tadahito Yasuda, Tomoyuki Uchihara, Huaito Wang, Hideo Baba, Takatsugu Ishimoto. Tumor cell-intrinsic factors promoting fibrotic tumor microenvironment in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5861.
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Trabolsi, Asaad, Artavazd Arumov, Nishant Gandhi, Alex Patrick Farrell, Irene Kang, Dave S. B. Hoon, Sam Wei, et al. "High transferrin receptor expression marks tumors with increased immune-effector infiltration and expression of targetable checkpoint molecules: Results of a multi-cancer analysis in solid tumors." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2613. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2613.
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2613 Background: The cell-surface transferrin receptor, TFR1, encoded by TFRC, imports iron-bound transferrin into cells to drive tumor proliferation. We have found worse prognosis with high TFRC expression across multiple tumor types. The mechanism by which TFRC drives tumor cell- intrinsic oncogenesis is multifactorial, but its interaction with the tumor microenvironment (TME) has not been studied. Here, we assessed TME infiltration by immune effector populations and immune checkpoint expression. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences: Next-gen sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA- seq (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. RNA deconvolution analysis by the Microenvironment Cell Populations (MCP)-counter method quantified immune populations to assess T cells, B cells, natural killer cells (NK) and myeloid dendritic cells (MDC). Analyses compared quartiles of TFRC mRNA expression between Q4 ( TFRC-H) high and Q1 ( TFRC-L) low expressors. Results: Among 27,607 patients with non-small cell lung cancer (NSCLC), 5,332 with prostate cancer (PC), and 14,287 with colorectal cancer (CRC), TFRC-H tumors were associated with high tumor mutational burden (TMB-high, ≥10 mutations/MB), and TP53 mutation (q<0.05). Multiple immune checkpoint genes showed significantly higher expression in TFRC-H relative to TFRC-L in all tumor types, including CD274 (PDL1), LAG3, PDCD1LG2 (PDL2), and CTLA4 (Table; All values are statistically significant: q<0.05). Moreover, TME assessment by MCP-counter showed significantly increased infiltration by total T cells, CD8+ cells, B cells, NK cells, and MDCs in TFRC-H (Table). Finally, among patients who received Check-point inhibitors (CPI), TFRC-L had improved survival (HR=0.807 (95% CI 0.76 – 0.85) p<0.00001) in NSCLC but no difference was found in CRC or PC. Conclusions: Our study is the first to reveal the TME characteristics associated with TFRC expression in a variety of solid tumor types. We found TFRC-H tumors have increased infiltration by immune effector populations but also express significantly higher levels of immune checkpoint molecules, highlighting immune exhaustion. Altered iron metabolism has been shown to promote tumorigenesis and here we identify a new role for TFRC in remodeling the TME. TFR1- targeting therapeutic agents are in clinical development and warrant further investigation in combination with CPIs. [Table: see text]
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Zhang, Jinzhong, Xiuzhi Zhang, Lingxiao Wang, Chunyan Kang, Ningning Li, Zhefeng Xiao, and Liping Dai. "Multiomics-based analyses of KPNA2 highlight its multiple potentials in hepatocellular carcinoma." PeerJ 9 (September 21, 2021): e12197. http://dx.doi.org/10.7717/peerj.12197.
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Dysregulation and prognostic roles of Karyopherin α2 (KPNA2) were reported in many malignancies including hepatocellular carcinoma (HCC). A multi-omics analysis of KPNA2 is needed to gain a deeper understanding of its multilevel molecular characteristics and provide novel clues for HCC diagnosis, prognosis, and target therapy. Herein multi-omic alterations of KPNA2 were analyzed at genetic, epigenetic, transcript, and protein levels with evaluation of their relevance with clinicopathological features of HCC by integrative analyses. The significant correlations of KPNA2 expression with its gene copy number variation (CNV) and methylation status were shown through Spearman correlation analyses. With Cox regression, Kaplan-Meier survival, and receiver operating characteristic (ROC) analyses, based on the factors of KPNA2 CNV, methylation, expression, and tumor stage, risk models for HCC overall survival (OS) and disease-free survival (DFS) were constructed which could discriminate the 1-year, 3-year, and 5-year OS/DFS status effectively. With Microenvironment Cell Populations-counter (MCP-counter), the immune infiltrations of HCC samples were evaluated and their associations with KPNA2 were shown. KPNA2 expression in liver was found to be influenced by low fat diet and presented significant correlations with fatty acid metabolism and fatty acid synthase activity in HCC. KPNA2 was detected lowered in HCC patient’s plasma by enzyme linked immunosorbent assay (ELISA), consistent with its translocation to nuclei of HCC cells. In conclusion, KPNA2 multilevel dysregulation in HCC and its correlations with immune infiltration and the fatty acid metabolism pathway indicated its multiple roles in HCC. The clinicopathological significance of KPNA2 was highlighted through the in-depth analyses at multilevels.
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He, Miao, Qihua He, Xiuyu Cai, Jun Liu, Hongshen Deng, Feng Li, Ran Zhong, et al. "Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer." Journal for ImmunoTherapy of Cancer 11, no. 4 (April 2023): e005539. http://dx.doi.org/10.1136/jitc-2022-005539.
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BackgroundTertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC).MethodsTissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients’ survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation.ResultsWhile GC+TLS was associated with better prognosis, GC−TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-γ response. Murine NSCLC models revealed that IFN-γ signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors.ConclusionsOur research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-γ signaling in this communication.
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Li, Jiawen, Qiangrong Huang, and Ligen Mo. "Comprehensive Analysis of Phagocytosis-Related Regulators to Aid Prognostic Prediction and Immunotherapy in Patients with Low-Grade Glioma." Disease Markers 2022 (April 12, 2022): 1–22. http://dx.doi.org/10.1155/2022/4142684.
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Antibody-dependent cellular phagocytosis- (ADCP-) related regulators (PRs) have been confirmed an important role in immunotherapy. However, the characterization of specific PRs in low-grade glioma (LGG) has not been comprehensively explored. In this study, we retrieved RNA-seq and CRISPR-Cas9 data to identify specific PRs in LGG patients and constructed a PRs-signature using the LASSO-Cox algorithm. The ROC analysis and Kaplan-Meier analysis showed that PRs-signature had a good predictive effect, and the multivariate Cox regression analysis showed that PRs-risk scores were independent prognostic factors correlated with overall survival (OS). In addition, CIBERSORT, ssGSEA, and MCP counter algorithms were used to explore immune cell content in different risk groups, especially in the correlation between macrophages and specific PRs. Finally, mRNA expression was upregulated in the high-risk group compared with the low-risk group at most immune checkpoints and proinflammatory factors. In conclusion, we constructed a prediction model for prognostic management and revealed the cross-talk between specific PRs and immunotherapy in LGG patients.
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Srinivasalu, Vijay Kumar, Nazia Chaudhary, Bhagyashree ., Nehanjali Dwivedi, Smitha P K, Rahul Thorat, Christopher Batulla, Sujan Kumar Dhar, Sorab N. Dalal, and Manjula Das. "LCN2 and colon cancer — Have we hit the jackpot." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15608-e15608. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15608.
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e15608 Background: Lipocalin2 (LCN2, also known as neutrophil gelatinase-associated lipocalin) is a protein that in humans is encoded by the LCN2 gene. Its abnormal expression serves critical roles in EMT transition, angiogenesis, cell migration and invasion in many cancers. We aim to assess the in vitro and in vivo effects of LCN2 as a potential chemo and radiosensitizer. Methods: Normalized RNAseq RSEM values of LCN2 were compared between normal and tumour samples from TCGA. Differences between median expression levels were assessed using Wilcoxon rank sum test. Kaplan-Meier model was used for survival analysis. Immune cell population in publicly available Colon Adenocarcinoma dataset was estimated using MCP Counter tool. Cell systems used to experimentally study the role of LCN2 in therapy resistance and tumor progression were HCT116, HT29 and DLD1. PKP3 and/or LCN2 were knocked down by shRNA. Tumor regression and therapy (5FU and radiation) sensitivity upon Anti-LCN2 treatment were demonstrated in Xenograft mouse models. Results: Analysis of 23 TCGA datasets containing gene expression data for both tumour and adjacent normal samples indicated that LCN2 levels are elevated in colon tumors. Colon cancer cell line HCT116 derived PKP3 knock-down or LCN2 over-expressing cells showed therapy resistance. A comparison of the tumor cell lines HCT116, HT29 and DLD1 show that increased LCN2 expression correlates with therapy resistance. LCN2 levels correlated with resistance to 5FU (p = 0.006) and its ability to clear ROS (p < 0.05) in vitro. Inhibiting LCN2 led to a decrease in invasion in vitro (p = 0.0005), increased sensitivity to 5FU in vitro (p = 0.001) and inhibition in tumor growth and increased sensitivity to 5FU and radiation (p = 0.005) in xenograft mouse models. On MCP counter analysis of TCGA, in Colon adenoca the normal samples show a correlation between LCN2 expression and T-cells (Pearson r = 0.45, p = 0.0028) and with the T-cell chemoattractant CXCL10 (Pearson r = 0.5, p < 0.0001). Such correlations are broken in tumour samples. Conclusions: LCN2 expression leads to chemo and radio resistance in colon cancer cell lines and xenograft mouse models. Inhibiting LCN2 function can inhibit tumor progression and sensitizes tumors to radiation and 5FU. These results suggest that LCN2 expression could be a marker that can be used to determine the choice of therapy offered to patients and that LCN2 could serve as a therapeutic target that sensitizes cells to radio and chemotherapy. LCN2 affects tumor progression and therapy sensitivity probably through T cell mediated immune pathway.
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de Vries-Brilland, Manon, Nathalie Rioux-Leclercq, Maxime Meylan, Jonathan Dauvé, Christophe Passot, Elena Spirina-Menand, Ronan Flippot, et al. "Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma." Journal for ImmunoTherapy of Cancer 11, no. 11 (November 2023): e006885. http://dx.doi.org/10.1136/jitc-2023-006885.
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BackgroundPapillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.MethodsWe performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.ResultsUnsupervised clustering identified two “TME subtypes”, in each of the cohorts: the “immune-enriched” and the “immune-low”. Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the “immune-enriched” group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations.ConclusionFor the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This “immune-enriched” group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies.Trial registration numberNCT02489695.
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Ogasawara, Aiko, Hirokazu Matsushita, Tuan Zea Tan, Daisuke Shintani, Jieru Ye, Shoji Nagao, Yukari Kobayashi, et al. "Analyses of tumor microenvironment affecting the survival in patients with ovarian cancer receiving intraperitoneal chemotherapy: Translational research from the phase 3 trial of intraperitoneal therapy for ovarian cancer with carboplatin (TRiPocc)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 5555. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.5555.
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5555 Background: The iPocc trial is a randomized, global phase (P) 3 study of intraperitoneal (IP) versus intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients that demonstrated an improved progression-free survival (PFS) but not overall survival (OS) in the former. IP chemotherapy induces an antitumor immune response and increases survival in a murine xenograft model. This study aimed to assess whether immunological background affected the clinical outcomes of patients receiving IP chemotherapy. Methods: Fresh frozen tumor samples at the time of primary surgery were obtained from 116 patients who joined the iPocc P3 trial for microarray analysis. Cell-type deconvolution was performed using MCP counter. Single sample Gene Set Enrichment Analysis was performed to evaluate the tumor immune microenvironment. Clinical data were obtained from the iPocc P3 trial. We stratified 116 patients according to the high or low values of each factor determined by the median values. The Kaplan-Meier method and log-rank test were used to analyze PFS and OS. Results: A total of 116 patients were assigned to either the IP (n=59) or IV (n=57) group. The most common histologic type was serous (58.6%), followed by endometrioid (17.2%) and clear cell (12.1%). The patients who received IP therapy had longer OS than those who received IV therapy in the group with a high infiltration of T cells, NK cells, or cytotoxic lymphocytes in the MCP counter (median OS: not reached (NR) vs 75.0 months, P=0.041, NR vs. 75.0 months, P=0.042, NR vs 65.2 months, P=0.031), but not in the group with a low infiltration. Similarly, the IP therapy improved OS in the patients with high expression of immune-related genes such as CD8A, FOXP3 or PDCD1 (median OS; NR vs 65.2 months, P=0.035, NR vs 65.2 months P=0.030, NR vs 53.1 months, P=0.016), but not in the patients with low expression of those genes. In addition, a multifaceted evaluation was conducted because of the limitations of evaluating the interaction between cancer and immunity using a single factor. When the patients were divided into two groups, “Immune Hot” and “Immune Cold” based on the hierarchical clustering analysis with 4 parameters representing “Innate immunity,” “T cells,” “Interferon gamma response” and “Inhibitory molecules,” the IP therapy increased both PFS and OS compared to the IV therapy in the “Immune Hot” group (median PFS; 35.5 vs 23.4 months, P=0.024, median OS; NR vs 75.0 months, P=0.040), but not in the “Immune Cold” group. Conclusions: IP therapy may improve the survivals in EOC patients with a high immunological background. Further studies are warranted to validate this hypothesis and to clarify the impact of IP therapy on the tumor immune microenvironment. Clinical trial information: NCT01506856 / GOTIC-001/ JGOG3019.
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Ma, He, Qingqing Qiu, Dan Tan, Qiaofeng Chen, Yaping Liu, Bing Chen, and Mingliang Wang. "The Cancer-Associated Fibroblasts-Related Gene COMP Is a Novel Predictor for Prognosis and Immunotherapy Efficacy and Is Correlated with M2 Macrophage Infiltration in Colon Cancer." Biomolecules 13, no. 1 (December 28, 2022): 62. http://dx.doi.org/10.3390/biom13010062.
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Background: Colon cancer is characterized by a sophisticated tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which make up the majority of the stromal cells in TME, participate in tumor development and immune regulation. Further investigations of CAFs would facilitate an in-depth understanding of its role in colon cancer TME. Methods: In this study, we estimated CAF abundance based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using the Microenvironment Cell Populations-counter (MCP-counter) algorithm. CAF-related genes were identified by differential gene expression analysis combined with weighted gene coexpression network analysis. For further selection, the least absolute shrinkage and selection operator (LASSO)-Cox regression was used, and the prognostic value of the selected gene was confirmed in numerous external cohorts. The function enrichment, immunological characteristics, tumor mutation signature, immunotherapy response, and drug sensitivity of the selected gene were subsequently explored. The bioinformatics analysis results were validated using immunohistochemistry on clinical samples from our institution. Results: According to our findings, cartilage oligomeric matrix protein (COMP) was uncovered as a candidate CAFs-driven biomarker in colon cancer and plays an important role in predicting prognosis in colon cancer. COMP upregulation was associated with enhanced stromal and immune activation, and immune cell infiltration, especially M2 macrophages. Genes that mutated differently between the high- and low-COMP expression subgroups may be correlated with TME change. Following verification, COMP reliably predicted the immunotherapy response and drug response. In addition, our experimental validation demonstrated that COMP overexpression is associated with colon cancer carcinogenesis and is strongly associated with CAFs and M2 macrophage infiltration. Conclusion: Our study uncovered that COMP was a key CAFs-driven gene associated with M2 macrophage infiltration and acted as a convincing predictor for prognosis and immunotherapy response in colon cancer patients.
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Zahner, Gunther, Melanie Schaper, Ulf Panzer, Malte Kluger, Rolf A. K. Stahl, Friedrich Thaiss, and André Schneider. "Prostaglandin EP2 and EP4 receptors modulate expression of the chemokine CCL2 (MCP-1) in response to LPS-induced renal glomerular inflammation." Biochemical Journal 422, no. 3 (August 27, 2009): 563–70. http://dx.doi.org/10.1042/bj20090420.
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The pro-inflammatory chemokine CCL2 [chemokine (Cys-Cys motif) ligand 2; also known as MCP-1 (monocyte chemotactic protein-1)] is up-regulated in the glomerular compartment during the early phase of LPS (lipopolysaccharide)-induced nephritis. This up-regulation also occurs in cultured MCs (mesangial cells) and is more pronounced in MCs lacking the PGE2 (prostaglandin E2) receptor EP2 or in MCs treated with a prostaglandin EP4 receptor antagonist. To examine a possible feedback mechanism of EP receptor stimulation on CCL2 expression, we used an in vitro model of MCs with down-regulated EP receptor expression. Selectively overexpressing the various EP receptors in these cells then allows the effects on the LPS-induced CCL2 expression to be examined. Cells were stimulated with LPS and CCL2 gene expression was examined and compared with LPS-stimulated, mock-transfected PTGS2 [prostaglandin-endoperoxide synthase 2, also known as COX-2 (cyclo-oxygenase-2)]-positive cells. Overexpression of EP1, as well as EP3, had no effect on LPS-induced Ccl2 mRNA expression. In contrast, overexpression of EP2, as well as EP4, significantly decreased LPS-induced CCL2 expression. These results support the hypothesis that PTGS2-derived prostaglandins, when strongly induced, counter-balance inflammatory processes through the EP2 and EP4 receptors in MCs.
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Kang, Joshua J., Mohammed A. Samad, Kye S. Kim, and Soochan Bae. "Comparative Anti-inflammatory Effects of Anti-arthritic Herbal Medicines and Ibuprofen." Natural Product Communications 9, no. 9 (September 2014): 1934578X1400900. http://dx.doi.org/10.1177/1934578x1400900932.
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Non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, are widely used over-the-counter drugs to treat arthritis, but they are often associated with side effects. Herbal medicines have been used to treat various diseases such as arthritis, but the scientific profiles are not well understood. In this study, we examined, in comparison with ibuprofen, the inhibitory effects on various inflammatory markers of the most commonly used herbal medicines to treat arthritis, boswellia (Boswellia sapindales), licorice (Glycyrrhiza glabra), guggul (Commiphora wightii), and neem (Azadirachta indica). To elicit inflammatory response, we exposed mouse myoblast C2C12 cells to lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-α) and monocyte chemotactic protein-1 (MCP-1), which are cytokines activated during an inflammatory response, were determined. The optimal non-toxic concentration was determined by exposing different concentrations of drugs (from 0.01 to 10 mg/mL). Cell death measurement revealed that the drug concentrations lower than 0.05 mg/mL were non-toxic concentrations for each drug, and these doses were used for the main experiments. We found that neem and licorice showed robust anti-inflammatory responses compared with ibuprofen. However, boswellia and guggul did not demonstrate significant anti-inflammatory responses. We concluded that neem and licorice are more effective than ibuprofen in suppressing LPS-induced inflammation in C2C12 cells.
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Mueller, Kristin, Nicole Michaela Blum, and Andreas Stefan Mueller. "Examination of the Anti-Inflammatory, Antioxidant, and Xenobiotic-Inducing Potential of Broccoli Extract and Various Essential Oils during a Mild DSS-Induced Colitis in Rats." ISRN Gastroenterology 2013 (February 28, 2013): 1–14. http://dx.doi.org/10.1155/2013/710856.
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Phytogenic compounds with antioxidant and anti-inflammatory properties are currently discussed as promising complementary agents in prevention and treatment of inflammatory bowel disease (IBD). Our study aimed to evaluate possible protective and curative effects of broccoli extract (BE) and of the essential oils of turmeric (Cuo), thyme (To), and rosemary (Ro) in a rat model with a mild dextran sulphate sodium- (DSS-) induced colitis. Therefore Wistar rats were fed a diet without an additive (Con) or diets with the addition of BE, Cuo, To, and Ro during the whole experiment. Pretreatment with Ro, Cuo, and To increased the expression of the tight junction protein Cldn3. All additives reduced mRNA of VCAM-1 which plays a crucial role in the first state of inflammatory response. Only Ro pretreatment affected the expression of the antioxidant enzymes HO1, GPx2, and of glutathione-S-transferases. All additives counteracted the DSS-induced rise in COX2 and VCAM-1 expression. Colonic IL-10 was increased by Cuo, To, and Ro. During the recovery phase DSS pretreatment increased NFκB, VCAM-1, and MCP-1: This response was counter-regulated by all additives. We conclude that the phytogenic additives tested have a promising anti-inflammatory potential in vivo and a particular role in the prevention of IBD.
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Lankadasari, Manendra B., Yuan Liu, Di He, Samhita Bapat, Brooke Mastrogiacomo, Harry B. Lengel, and David R. Jones. "Abstract 3142: BRMS1 alters the tumor inflammatory signature and immune infiltration in lung adenocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3142. http://dx.doi.org/10.1158/1538-7445.am2022-3142.
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Abstract Background: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths. Metastatic cancer is highly fatal which contributes to at least 90% of cancer-associated morbidities and mortalities. During metastasis, tumor cells alter their signaling cascade and interact with the immune cells in the tumor microenvironment Therefore, it is necessary to characterize and understand how these cancer cells influence tumor-infiltrating immune cells to facilitate and even enhance their ability to metastasize. BRMS1 is a metastasis suppressor gene which is frequently downregulated in LUAD. We, and others, have shown that loss of BRMS1 results in distant metastatic disease. Given the strong correlation between immune suppression, metastasis, and therapy resistance we sought to elucidate if BRMS1 contributes to these processes. Specifically, we hypothesized that LUAD cells downregulate BRMS1 which influences the immune cell composition in the tumor. This creates an immune-suppressive tumor microenvironment aiding in metastasis. Methods: To test our hypothesis, we generated KrasG12D P53fl/fl Brms1-/- mice which spontaneously develop tumors with Ad-Cre intratracheal inoculation. To elucidate the role of BRMS1 in the context of cancer, we performed RNA sequencing on tumors from Brms1 wild type and knockout background. We used MCP counter, an in silico cellular deconvolution algorithm on our bulk RNA seq data to identify various subsets of tumor-infiltrating immune cells. Furthermore, our observations were validated by immunofluorescence and flow cytometry. Results: Differential gene expression analysis using RNA seq data revealed a reduction in CXCL9, CCL5, CLEC1B, CCL9, CCL7 and other proinflammatory molecules in the Brms1-/- tumors. Gene ontology and gene set enrichment analysis highlighted a diminished immune response signature in Brms1-/- tumors. Hallmarks like interferon and IL6 signaling, complement and inflammation are highly enriched in Brms1+/+ tumors. MCP counter also suggested a significant increase in NK cells and reduction in CD8+ T cell population in the Brms1-/- tumors. To validate our observation, we performed immunofluorescence and flow cytometry to assess the number of infiltrating immune cells in the tumor microenvironment. Immunofluorescence data showed reduced cytotoxic T cells (CD8+ T cells) in Brms1-/- mice. The flow cytometric analysis also revealed a reduction in the proliferative potential of these CD8+ T cells along with the increased presence of myeloid-derived suppressor cells in the Brms1-/- mice. Conclusion: Our data suggest for the first time that reduced BRMS1 expression which is generally observed in multiple tumors not only influences metastasis but also alters tumor-infiltrating immune cell composition. Thus, BRMS1 downregulation presents as one of the potential immune evasion mechanisms that could be targeted for an improved therapy outcome in LAUD. Citation Format: Manendra B. Lankadasari, Yuan Liu, Di He, Samhita Bapat, Brooke Mastrogiacomo, Harry B. Lengel, David R. Jones. BRMS1 alters the tumor inflammatory signature and immune infiltration in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3142.
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Zeng, Wen-Jing, Yu-Fang Cao, He Li, Zhi-Cheng Gong, Wantao Wu, Peng Luo, Jian Zhang, Zaoqu Liu, Hao Zhang, and Quan Cheng. "A Novel Thrombosis-Related Signature for Predicting Survival and Drug Compounds in Glioblastoma." Journal of Oncology 2022 (July 13, 2022): 1–16. http://dx.doi.org/10.1155/2022/6792850.
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Glioblastoma is the most common primary tumor in the central nervous system, and thrombosis-associated genes are related to its occurrence and progression. Univariate Cox and LASSO regression analysis were utilized to develop a new prognostic signature based on thrombosis-associated genes. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and HALLMARK were used for functional annotation of risk signature. ESTIMATE, MCP-counter, xCell, and TIMER algorithms were used to quantify immune infiltration in the tumor microenvironment. Genomics of Drug Sensitivity in Cancer (GDSC) was used for selecting potential drug compounds. Risk signature based on thrombosis-associated genes shows moderate performance in prognosis prediction. The functional annotation of the risk signature indicates that the signaling pathways related to the cell cycle, apoptosis, tumorigenesis, and immune suppression are rich in the high-risk group. Somatic mutation analysis shows that tumor-suppressive gene TP53 and oncogene PTEN have higher expression in low-risk and high-risk groups, respectively. Potential drug compounds are explored in risk score groups and show higher AUC values in the low-risk score group. A nomogram with valuable prognostic factors exhibits high sensitivity in predicting the survival outcome of GBM patients. Our research screens out multiple thromboses-associated genes with remarkable clinical significance in GBM and further develops a meaningful prognostic risk signature predicting drug sensitivity and survival outcome.
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Shen, Xiaorong, Ziyi Yan, Yuanli Huang, Qing Zhu, Guanghui Zhang, Hongfei Ci, Qiong Wu, and Ligao Wu. "ALDH2 as an immunological and prognostic biomarker: Insights from pan-cancer analysis." Medicine 103, no. 16 (April 19, 2024): e37820. http://dx.doi.org/10.1097/md.0000000000037820.
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Aldehyde dehydrogenase 2 (ALDH2) plays a critical role in safeguarding cells against acetaldehyde toxicity and is closely linked to human metabolism. Nevertheless, the involvement of ALDH2 in cancer remains enigmatic. This investigation seeks to comprehensively assess ALDH2’s significance in pan-cancer. We conducted an all-encompassing analysis of pan-cancer utilizing multiple databases, including TCGA, linkedomicshs, UALCAN, and Kaplan–Meier plotter. We employed diverse algorithms such as EPIC, MCPCOUNTER, TIDTIMER, xCell, MCP-counter, CIBERSORT, quanTIseq, and EPIC to examine the connection between ALDH2 expression and immune cell infiltration. Single-cell sequencing analysis furnished insights into ALDH2’s functional status in pan-cancer. Immunohistochemical staining was performed to validate ALDH2 expression in cancer tissues. In a comprehensive assessment, we observed that tumor tissues demonstrated diminished ALDH2 expression levels compared to normal tissues across 16 different cancer types. ALDH2 expression exhibited a significant positive correlation with the infiltration of immune cells, including CD4 + T cells, CD8 + T cells, neutrophils, B cells, and macrophages, in various tumor types. Moreover, this study explored the association between ALDH2 and patient survival, examined the methylation patterns of ALDH2 in normal and primary tumor tissues, and delved into genetic variations and mutations of ALDH2 in tumors. The findings suggest that ALDH2 could serve as a valuable prognostic biomarker in pan-cancer, closely linked to the tumor’s immune microenvironment.
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Sanchez-Canteli, Mario, Francisco Hermida-Prado, Christian Sordo-Bahamonde, Irene Montoro-Jiménez, Esperanza Pozo-Agundo, Eva Allonca, Aitana Vallina-Álvarez, et al. "Lectin-Like Transcript 1 (LLT1) Checkpoint: A Novel Independent Prognostic Factor in HPV-Negative Oropharyngeal Squamous Cell Carcinoma." Biomedicines 8, no. 12 (November 25, 2020): 535. http://dx.doi.org/10.3390/biomedicines8120535.
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Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy.
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Besse, Benjamin, DIB Colette, Eladio Marquez, Joon Sang Lee, Shu Yan, Marielle Chiron, Cecile Combeau, et al. "284 Integrated molecular characterization of primary resistance mechanisms to immune checkpoint blockade in advanced non-small cell lung carcinoma (a-NSCLC)." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A308. http://dx.doi.org/10.1136/jitc-2021-sitc2021.284.
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BackgroundReinvigoration of anti-tumor immunity via immune checkpoint blockade (ICB) has transformed outcomes in a-NSCLC. However, a majority of patients are innately resistant to ICB, and a better understanding of the resistance mechanisms may guide the development of new treatment strategies and therapies for patients.MethodsBiopsies performed immediately before treatment with single agent ICB in patients with a-NSCLC (MATCH-R trial [NCT02517892]) were analyzed. The stromal microenvironment and immune context were characterized via an integrated analysis of whole transcriptome (RNA-seq), whole exome sequencing (WES), and immunohistochemistry (IHC) of CD3, CD8, FOXP3 and PDL1. Specifically, the immune context and the relative abundance of 10 immune and stromal cell types were assessed with integrated IHC and Cell Populations-counter (MCP-counter) [1] analysis of the RNA-seq. Somatic mutations and Tumor Mutation Burden (TMB) were evaluated. The transcriptional state of the tumor and its microenvironment were assessed by GSVA analysis [2] of the MSigDB collection [3]. Patient‘s outcome was associated to molecular data. Primary resistance to ICB was defined as PD (progressive disease) in the first radiological examination, or a median PFS inferior to 3 months.ResultsFifty-two patients with NSCLC were enrolled (43 adeno, 6 squamous, and 3 other carcinoma): Median age was 61 (34–93), 18 were female, 46 were smokers, 22 were responders, and 30 were non-responders. Median tumor cellularity was 60% (30%–90%).Patients may be divided into two groups (HIGH and LOW) at baseline based on their degree of immune infiltration as assessed by RNAseq or IHC. A hallmark of the HIGH infiltration group is an increase in Interferon Gamma (IFN-γ) pathway signature [4]. In contrast, patients in the LOW infiltration group (relative to the HIGH infiltration group) exhibit a decrease in IFN-γ pathway signaling and concomitantly an increase in hypoxia and gluconeogenic pathway signatures. Response rates to ICB were not associated to immune infiltration groups at baseline, but an analysis within each infiltration group revealed that high TMB is only associated to response in the HIGH infiltration group. Furthermore, only in the LOW infiltration group was increased the transforming growth factor (TGF-β) pathway signature associated to ICB response.ConclusionsThis study suggests that the tumor and its microenvironment influence baseline immune infiltration. Tumors with LOW baseline infiltration show altered metabolism such as gluconeogenic activation and hypoxia activation. In contrast, factors such as TMB are not associated with baseline infiltration
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Mancini, Leonardo, Vincenzo Quinzi, Stefano Mummolo, Giuseppe Marzo, and Enrico Marchetti. "Angiotensin-Converting Enzyme 2 as a Possible Correlation between COVID-19 and Periodontal Disease." Applied Sciences 10, no. 18 (September 8, 2020): 6224. http://dx.doi.org/10.3390/app10186224.
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SARS-CoV-2 propagation in the world has led to rapid growth and an acceleration in the discoveries and publications of various interests. The main focus of a consistent number of studies has been the role of angiotensin-converting enzyme 2 (ACE2) in binding the virus and its role in expression of the inflammatory response after transmission. ACE2 is an enzyme involved in the renin–angiotensin system (RAS), whose key role is to regulate and counter angiotensin-converting enzyme (ACE), reducing the amount of angiotensin II and increasing angiotensin 1–7 (Ang1–7), making it a promising drug target for treating cardiovascular diseases. The classical RAS axis, formed by ACE, angiotensin II (Ang II), and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signalling pathways related to tissue injury and inflammation. In contrast, the RAS axis composed of ACE2, Ang1–7, and Mas receptor (MasR) exerts the opposite effect concerning the inflammatory response and tissue fibrosis. Recent studies have shown the presence of the RAS system in periodontal sites where osteoblasts, fibroblasts, and osteoclasts are involved in bone remodelling, suggesting that the role of ACE2 might have a fundamental function in the under- or overexpression of cytokines such as interleukin-6 (IL-6), interleukin-7 (IL-7), tumour necrosis factor alpha (TNF-α), interleukin-2 (IL-2), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-β), associated with a periodontal disorder, mainly during coinfection with SARS-CoV-2, where ACE2 is underexpressed and cannot form the ACE2–Ang1–7–MasR axis. This renders the patient unresponsive to an inflammatory process, facilitating periodontal loss.
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Connor, Kate, Kieron White, James Clerkin, Kieron Sweeney, Liam Shiels, Thomas van Brussel, Ingrid Arijs, et al. "Abstract 1441: Establishing a novel clinically relevant disease model of glioblastoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1441. http://dx.doi.org/10.1158/1538-7445.am2024-1441.
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Abstract Introduction: GBM is the most common primary malignancy of the CNS. Historically pre-clinical models have failed to predict response in humans, despite promising preclinical data. Moreover, current models seldom incorporate surgical resection and/or standard of care chemotherapy treatment. These models also commonly employ young animals exclusively, whose immune contexture differs from older patients. We therefore sought to establish an improved, orthotopic, preclinical GBM model, which better recapitulates patient response to standard-of-care and targeted treatments. Methods: NFpp10a-Luc2 GBM cells were orthotopically implanted into C57BL/6-mice (aged[>18months] and young[6-8weeks]) and weekly bioluminescence imaging performed to monitor tumor growth. Overall survival (OS) and tumor growth were assessed in response to (1) Surgical Resection, (2) Temozolomide (TMZ) (3) anti-PD1 (4) neoadjuvant anti-PD1 and (5) Regorafenib (REGO) therapy. Tissue collected post-mortem underwent bulk RNA sequencing followed by analysis via microenvironment cell population counter (MCP) and gene set enrichment (GSEA) to determine changes in the GBM-TME following treatment. Results: We demonstrated OS advantage in aged mice undergoing surgical resection (Resection:33.5 days vs Non-Resection: 18 days; p=0.0166) and observed age to be a significant prognostic factor (Young:62 days vs Aged: 22 days; p=0.0002). Subsequently, we observed that TMZ and anti-PD1 monotherapies had no impact on NFpp10-Luc2 growth (p=0.9001, p=0.7933) or survival (p=0.3035, p=0.6328). Neoadjuvant anti-PD1 treated mice demonstrated no significant survival advantage compared to IgG control (33 days vs 35 days; p=0.9429). Lastly, REGO treatment demonstrated a trend towards improved OS vs Vehicle (p=0.096). MCP analysis revealed both neoadjuvant anti-PD1 and REGO treatment induced influx of CD8+ T cells, B cells and monocytes into the TME, with neoadjuvant anti-PD1 associated with an upregulation of CXCR3 (p=0.0045). Conclusions: We have, for the first time, established and characterized response of the NFpp10a-C57BL/6 model to surgical resection, TMZ, anti-PD1 and REGO therapy in both young and aged mice. We have shown the model is markedly insensitive to intervention with chemotherapy and immune checkpoint therapy, mirroring what is seen clinically in patients. The model may therefore be employed in future pre-clinical studies to guide clinical trials in the setting of mesenchymal GBM. Citation Format: Kate Connor, Kieron White, James Clerkin, Kieron Sweeney, Liam Shiels, Thomas van Brussel, Ingrid Arijs, Diether Lambrechts, Gautam Shankar, Frederik de Smet, Stephen G. Maher, Laure Marignol, Patrick Dicker, Jochen Prehn, David O'Brien, Annette T. Byrne. Establishing a novel clinically relevant disease model of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1441.
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Cao, Tengfei, Mengjie Huang, Xinyue Huang, and Tian Tang. "Research and experimental verification on the mechanisms of cellular senescence in triple-negative breast cancer." PeerJ 12 (February 29, 2024): e16935. http://dx.doi.org/10.7717/peerj.16935.
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Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high heterogeneity, poor prognosis, and a low 10-year survival rate of less than 50%. Although cellular senescence displays extensive effects on cancer, the comprehensions of cellular senescence-related characteristics in TNBC patients remains obscure. Method Single-cell RNA sequencing (scRNA-seq) data were analyzed by Seurat package. Scores for cellular senescence-related pathways were computed by single-sample gene set enrichment analysis (ssGSEA). Subsequently, unsupervised consensus clustering was performed for molecular cluster identification. Immune scores of patients in The Cancer Genome Atlas (TCGA) dataset and associated immune cell scores were calculated using Estimation of STromal and Immune cells in MAlignantTumours using Expression data (ESTIMATE) and Microenvironment Cell Populations-counter (MCP-counter), Tumor Immune Estimation Resource (TIMER) and Estimating the Proportion of Immune and Cancer cells (EPIC) methods, respectively. Immunotherapy scores were assessed using TIDE. Furthermore, feature genes were identified by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses; these were used to construct a risk model. Additionally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and transwell assay were conducted for in vitro validation of hub genes. Result TNBC was classified into three subtypes based on cellular senescence-related pathways as clusters 1, 2, and 3. Specifically, cluster 1 showed the best prognosis, followed by cluster 2 and cluster 3. The levels of gene expression in cluster 2 were the lowest, whereas these were the highest in cluster 3. Moreover, clusters 1 and 3 showed a high degree of immune infiltration. TIDE scores were higher for cluster 3, suggesting that immune escape was more likely in patients with the cluster 3 subtype who were less likely to benefit from immunotherapy. Next, the TNBC risk model was constructed and validated. RT-qPCR revealed that prognostic risk genes (MMP28, ACP5 and KRT6A) were up-regulated while protective genes (CT83) were down-regulated in TNBC cell lines, validating the results of the bioinformatics analysis. Meanwhile, cellular experiments revealed that ACP5 could promote the migration and invasion abilities in two TNBC cell lines. Finally, we evaluated the validity of prognostic models for assessing TME characteristics and TNBC chemotherapy response. Conclusion In conclusion, these findings help to assess the efficacy of targeted therapies in patients with different molecular subtypes, have practical applications for subtype-specific treatment of TNBC patients, and provide information on prognostic factors, as well as guidance for the revelation of the molecular mechanisms by which senescence-associated genes influence TNBC progression.
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Schulze, Hendrik, Johann Hornbacher, Paulina Wasserfurth, Thomas Reichel, Thorben Günther, Ulrich Krings, Karsten Krüger, Andreas Hahn, Jutta Papenbrock, and Jan P. Schuchardt. "Immunomodulating Effect of the Consumption of Watercress (Nasturtium officinale) on Exercise-Induced Inflammation in Humans." Foods 10, no. 8 (July 30, 2021): 1774. http://dx.doi.org/10.3390/foods10081774.
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The vegetable watercress (Nasturtium officinale R.Br.) is, besides being a generally nutritious food, a rich source of glucosinolates. Gluconasturtiin, the predominant glucosinolate in watercress, has been shown to have several health beneficial properties through its bioactive breakdown product phenethyl isothiocyanate. Little is known about the immunoregulatory effects of watercress. Moreover, anti-inflammatory effects have mostly been shown in in vitro or in animal models. Hence, we conducted a proof-of-concept study to investigate the effects of watercress on the human immune system. In a cross-over intervention study, 19 healthy subjects (26.5 ± 4.3 years; 14 males, 5 females) were given a single dose (85 g) of fresh self-grown watercress or a control meal. Two hours later, a 30 min high-intensity workout was conducted to promote exercise-induced inflammation. Blood samples were drawn before, 5 min after, and 3 h after the exercise unit. Inflammatory blood markers (IL-1β, IL-6, IL-10, TNF-α, MCP-1, MMP-9) were analyzed in whole blood cultures after ex vivo immune cell stimulation via lipopolysaccharides. A mild pro-inflammatory reaction was observed after watercress consumption indicated by an increase in IL-1β, IL-6, and TNF-α, whereas the immune response was more pronounced for both pro-inflammatory and anti-inflammatory markers (IL-1β, IL-6, IL-10, TNF-α) after the exercise unit compared to the control meal. During the recovery phase, watercress consumption led to a stronger anti-inflammatory downregulation of the pro-inflammatory cytokines IL-6 and TNF-α. In conclusion, we propose that watercress causes a stronger pro-inflammatory response and anti-inflammatory counter-regulation during and after exercise. The clinical relevance of these changes should be verified in future studies.
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Smeby, Jørgen, Anita Sveen, Christian H. Bergsland, Ina A. Eilertsen, Stine A. Danielsen, Peter W. Eide, Merete Hektoen, et al. "Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer." ESMO Open 4, no. 3 (June 2019): e000523. http://dx.doi.org/10.1136/esmoopen-2019-000523.
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BackgroundAccumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC).Materials and methodsIn a single-hospital series of 401 stage I–IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582).ResultsTP53 mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2−4>0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028).ConclusionsIntegration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation.
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Lian, Qi-xin, Yang Song, Lili Han, Zunxian Wang, and Yinhui Song. "Development of a circHIPK3-based ceRNA network and identification of mRNA signature in breast cancer patients harboring BRCA mutation." PeerJ 11 (July 5, 2023): e15572. http://dx.doi.org/10.7717/peerj.15572.
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Background Exploring the regulatory network of competing endogenous RNAs (ceRNAs) as hallmarks for breast cancer development has great significance and could provide therapeutic targets. An mRNA signature predictive of prognosis and therapy response in BRCA carriers was developed according to circular RNA homeodomain-interacting protein kinase 3 (circHIPK3)-based ceRNA network. Method We constructed a circHIPK3-based ceRNA network based on GSE173766 dataset and identified potential mRNAs that were associated with BRCA mutation patients within this ceRNA network. A total of 11 prognostic mRNAs and a risk model were identified and developed by univariate Cox regression analysis and the LASSO regression analysis as well as stepAIC method. Genomic landscape was treated by mutect2 and fisher. Immune characteristics was analyzed by ESTIMATE, MCP-counter. TIDE analysis was conducted to predict immunotherapy. The clinical treatment outcomes of BRCA mutation patients were assessed using a nomogram. The proliferation, migration and invasion in breast cancer cell lines were examined using CCK8 assay and transwell assay. Result We found 241 mRNAs within the circHIPK3-based ceRNA network. An 11 mRNA-based signature was identified for prognostic model construction. High risk patients exhibited dismal prognosis, low response to immunotherapy, less immune cell infiltration and tumor mutation burden (TMB). High-risk patients were sensitive to six anti-tumor drugs, while low-risk patient were sensitive to 47 drugs. The risk score was the most effective on evaluating patients’ survival. The robustness and good prediction performance were validated in The Cancer Genome Atlas (TCGA) dataset and immunotherapy datasets, respectively. In addition, circHIPK3 mRNA level was upregulated, and promoted cell viability, migration and invasion in breast cancer cell lines. Conclusion The current study could improve the understanding of mRNAs in relation to BRCA mutation and pave the way to develop mRNA-based therapeutic targets for breast cancer patients with BRCA mutation.
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Wen, Haopeng, Tengfei Ji, Liteng Lin, Nan Cheng, Kangshun Zhu, and Liangqi Cao. "High Expression of Ten Eleven Translocation 1 Is Associated with Poor Prognosis in Hepatocellular Carcinoma." Mediators of Inflammation 2023 (May 4, 2023): 1–22. http://dx.doi.org/10.1155/2023/2664370.
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Background. DNA methylation patterns have been found to be distinct between tumor and normal patients. However, the effect of DNA demethylation enzymes, ten eleven translocation (TET) proteins, has not been comprehensively characterized in liver cancer. In this research, we sought to unravel the linkage of TET proteins with prognosis, immune characteristics and biological pathways in hepatocellular carcinoma (HCC). Materials and Methods. Four independent datasets with gene expression data and clinical data of HCC samples were downloaded from public databases. CIBERSORT, single sample Gene Set Enrichment Analysis (ssGSEA), MCP-counter, and TIMER were implemented to evaluate immune cell infiltration. limma was employed to screen differentially expressed genes (DEGs) between two groups. The demethylation-related risk model was established by using univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO), and stepwise Akaike information criterion (stepAIC). Results. TET1 was significantly higher expressed in tumor samples than that in normal samples. HCC patients with advanced stages (III+IV) and grades (G3+G4) had higher TET1 expression compared to early stages (I+II) and grades (G1+G2). HCC samples with high TET1 expression had worse prognosis than that with low expression. High and low TET1 expression groups had distinct immune cell infiltration and response to immunotherapy and chemotherapy. We identified 90 DEGs related to DNA demethylation in high vs. low TET1 expression groups. Furthermore, we established a risk model based on 90 DEGs containing seven key prognostic genes (SERPINH1, CDC20, HACD2, SPHK1, UGT2B15, SLC1A5, and CYP2C9) with effectiveness and robustness in predicting HCC prognosis. Conclusions. Our study suggested TET1 as a potential indicator in HCC progression. TET1 was closely involved in immune infiltration and activation of oncogenic pathways. The DNA demethylation-related risk model was potential to be applied for predicting HCC prognosis in clinics.
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Li, Teng, Xiaocong Pang, Junyun Wang, Shouzheng Wang, Yiying Guo, Ning He, Puyuan Xing, and Junling Li. "Exploration of the Tumor-Suppressive Immune Microenvironment by Integrated Analysis in EGFR-Mutant Lung Adenocarcinoma." Frontiers in Oncology 11 (May 31, 2021). http://dx.doi.org/10.3389/fonc.2021.591922.
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BackgroundClinical evidence has shown that few non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can benefit from immunotherapy. The tumor immune microenvironment (TIME) is a significant factor affecting the efficacy of immunotherapy. However, the TIME transformational process in EGFR-mutation patients is unknown.MethodsThe mRNA expression and mutation data and lung adenocarcinoma (LUAD) clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Profiles describing the immune landscape of patients with EGFR mutations were characterized by differences in tumor mutation burden (TMB), ESTIMATE, CIBERSORT, and microenvironment cell populations-counter (MCP-counter).ResultsIn total, the TCGA data for 585 patients were analyzed. Among these patients, 98 had EGFR mutations. The TMB was lower in the EGFR group (3.94 mut/Mb) than in the KRAS mutation group (6.09 mut/Mb, P < 0.001) and the entire LUAD (6.58 mut/Mb, P < 0.001). The EGFR group had a lower population of activated immune cells and an even higher score of immunosuppressive cells. A further inter-group comparison showed that differences in the TMB and tumor-infiltrating lymphocytes were only found between patients with oncogenic mutations and unknown mutation. Meanwhile, there were more myeloid dendritic cells (DCs) in EGFR 19del than in L858R-mutation patients and in common mutation patents than in uncommon mutation patients (P < 0.05). Additionally, we established a D score, where D = MCP-counter score for cytotoxic T lymphocytes (CTLs)/MCP-counter score for myeloid DCs. Further analysis revealed that lower D scores indicated immune suppression and were negatively related to several immunotherapy biomarkers.ConclusionsThe TIME of EGFR mutant NSCLC was immunosuppressive. Myeloid DCs gradually increased in EGFR 19del, L858R, and uncommon mutations. The potential role of CTLs and DCs in the TIME of patients requires further investigation.
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"Evolution in der Beschreibung von Gegenlaufflächen." Konstruktion 74, no. 05 (2022): 39–42. http://dx.doi.org/10.37544/0720-5953-2022-05-39.
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In Hydraulikzylindern ist das Zusammenspiel von Dichtungswerkstoff und Oberflächengüte der Gegenlauffläche entscheidend für die gewünschte Funktionalität und Langlebigkeit. Freudenberg hat mit den Merkel Counter Surface Parametern (MCP) ein wegweisendes Konzept entwickelt, um die Eignung von tribologischen Funktionsoberflächen in Kontakt mit Dichtungen zu beschreiben. Heute läutet das Unternehmen die nächste Stufe der Beurteilung ein, die Freudenberg Counter Surface Parameters FCP 2.0. Untersuchungen zeigen, dass sich in Verbindung mit aktuellen Veredelungsverfahren von Oberflächen – beispielsweise das Hochgeschwindigkeits-Flammspritzen – die erforderliche Anzahl an Parametern für die Eignungsbeurteilung von Oberflächen auf ein Minimum reduzieren lässt.
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Yu, Haozhen, Lanxin Gu, Linfang Du, Zhao Dong, Zhuang Li, Mujun Yu, Yue Yin, Yishi Wang, Lu Yu, and Heng Ma. "Identification and analysis of key hypoxia- and immune-related genes in hypertrophic cardiomyopathy." Biological Research 56, no. 1 (August 9, 2023). http://dx.doi.org/10.1186/s40659-023-00451-4.
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Abstract Background Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is the main cause of sudden death in adolescents and athletes globally. Hypoxia and immune factors have been revealed to be related to the pathology of HCM. There is growing evidence of a role for hypoxia and inflammation as triggers and enhancers in the pathology in HCM. However, the role of hypoxia- and immune-related genes in HCM have not been reported. Methods Firstly, we obtained four HCM-related datasets from the Gene Expression Omnibus (GEO) database for differential expression analysis. Immune cells significantly expressed in normal samples and HCM were then screened by a microenvironmental cell population counter (MCP-counter) algorithm. Next, hypoxia- and immune-related genes were screened by the LASSO + support vector machine recursive feature elimination (SVM-RFE) and weighted gene co-expression network analysis (WGCNA). Single-gene enrichment analysis and expression validation of key genes were then performed. Finally, we constructed a competing endogenous RNA (ceRNA) network of key genes. Results In this study, 35 differentially expressed hypoxia genes were found. By using LASSO + SVM-RFE analysis, 10 more targets with differentially expressed hypoxia genes were identified. The MCP-count algorithm yielded five differentially expressed immune cells, and after assessing them for WGCNA characteristics, 612 immune genes were discovered. When hypoxia and immune genes were combined for cross-tabulation analysis, three hypoxia- and immune-related genes (ATP2A2, DDAH1, and OMA1) were identified. Conclusion Based on hypoxia characteristic genes, three key genes were identified. These were also significantly related to immune activation, which proves a theoretical basis and reference value for studying the relationship between HCM and hypoxia and immunity. Graphical Abstract
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Okubo, Ryogo. "MCP-PMT quantum efficiency monitoring and operation status of the TOP counter at the Belle II experiment." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, August 2023, 168627. http://dx.doi.org/10.1016/j.nima.2023.168627.
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