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Lymphocytic infiltration of CD45+ cells in the normal colon was more pronounced than that in the paired tumor stroma (p = 0.0008). The mean immunoscore of CD45+TILs was decreased in CRC compared with the controls (p = 0.0010). The percentage of CD3+ cells was higher in stage II than in stage IV (p = 0.0218) and showed a negative correlation with the TNM classification (r = -0.2867, p = 0.0109). The number of stromal CD4+TILs was higher in stage I than in stage III (p = 0.0116) and IV (p = 0.0104), and there was a negative correlation between this number and the stage (r = -0.3708, p = 0.0008). There was a positive correlation between the Ki-67 and CD45+ (r = 0.2468, p = 0.0294), CD3+ (r = 0.3822, p = 0.0006), and CD4+ cells (r = 0.5465, p \u003C 0.0001). The levels of cancer-associated fibroblast (CAF) markers such as α-SMA, thrombin and fibronectin were significantly higher in CRC than in normal colonic mucosa. The immunohistochemical expression of α-SMA was negatively correlated with TILs, while fibronectin showed positive coexpression. A higher number of cells expressing IL-2Rα, PD-L1, CD33 and CD14 were found in colorectal adenocarcinomas than in controls. The number of CD14+ cells was also dependent on the TNM stage (p = 0.0444) and tumor budding (p = 0.0324). These findings suggest a suppressive impact of CRC on the adaptive immune response and emphasize the importance of CAFs in regulating tumor immunity.",{"EN":274,"VI":275},"Interplay of stromal tumor-infiltrating lymphocytes, normal colonic mucosa, cancer-associated fibroblasts, clinicopathological data and the immunoregulatory molecules of patients diagnosed with colorectal cancer","Tác động qua lại giữa lympho xâm nhập khối u vùng đệm, niêm mạc đại tràng bình thường, nguyên bào sợi liên kết với ung thư, dữ liệu bệnh học lâm sàng và các phân tử điều hòa miễn dịch của bệnh nhân được chẩn đoán ung thư đại trực tràng",{"VOID":277},"Keum N, Giovannucci E (2019) Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41575-019-0189-8\nPawelec G (2017) Immunosenescence and cancer. 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J Immunol Res 2019:2368249. https:\u002F\u002Fdoi.org\u002F10.1155\u002F2019\u002F2368249\nShive CL, Jiang W, Anthony DD, Lederman MM (2015) Soluble CD14 is a nonspecific marker of monocyte activation. AIDS 29(10):1263–1265. https:\u002F\u002Fdoi.org\u002F10.1097\u002FQAD.0000000000000735\nOmura Y, Toiyama Y, Okugawa Y, Yin C, Shigemori T, Kusunoki K, Kusunoki Y, Ide S, Shimura T, Fujikawa H, Yasuda H, Hiro J, Ohi M, Kusunoki M (2020) Prognostic impacts of tumoral expression and serum levels of PD-L1 and CTLA-4 in colorectal cancer patients. Cancer Immunol Immunother. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs00262-020-02645-1\nWatson MM, Lea D, Gudlaugsson E, Skaland I, Hagland HR, Søreide K (2020) Prevalence of PD-L1 expression is associated with EMAST, density of peritumoral T-cells and recurrence-free survival in operable non-metastatic colorectal cancer. 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J Clin Pathol 69(3):209–214. https:\u002F\u002Fdoi.org\u002F10.1136\u002Fjclinpath-2015-202985\nLi P, Xiao ZT, Braciak TA, Ou QJ, Chen G, Oduncu FS (2016) Association between Ki67 index and clinicopathological features in colorectal cancer. Oncol Res Treat 39(11):696–702. https:\u002F\u002Fdoi.org\u002F10.1159\u002F000450623\nRemmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8(3):138–140\nFuchs TL, Sioson L, Sheen A, Jafari-Nejad K, Renaud CJ, Andrici J, Ahadi M, Chou A, Gill AJ (2020) Assessment of tumor-infiltrating lymphocytes using international tils working group (ITWG) system is a strong predictor of overall survival in colorectal carcinoma: a study of 1034 patients. 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Pathology and Genetics of Tumours of the Digestive System. IARC Press, Lyon\nPagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27(35):5944–5951. https:\u002F\u002Fdoi.org\u002F10.1200\u002FJCO.2008.19.6147\nZadka Ł, Grybowski DJ, Dzięgiel P (2020) Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance. Cell Oncol (Dordr) 43(4):539–575. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs13402-020-00519-3\nBetts G, Jones E, Junaid S, El-Shanawany T, Scurr M, Mizen P, Kumar M, Jones S, Rees B, Williams G, Gallimore A, Godkin A (2012) Suppression of tumour-specific CD4 T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 61(8):1163–1171. https:\u002F\u002Fdoi.org\u002F10.1136\u002Fgutjnl-2011-300970\nKuwahara T, Hazama S, Suzuki N, Yoshida S, Tomochika S, Nakagami Y, Matsui H, Shindo Y, Kanekiyo S, Tokumitsu Y, Iida M, Tsunedomi R, Takeda S, Yoshino S, Okayama N, Suehiro Y, Yamasaki T, Fujita T, Kawakami Y, Ueno T, Nagano H (2019) Intratumoural-infiltrating CD4 + and FOXP3 + T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer. Br J Cancer 121(8):659–665. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41416-019-0559-6\nNagata N, Ohta H, Yamada A, Teoh YB, Ichii O, Morishita K, Sasaki N, Takiguchi M (2020) Activities of matrix metalloproteinase-2, matrix metalloproteinase-9, and serine proteases in samples of the colorectal mucosa of Miniature Dachshunds with inflammatory colorectal polyps. Am J Vet Res 81(7):572–580. https:\u002F\u002Fdoi.org\u002F10.2460\u002Fajvr.81.7.572\nWang Z, Zhang J (2020) FOXP3 promotes colorectal carcinoma liver metastases by evaluating MMP9 expression via regulating S-adenosylmethionine metabolism. Ann Transl Med. 8(9):592\nKraft S, Klemis V, Sens C, Lenhard T, Jacobi C, Samstag Y, Wabnitz G, Kirschfink M, Wallich R, Hänsch GM, Nakchbandi IA (2016) Identification and characterization of a unique role for EDB fibronectin in phagocytosis. J Mol Med (Berl) 94(5):567–581. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs00109-015-1373-0\nYe Y, Zhang R, Feng H (2020) Fibronectin promotes tumor cells growth and drugs resistance through a CDC42-YAP-dependent signaling pathway in colorectal cancer. Cell Biol Int. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fcbin.11390\nMarelli G, Avigni R, Allavena P, Garlanda C, Mantovani A, Doni A, Erreni M (2018) Optical in vivo imaging detection of preclinical models of gut tumors through the expression of integrin αVβ3. Oncotarget. 9(59):31380–31396 https:\u002F\u002Fdoi.org\u002F10.18632\u002Foncotarget.25826\nChin YT, Wei PL, Ho Y, Nana AW, Changou CA, Chen YR, Yang YS, Hsieh MT, Hercbergs A, Davis PJ, Shih YJ, Lin HY (2018) Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr Relat Cancer 25(5):533–545. https:\u002F\u002Fdoi.org\u002F10.1530\u002FERC-17-0376\nVannini A, Leoni V, Barboni C, Sanapo M, Zaghini A, Malatesta P, Campadelli-Fiume G, Gianni T (2019) αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion. Proc Natl Acad Sci U S A 116(40):20141–20150. https:\u002F\u002Fdoi.org\u002F10.1073\u002Fpnas.1901931116\nCui L, Chen SY, Lerbs T, Lee JW, Domizi P, Gordon S, Kim YH, Nolan G, Betancur P (2020) Wernig G (2020) Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity. Nat Commun 11(1):2795. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41467-020-16466-4\nTakahashi H, Sakakura K, Kawabata-Iwakawa R, Rokudai S, Toyoda M, Nishiyama M, Chikamatsu K (2015) Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol Immunother 64(11):1407–1417. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs00262-015-1742-0\nKang JH, Jung MY, Choudhury M, Leof EB (2020) Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD-L1 into extracellular vesicles. FASEB J 34(2):2213–2226. https:\u002F\u002Fdoi.org\u002F10.1096\u002Ffj.201902354R\nZadka Ł, Piotrowska A, Opalińska A, Haczkiewicz-Leśniak K, Grybowski D, Ceremuga I, Chabowski M, Dzięgiel P (2020) Comparative analysis of exosome markers and extracellular vesicles between colorectal cancer and cancer-associated normal colonic mucosa. Pol Arch Intern Med 22 https:\u002F\u002Fdoi.org\u002F10.20452\u002Fpamw.15462\nChen J, Ma Y, Wang Z, Wang H, Wang L, Xiao F, Wang H, Tan J, Guo Z (2014) Thrombin promotes fibronectin secretion by bone marrow mesenchymal stem cells via the protease-activated receptor mediated signalling pathways. Stem Cell Res Ther 5(2):36. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fscrt424\nMetelli A, Wu BX, Riesenberg B, Guglietta S, Huck JD, Mills C, Li A, Rachidi S, Krieg C, Rubinstein MP, Gewirth DT, Sun S, Lilly MB, Wahlquist AH, Carbone DP, Yang Y, Liu B, Li Z (2020) Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β. Sci Transl Med. https:\u002F\u002Fdoi.org\u002F10.1126\u002Fscitranslmed.aay4860\nShirato K, Osawa H, Kaizuka M, Nakamura N, Sugawara T, Nakamura M, Tamura M, Yamabe H, Okumura K (2003) Thrombin stimulates production of fibronectin by human proximal tubular epithelial cells via a transforming growth factor-beta-dependent mechanism. Nephrol Dial Transplant 18(11):2248–2254. https:\u002F\u002Fdoi.org\u002F10.1093\u002Fndt\u002Fgfg398\nWhite MJ, Gomer RH (2015) Trypsin, tryptase, and thrombin polarize macrophages towards a pro-fibrotic M2a phenotype. PLoS ONE 10(9):e0138748. https:\u002F\u002Fdoi.org\u002F10.1371\u002Fjournal.pone.0138748\nGuinney J, Dienstmann R, Wang X et al (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21(11):1350–1356. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnm.3967\nLam M, Roszik J, Kanikarla-Marie P, Davis JS, Morris J, Kopetz S, Menter DG (2017) The potential role of platelets in the consensus molecular subtypes of colorectal cancer. Cancer Metastasis Rev 36(2):273–288. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs10555-017-9678-9\nSheng IY, Diaz-Montero CM, Rayman P, Wei W, Finke JH, Kim JS, Pavicic PG Jr, Lamenza M, Company D, Stephenson A, Campbell S, Haber G, Lee B, Mian O, Gilligan TD, Rini BI, Garcia JA, Grivas P, Ornstein MC (2020) Blood myeloid-derived suppressor cells correlate with neutrophil-to-lymphocyte ratio and overall survival in metastatic urothelial carcinoma. Target Oncol 15(2):211–220. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs11523-020-00707-z\nXiang H, Ramil CP, Hai J, Zhang C, Wang H, Watkins AA, Afshar R, Georgiev P, Sze MA, Song XS, Curran PJ, Cheng M, Miller JR, Sun D, Loboda A, Jia Y, Moy LY, Chi A, Brandish PE (2020) Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma. Cancer Immunol Res 8(4):436–450. https:\u002F\u002Fdoi.org\u002F10.1158\u002F2326-6066.CIR-19-0507",{"VOID":279},"10.1007\u002Fs00262-021-02863-1","PUBLICATION","VERIFIED","2024-12-14T20:09:55.370+00:00","Auto Verify",[285],"VI","https:\u002F\u002Flink.springer.com\u002F10.1007\u002Fs00262-021-02863-1",[288,304,329,345,359],{"id":289,"sortIndex":19,"researcher":18,"roles":290,"affiliations":292,"properties":301,"displayName":303,"givenName":18,"familyName":18},"8aef92f8-51d1-42d1-aa03-7cd77d3645d3",[291],"AUTHOR",[293],{"id":294,"sortIndex":19,"affiliation":295,"properties":18},"2794bbe7-161f-44d5-aa09-fe625a3471eb",{"id":294,"createTime":18,"updateTime":18,"relativeEntities":296,"slug":18,"properties":297,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":300,"statistic":18},[],{"title":298},{"VI":299},"Department of Human Morphology and Embryology, Division of Histology and Embryology, Wrocław, 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transfer of human peripheral blood mononuclear cells (hu-PBMC) from adult Epstein-Barrvirus(EBV)-seropositive honors in SCID (severe combined immunodeficiency) mice frequently leads to the development of a human B lymphoproliferative syndrome (hu-BLPS). Therefore, as 90% of adult potential donors are EBV-seropositive, efforts have to be made to avoid the occurrence of this B lymphoproliferative disorder. McCune et al. [Science 241;1632 (1988)] used human fetal organs for a human SCID graft. This system does not give rise to hu-BLPS but human fetal organs are much less available than peripheral blood leucocytes. The experiments reported in this paper show how crucial is the presence offunctional T lymphocytes for a graft to take and for development of hu-BLPS in hu-PBMC-reconstituted SCID mice, since inhibition of T lymphocyte by a rat anti-(human CD2) monoclonal antibody (LO-CD2a) during the first 10 days of the graft prevents successful engraftment of human normal lymphocytes as well as hu-BLPS in SCID mice. The transfer of B cells alone or B cells plus monocytes in SCID mice does not permit either long-term engraftment or development of hu-BLPS. We also demonstrate that hu-PBMC treated withL-leucine methyl ester are less susceptible to the development of hu-BLPS after engraftment in SCID mice than are untreated hu-PBMC. The mechanism of action ofL-leucine methyl ester on these cells is discussed.",{"EN":451},"A rat monoclonal anti-(human CD2) andL-leucine methyl ester impacts on human\u002FSCID mouse graft and B lymphoproliferative syndrome",{"VOID":453},"[\"385038519052323038\"]",{"VOID":455},"Bazin H, Xhurdebise LM, Burtonboy G, Lebacq AM, De Clercq L, Cormont F (1984) Rat rat monoclonal antibodies. I. Rapid purification from in vitro culture supernatants. J Immunol Methods 66:261\nBazin H, Pear WS, Klein G, Sümeji J (1990) Rat immunocytomas (IR). In: Bazin H (ed) Rat hybridomas and rat monoclonal antibodies. CRC, Boca Raton, Fl, p 53\nBerg LC, Copenhaver CM, Morrison VA, Gruber SA, Dunn DL, Gajl-Peczalska K, Strickler JG (1992) B-cell lymphoproliferative disorders in solid-organ transplant patients: detection of Epstein-Barr virus by in situ hybridization. Hum Pathol 23:159\nBorrebaeck CAK (1988) Human mAbs produced by primary in vitro immunization. Immunol Today 9:355\nBosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301:527\nBosma GC, Fried M, Custer RP, Carroll A, Gibson DM, Bosma MJ (1988) Evidence of functional lymphocyte in some (leaky) SCID mice. J Exp Med 167:1016\nBruggeman M, Spicer C, Buluwela L, Rosewell I, Barton S, Surani MA, Rabbitts TH (1991) Human antibody production in transgenic mice: expression from 100 kb human IgH locus. Eur J Immunol 21:1323\nCarlsson R., Martesson C., Kalliomaki S., Ohlin M, Borrebaeck CAK (1992) Human peripheral blood lymphocytes transplanted into SCID mice constitute an in vivo culture system exhibiting several parameters found in a normal humoral immune response and are a source of immunocytes for the production of human monoclonal antibodies. J Immunology 148:1065\nDorshkind K, Keller GM, Philips RA, Miller RG, Bosma GC, O'Toole M, Bosma MJ (1984) Functional status of cells from lymphoïd and myeloïd tissues in mice with severe combined immunodeficiency disease. J Immunol 132:1804\nDuhosal MA, Eming SA, Fischer P, Le turcq D, Barbas CF III, Thornton GB, Dixon FJ, Burton DR (1992) Immunization of Hu-PBL-Scid mice and the rescue of human monoclonal Fab fragments through combinatorial libraries. Nature 355:258\nHoffmann-Fezer G, Kranz B, Gall C, Thierfelder S (1992) Peritoneal sanctuary for human lymphopoiesis in SCID mice injected with human peripheral blood lymphocytes from Epstein-Barr virus-negative donors. Eur J Immunol 22:3161\nKamel-Reid S, Dick JE (1988) Engraftment of immunodeficient mice with human hematopoietic stem cells. Science 242:1706\nMalynn BA, Blackwell JK, Fulop GM, Rathbun GA, Furley AJW, Ferrier P, Heinke LB, Philips RA, Yancopoulos GD, Alt FW (1988) The SCID defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell 54:453\nMcCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL (1988) The SCID-hu mouse: murine model for the analyses of human hematolymphoïd differentiation and function. Science 241:1632\nMcCune JM, Namikawa R, Shih C, Rabin L, Kaneshima H (1990) Suppression of HIV infection in AZT-treated SCID-hu mice. Science 247:564\nMosier DE, Gulizia RJ, Baird SM, Wilson DB (1988) Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256\nNamikawa R, Weilbaecher KN, Kaneshima H, Yee EJ, McCune JM (1990) Long term human hematopoiesis in the SCID-hu mouse. J Exp Med 172:1055\nOhlin M, Danielsson L, Carlsson R, Borrebaeck CAK (1989) The effect of leucyl-leucine methyl ester on proliferation and Ig secretion of EBV-transformed human B lymphocyte. Immunology 66:485\nPflumio F, Lapidot T, Murdoch B, Patterson B, Dick JE (1993) Engraftment of human lymphoid cells into newborn Scid mice leads to graft-versus-host disease. Int Immunol 5:1509\nPhillips RA, Jewett MAS, Gallie BL (1989) Growth of human tumors in immune-deficient SCID mice and nude mice. Curr Top Microbiol Immunol 152:259\nPisa P, Cannon MJ, Pisa EK, Cooper NR, Fow RI (1992) Epstein-Barr Barr virus induced lymphoproliferative tumours in severe combined immunodeficient mice are oligoclonal. 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A single arm study of ipilimumab monotherapy in patients with previously treated unresectable stage III or IV melanoma. http:\u002F\u002Fclinicaltrials.gov\u002Fct\u002Fshow\u002FNCT00289627",{},{"id":18,"text":1207,"url":18,"identifiers":1208},"ClinicalTrials.gov. A companion study for patients enrolled in prior\u002Fparent ipilimumab studies. http:\u002F\u002Fclinicaltrials.gov\u002Fshow\u002FNCT00162123",{},{"id":18,"text":1210,"url":18,"identifiers":1211},"Fischkoff SA, Hersh E, Weber J, Powderly J, Khan K, Pavlick A, Samlowski W, O’Day S, Nichol G, Yellin M (2005) Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma (abstract 7525). J Clin Oncol 23(suppl)",{"doi":1212},"10.1200\u002Fjco.2005.23.16_suppl.7525",{"id":18,"text":1214,"url":18,"identifiers":1215},"Hamid O, Urba WJ, Yellin M, Nichol GM, Weber J, Hersh EM, Tchekmedyian S, Hodi FS, Weber R, O’Day S (2007) Ipilimumab (MDX-010) in patients with stage III\u002FIV melanoma: kinetics and duration of response. Eur J Cancer Suppl 5:396",{"doi":1216},"10.1016\u002FS1359-6349(07)71459-3",{"id":18,"text":1218,"url":18,"identifiers":1219},"Hersh EM, O’Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer L, Samlowski WE, Nichol GM, Yellin MJ, Fischkoff SA, Weber JS (2008) Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab with or without dacarbazine. J Clin Oncol (submitted)",{"doi":1220},"10.1200\u002Fjco.2008.26.15_suppl.9022",{"id":18,"text":1222,"url":18,"identifiers":1223},"Hodi FS, The Global Ipilimumab Melanoma Study Group (2008) Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody (abstract 3008). J Clin Oncol 26(suppl)",{"doi":1224},"10.1200\u002Fjco.2008.26.15_suppl.3008",{"id":18,"text":1226,"url":18,"identifiers":1227},"Lin R, Yellin MJ, Lowy I, Safferman A, Chin K, Ibrahim R (2008) An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhea\u002Fcolitis: prevention of gastrointestinal perforation and\u002For colectomy (abstract 9063). J Clin Oncol 26(suppl)",{"doi":1228},"10.1200\u002Fjco.2008.26.15_suppl.9063",{"id":18,"text":1230,"url":18,"identifiers":1231},"Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Hughes M, Yellin MJ, Haworth LR, Levy C, Allen T, Mavroukakis SA, Attia P, Rosenberg SA (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455–463",{"doi":1232},"10.1097\u002F01.cji.0000208259.73167.58",{"id":18,"text":1234,"url":18,"identifiers":1235},"O’Day S, Boasberg P (2006) Management of metastatic melanoma 2005. Surg Oncol Clin N Am 15:419–437",{"doi":1236},"10.1016\u002Fj.soc.2005.12.002",{"id":18,"text":1238,"url":18,"identifiers":1239},"O’Day SJ, Hamid O, Urba WJ (2007) Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 110:2614–2627",{"doi":1240},"10.1002\u002Fcncr.23086",{"id":18,"text":1242,"url":18,"identifiers":1243},"Saenger Y, Wolchok J (2008) The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun 8:1",{},{"id":18,"text":1245,"url":18,"identifiers":1246},"Sasse AD, Sasse EC, Clark LGO, Ulloa L, Clark OAC (2007) Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database of Systematic Reviews 2007, Iss 1. Art No: CD005413. doi: 10.1002\u002F14651858.CD005413.pub2",{"doi":1247},"10.1002\u002F14651858.CD005413.pub2",{"id":18,"text":1249,"url":18,"identifiers":1250},"Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS (2007) Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol 25:3802–3807",{"doi":1251},"10.1200\u002FJCO.2006.10.2822",{"id":18,"text":1253,"url":18,"identifiers":1254},"Weber J (2007) Anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse effects. Oncologist 12:864–872",{"doi":1255},"10.1634\u002Ftheoncologist.12-7-864",{"id":18,"text":1257,"url":18,"identifiers":1258},"Weber JS, Hersh EM, Yellin M, Nichol GM, Urba W, Powderly JD, O’Day SJ (2007) The efficacy and safety of ipilimumab (MDX-010) in patients with unresectable stage III or stage IV malignant melanoma [abstract 8523]. J Clin Oncol 25(suppl)",{"doi":1259},"10.1016\u002FS1359-6349(07)71457-X",{"id":18,"text":1261,"url":18,"identifiers":1262},"Weber JS, Targan S, Scotland R, Snively J, Garcia M, Yellin M, Fischkoff S, Nichol G (2006) Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma (abstract 2510). J Clin Oncol 18(suppl)",{"doi":1263},"10.1200\u002Fjco.2006.24.18_suppl.2510",{"id":18,"text":1265,"url":18,"identifiers":1266},"Wolchok JD, The Global Ipilimumab Melanoma Study Group (2008) Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment (abstract 3020). J Clin Oncol 26(suppl)",{"doi":1267},"10.1200\u002Fjco.2008.26.15_suppl.3020",{"id":1269,"createTime":1270,"updateTime":1271,"relativeEntities":1272,"slug":1273,"properties":1274,"entityType":280,"verifyStatus":281,"verifyTime":1287,"verifyNote":283,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":1288,"fullTextUrl":18,"authors":1289,"publicationType":373,"publisherRelationship":1370,"citationCount":19,"citationInfo":1428,"publishDate":1431,"publishYear":1429,"citationAnalyzeStatus":1432,"lastCitationAnalyze":1271,"indexDatabases":1433,"openAccess":18,"references":18,"isForceReanalyzing":440},"feed2266-7020-467e-8166-c43c135513e0","2024-04-06T15:09:41.007+00:00","2026-07-28T17:34:00.958+00:00",[],"Effect-of-BCG-on-hematopoietic-stem-cells-Experimental-and-clinical-study",{"abstract":1275,"title":1277,"gsPaper":1279,"keywords":1281,"references":1283,"doi":1285},{"EN":1276},"In (DBA\u002F2×C57Bl\u002F6) F1 mice the i.v. injection of 1 mg of living BCG does not increase the total number of CFU\u002Fs per femur, but a marked increase in the percentage of CFU\u002Fs in S phase is noted as early as the 8th hr. BCG injected i.v. also increases the absolute number of colony-forming units in agar per femur. The effect of BCG appears quite different from the known effect of bacterial endotoxin, and in particular it does not induce a significant increase in the level of CSF. The administration of BCG 24 hrs after treatment with a single dose of 200 mg\u002Fkg of cyclophosphamide significantly reduces the time of hematologic restoration, but the same dose of BCG given after a lethal dose of total body irradiation does not increase survival time in mice. These different effects of BCG seem to be related to the role of BCG in stimulating the multiplication maturation pool of the bone marrow without producing any increase in the reserve pool.",{"EN":1278},"Effect of BCG on hematopoietic stem cells: Experimental and clinical study",{"VOID":1280},"[\"8137543920666824923\"]",{"EN":1282},"",{"VOID":1284},"Becker, A. J. McCulloch, E. A., Siminovitch, L., Till, J. E.: The effect of differing demands for blood cell production on DNA synthesis by hemopoietic colony forming cells of mice. Blood 26, 296 (1965)\nBoogs, S. S., Chervenick, P. A., Boggs, D. R.: The effect of post-irradiation bleeding or endotoxin on proliferation and differentiation of hematopoietic stem cells. Blood 40, 375 (1972)\nBradley, T. R., Metcalf, D.: The growth of mouse bone marrow cells in vitro. Aust. J. Exp. Biol. Med. Sci. 44, 287 (1966)\nBruce, W. R., Meeker, B. E.: Comparison of the sensitivity of hematopoietic colony forming cells in different proliferative status to 5-fluoro-uracil. J. Natl. Cancer Inst. 38, 401 (1967)\nEaves, A. C., Bruce, W. R.: Endotoxin induced sensitivity of hematopoietic stem cells to chemotherapeutic agents. Ser. Haematol. 5, 64 (1972)\nHanks, G. E., Ainsworth, E. J.: Endotoxin protection and colony forming units. Radiat. Res. 32, 367 (1967)\nHaskill, J. S., McNeill, T. A., Moore, M. A. S.: Density distribution analysis of in vivo and in vitro colony forming cells in bone marrow. J. Cell. Physiol. 75, 167 (1970)\nIsrael, L.: A randomized study of chemotherapy versus chemotherapy and immune therapy with Corynebacerium parvum in advanced breast cancer. In: Symposium 44. Breast Cancer: Management of Inoperable Patients. XIth International Cancer Congress, Florence, Oct. 1974, p. 222\nMathé, G.: Active immunotherapy. Adv. Cancer Res. 14, 1 (1971)\nMcNeil, T. A.: Antigenic stimulation of bone marrow colony forming cells. Immunology 18, 61 (1970)\nQuesenberry, P., Morley, A., Stohlman, F., Jr., Rickard, K., Howard, D., Smith, M.: Effect of endotoxin on granulopoiesis and colony stimulating factor. N. Engl. J. Med. 286, 227 (1972)\nQuesenberry, P. J., Morley, A., Ryan, M., Howard, D., Stohlman, F., Jr.: The effect of endotoxin on murine stem cells. J. Cell. Physiol. 82, 239 (1973)\nPluznick, D. H., Sachs, L.: The cloning of normal “mast cells” in tissue culture. J. Cell. Comp. Physiol. 66, 319 (1965)\nPouillart, P., Schwarzenberg, L., Mathé, G., Schneider, M., Jasmin, C., Hayat, M., Weiner, R., de Vassal, F., Amiel, J. L., Beyer, H. P., Fajbisowicz, S.: Essai clinique de combinaisons chimiothérapiques basées sur la notion de tentative de synchronisation cellulaire. Nouv. Presse Med. 1, 1957 (1972)\nSmith, W. W., Brecher, G., Budd, R. A., Fred, S.: Effects of bacterial endotoxin on the occurrence of spleen colonies in irradiated mice. Radiat. Res. 27, 369 (1966)\nSmith, W. W., Brecher, G., Fred, S., Budd, R. A.: Effect of endotoxin on the kinetics of hemopoietic colony forming cells in irradiated mice. Radiat. Res. 27, 710 (1966)\nTill, J. E., McCulloch, E. A.: A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14 213 (1961)\nValeriote, F. A., Bruce, W. R.: Comparison of the sensitivity of hematopoietic colony forming cells in different proliferative states to vinblastine. J. Natl. Cancer Inst. 38, 393 (1967)",{"VOID":1286},"10.1007\u002FBF00205461","2024-09-13T09:03:22.966+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002FBF00205461",[1290,1305,1318,1331,1344,1357],{"id":1291,"sortIndex":19,"researcher":18,"roles":1292,"affiliations":1293,"properties":1302,"displayName":1304,"givenName":18,"familyName":18},"e69477dd-0320-4da5-a4ff-550a5b527bf2",[291],[1294],{"id":1295,"sortIndex":19,"affiliation":1296,"properties":18},"82dd41eb-9a5b-4341-b696-8639ebbae29e",{"id":1295,"createTime":18,"updateTime":18,"relativeEntities":1297,"slug":18,"properties":1298,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":1301,"statistic":18},[],{"title":1299},{"VI":1300},"Institut de Cancérologie et d'Immunogénétique, (INSERM et Association Claude Bernard), Hôpital Paul-Brousse, Villejuif, France",[],{"title":1303},{"VI":1304},"P. 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the perspective of therapeutic approaches the monoclonal antibody, MBr1, with a quite restricted spectrum of reactivity for human breast carcinoma, was coupled to restrictocin (Res), a ribosome inactivating protein produced by Aspergillus restrictus. In a cell-free system this toxin was found to have an activity comparable to that of other plant toxins, but its in vitro toxicity was shown to be low on different cell lines. Three batches of MBr1-Res conjugate were prepared and their specificity, efficiency, and maximum level of cytotoxicity were analyzed on the cell line MCF-7 expressing the relevant antigen, on several irrelevant tumor cell lines, and on normal cells. Conjugates were from 600 to 1500 times more efficient than the uncoupled derivatized Res towards MCF-7 cells and were completely ineffective on the other target cells. The antigen-driven cytotoxicity was confirmed by the nontoxicity of an irrelevant conjugate on MCF-7 cells. The cytotoxic efficiency of MBr1-Res was low when compared to the binding level of MBr1 at the same concentration and a portion of treated cells (from 10% to 30%) survived the treatment. The heterogeneity of expression of the relevant antigen, together with its only partial internalization, could account for these limitations. The lysosomotropic agent ammonium chloride and the carboxylic ionophore monensin were tested as potentiating agents but in both cases the cytotoxicity remained unmodified. A neutralization assay performed on a xenogenic model indicated that the MBr1-Res conjugate was capable of reducing the tumor take. These data indicate the possibility of using the Res to prepare a reproducible and highly selective breast cancer conjugate. However, there are still a number of problems which must first be solved before we can consider its clinical application.",{"EN":1444},"Immunoconjugate generation between the ribosome inactivating protein restrictocin and an anti-human breast carcinoma MAB",{"VOID":1446},"[\"3187705515546634237\"]",{"VOID":1448},"Barbieri L, Stirpe F (1982) Ribosome-inactivating proteins from plants: properties and possible uses. Cancer Surg 1:489\nBjorn MJ, Ring D, Frankel A (1985) Evaluation of monoclonal antibodies for the development of breast cancer immunotoxins. Cancer Res 45:1214\nBjorn MJ, Groetsema G, Scalapino L (1986) Antibody-Pseudomonas exotoxin A conjugates cytotoxic to human breast cancer cells in vitro. Cancer Res 46:3262\nBremer EG, Levery SB, Sonnino S, Ghidoni R, Canevari S, Kannagi R, Hakomori S-i (1984) Characterization of a glycolipid antigen defined by the monoclonal antibody MBrl expressed in normal and neoplastic epithelial cells of human mammary gland. J Biol Chem 259:14773\nCanevari S, Fossati G, Balsari A, Sonnino S, Colnaghi MI (1983) Immunochemical analysis of the determinant recognized by a monoclonal antibody (MBr1) which specifically binds to human mammary epithelial cells. Cancer Res 43:1301\nCanevari S, Orlandi R, Ripamonti M, Tagliabue E, Aguanno S, Miotti S, Ménard S, Colnaghi MI (1985) Ricin A chain conjugated with monoclonal antibodies selectively killing human carcinoma cells in vitro. J Natl Cancer Inst 75:831\nCarlsson J, Drevin H, Axen R (1978) Protein thiolation and reversible protein-protein conjugation. Biochem J 173:723\nConde FP, Fernandez-Puentes C, Montero MTV, Vazquez D (1978) Protein toxins that catalytically inactivate ribosomes from eukaryotic microorganisms. Studies on the mode of a action of alpha sarcin, mitogillin and restrictocin: response to alpha sarcin antibodies. FEMS Microbiol Lett 4:349\nDella Torre G, Canevari S, Orlandi R, Colnaghi MI (1987) Internalization of a monoclonal antibody against human breast cancer by immunoelectron microscopy. Br J Cancer 55:357\nEndo Y, Huber PW, Wool IG (1982) The ribonuclease activity of the cytotoxin α-Sarcin. J Biol Chem 258:2662\nFernandez-Luna JL, López-Otin C, Soriano F, Méndez E (1985) Complete amino acid sequence of the Aspergillus cytotoxin mitogillin. Biochemistry 24:861\nFernandez-Puentes C, Carrasco L (1980) Viral infection permeabilizes mammalian cells to protein toxins. Cell 20:769\nFilipovich AH, Vallera DA, Youle RJ, Quinones RR, Neville DM Jr, Kersey JH (1984) Ex vivo treatment of donor bone marrow with anti-T-cell immunotoxins for prevention of graft-versus-host disease. Lancet I:469\nForrester JA, McIntosh DP, Cumber AJ, Parnell GD, Ross WCJ (1984) Delivery of Ricin and Abrin A chains to human carcinoma cells in culture following covalent linkage to monoclonal antibody LICR-LOND-Fib 75. Cancer Drug Delivery 1:283\nFrankel AE, Houston LL, Issell BF, Fathman G (1986) Prospects for immunotoxin therapy in cancer. Ann Rev Med 37:125\nGreenwood FC, Hunter WM, Glover JS (1963) The preparation of 131I-labelled human growth hormone of high specific radioactivity. Biochem J 89:114\nLaemli UK (1970) Cleavage of structural proteins during the assembly of the head of the bacteriophage T4. Nature 227:680\nLambert JM, Senter PD, Yau-Young A, Blattler WA, Goldmacher VS (1985) Purified immunotoxins that are reactive with human lymphoid cells. J Biol Chem 260:12035\nLeMaistre CF, Edwards DP, Krolick KA, McGuire WL (1987) An immunotoxin cytotoxic for breast cancer cells in vitro. Cancer Res 47:730\nLin JY, Tserng KY, Chen CC, Lin K, Tung TC (1970) Abrin and Ricin: New antitumor substances. Nature 227:292\nLòpez-Otin C, Barber D, Fernandez-Luna JL, Soriano F, Méndez E (1984) The primary structure of the cytotoxin restrictocin. Eur J Biochem 143:621\nMariani-Costantini R, Colnaghi MI, Leoni F, Ménard S, Cerasoli S, Rilke F (1984) Immunohistochemical reactivity of a monoclonal antibody prepared against human breast carcinoma. Virchows Arch (A) 402:389\nMénard S, Tagliabue E, Canevari S, Fossati G, Colnaghi MI (1983) Generation of monoclonal antibodies reacting with normal and cancer cells of human breast. Cancer Res 43:1295\nOlsnes S, Sandvig K (1983) Entry of toxic proteins into cells. In: Cuatrecasas P, Roth TF (eds) Receptor-mediated endocytosis. London, Chapman and Hall, 15:189\nOlson BH, Goerner GL (1986) Alpha sarcin, a new antitumor agent. I. Isolation, purification, chemical composition, and the identity of a new amino acid. Appl Microbiol 13:314\nOrlandi R, Canevari S, Leoni F, Mezzanzanica D, Ripamonti M, Colnaghi MI (1986) Change in binding reactivity of an anti-tumor monoclonal antibody after the introduction of 2-pyridyl disulphide groups. Hybridoma 5:1\nPirker R, Fitzgerald D, Hamilton T, Ozols R, Willingham M, Pastan I (1985) Anti-transferrin receptor-antibody linked to Pseudomonas exotoxin as a model immunotoxin in human ovarian carcinoma cell lines. Cancer Res 45:751\nRamakrishnan S, Houston LL (1984) Inhibition of human acute lymphoblastic leukemia cells by immunotoxins: potentiation by chloroquine. Science 223:58\nRipamonti M, Canevari S, Ménard S, Mezzanzanica D, Miotti S, Orlandi R, Rilke F, Tagliabue E, Colnaghi MI (1987) Human carcinoma cell lines xenografted in athymic mice: biological and antigenic characteristics of an intraabdominal model. Cancer Immunol Immunother 24:13\nTagliabue E, Porro G, Barbanti P, Della Torre G, Ménard S, Rilke F, Cerasoli S, Colnaghi MI (1986) Improvement of tumor cell detection using a pool of monoclonal antibodies. Hybridoma 5:107\nThorpe PE, Ross WCJ, Brown ANF, Myers CD, Cumber AJ, Foxwell BMJ, Forrester JT (1984) Blockade of the galactose-binding sites of ricin by its linkage to antibody. Eur J Biochem 140:63\nThorpe PE, Brown ANF, Bremner JAG Jr, Foxwell BMJ, Stirpe F (1985) An immunotoxin composed of monoclonal anti-Thy 1.1 antibody and a ribosome-inactivating protein from Saponaria officinalis: potent antitumor effects in vitro and in vivo. J Natl Cancer Inst 75:151\nUckun FM, Gajl-Peczalska KJ, Kersey JH, Houston LL, Vallera DA (1986) Use of a novel colony assay to evaluate the cytotoxicity of an immunotoxin containing pokeweed antiviral protein against blast progenitor cells freshly obtained from patients with common B-lineage acute lymphoblastic leukemia. J Exp Med 163:347\nYoule RJ, Murray GJ, Neville DM Jr (1979) Ricin linked to monophosphopentamannose binds to fibroblast lysosomal hydrolase receptors, resulting in a cell-type specific toxin. 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cell-mediated cytotoxicity (ADCC) has been considered to be one of the main effector mechanisms by which unconjugated monoclonal antibody (mAb) 17-1A can exert an antitumor effect in vivo. Since the apoptotic pathway as well as the necrotic pathway have been shown to be utilized in various cytotoxic effector mechanisms, we investigated the role of apoptosis in ADCC mediated by monocytes (ADMC) using mAb 17-1A as an antibody and the human colorectal carcinoma cell line, COLO205, as target cells in vitro. The implications of the apoptosis during ADMC was demonstrated by means of both a DNA fragmentation assay and a TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Furthermore, interferon γ (IFNγ) was also found to enhance the induction of apoptosis significantly. The addition of superoxide dismutase did not reduce the level of the apoptosis, although superoxide anion (O2\n–) was observed to be produced. However, the release of tumor necrosis factor α (TNFα) was significantly enhanced during ADMC, while, in addition, apoptosis was significantly inhibited by the addition of anti-TNFα antibody. These findings indicated that apoptosis might be implicated in ADMC with mAb 17-1A, which was augmented by IFNγ, while, in addition, TNFα may also be one of the major mediators of apoptosis.",{"EN":1629},"Apoptosis in antibody-dependent monocyte-mediated cytotoxicity with monoclonal antibody 17-1A against human colorectal carcinoma cells: enhancement with interferon 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sự kiện phụ liên quan đến miễn dịch tại gan (irAE) bao gồm các xét nghiệm chức năng gan tăng cao (transaminase) xảy ra ở 1.4–22.3% bệnh nhân melanoma nhận liệu pháp ức chế điểm kiểm soát miễn dịch (ICPI) và cấu thành một độc tính tiềm ẩn nghiêm trọng khó điều trị. Trái ngược với các transaminase gan alanine aminotransferase (ALT) và aspartate aminotransferase (AST), vẫn còn rất ít thông tin được biết đến về tần suất và tác động của sự gia tăng gamma-glutamyl transferase (GGT). GGT được xác định trước và trong quá trình điều trị ở bệnh nhân melanoma di căn được điều trị bằng ICPI đã được đánh giá hồi cứu trong hai nhóm độc lập (PD-1: n = 218, Ipi + Nivo: n = 148). Thời gian sống sót toàn bộ (OS) và phản ứng khách quan tốt nhất đã được phân tích theo mức GGT cơ bản và gia tăng GGT liên quan đến miễn dịch (irGGT) trong quá trình điều trị. Trong phân tích đa biến, OS giảm ở những bệnh nhân có GGT cơ bản tăng cao (nhóm PD-1: tỷ lệ nguy cơ [HR] 1.76, p = 0.0073; nhóm Ipi + Nivo: HR 1.77, p = 0.032). Sự gia tăng GGT liên quan đến miễn dịch đã được ghi nhận ở 17% (nhóm PD-1) và 38.5% (nhóm Ipi + Nivo). Trong số bệnh nhân này, phần lớn (81 và 68%, tương ứng) có ALT và AST bình thường và không cho thấy dấu hiệu lâm sàng của độc tính gan. Các bệnh nhân gặp phải sự gia tăng irGGT có phản ứng tốt hơn (nhóm PD-1: tỷ lệ odds [OR] 3.57, p = 0.00072; nhóm Ipi + Nivo: OR 1.74, p = 0.12) và OS (nhóm PD-1: HR 0.37, p = 0.0016; nhóm Ipi + Nivo: HR 0.33, p = 0.00050). Tần suất của các sự kiện phụ liên quan đến gan hiện tại đang bị đánh giá thấp. Việc bổ sung enzym nhạy cảm GGT vào bảng xét nghiệm trước và trong quá trình điều trị bằng ICPI cho phép phát hiện gấp hai đến ba lần số bệnh nhân phát triển độc tính gan hoặc đường mật hơn so với những gì đã biết cho đến nay. Sự gia tăng GGT liên quan đến miễn dịch tương quan với phản ứng và thời gian sống sót thuận lợi.","Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4–22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050). The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.",{"EN":2082,"VI":2083},"Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors","Vai trò tiên lượng của gamma-glutamyl transferase ở bệnh nhân melanoma di căn được điều trị bằng các chất ức chế điểm kiểm soát miễn dịch",{"VOID":2085},"11386541061887465571",{"VI":2087},"bệnh nhân melanoma, gamma-glutamyl transferase, ức chế điểm kiểm soát miễn dịch, độc tính gan, tần suất sự kiện bất lợi",{"VOID":2089},"10.1007\u002Fs00262-020-02768-5","2024-04-29T01:20:16.787+00:00",[285],"https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00262-020-02768-5",[2094,2109,2122,2135,2148,2161,2174,2189,2202,2215,2228,2241,2254],{"id":2095,"sortIndex":19,"researcher":18,"roles":2096,"affiliations":2097,"properties":2106,"displayName":2108,"givenName":18,"familyName":18},"7d4c4a11-9ef5-4684-bcd7-4266f7ea484e",[291],[2098],{"id":2099,"sortIndex":19,"affiliation":2100,"properties":18},"97b087ad-5797-47fe-af90-30f3773431ff",{"id":2099,"createTime":18,"updateTime":18,"relativeEntities":2101,"slug":18,"properties":2102,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":2105,"statistic":18},[],{"title":2103},{"EN":2104},"Department of Dermatology, University Hospital Tübingen, Tübingen, Germany",[],{"title":2107},{"VI":2108},"Johanna Winter",{"id":2110,"sortIndex":306,"researcher":18,"roles":2111,"affiliations":2112,"properties":2119,"displayName":2121,"givenName":18,"familyName":18},"dc283897-97c9-4f5b-8032-ad18326e5f5c",[291],[2113],{"id":2099,"sortIndex":19,"affiliation":2114,"properties":18},{"id":2099,"createTime":18,"updateTime":18,"relativeEntities":2115,"slug":18,"properties":2116,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":2118,"statistic":18},[],{"title":2117},{"EN":2104},[],{"title":2120},{"VI":2121},"Max M. 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