In this paper, we present the role of autologous and allogeneic monocytes from healthy individuals and those of the cancer patients, with a number of distinct cancers, in activating the function of natural killer (NK) cells, in particular, in induction of IFN-γ secretion by the NK cells and the functional capability of secreted IFN-γ in driving differentiation of the tumor cells. In addition, we compared the roles of CD16 signaling as well as sonicated probiotic bacteria AJ2 (sAJ2)-mediated induction and function of IFN-γ-mediated differentiation in tumor cells. We found that monocytes from cancer patients had lower capability to induce functional IFN-γ secretion by the autologous CD16 mAb-treated NK cells in comparison to those from healthy individuals. In addition, when patient monocytes were cultured with NK cells from healthy individuals, they had lower capability to induce functional IFN-γ secretion by the NK cells when compared to those from autologous monocyte/NK cultures from healthy individuals. Activation by sAJ2 or addition of monocytes from healthy individuals to patient NK cells increased the secretion of functional IFN-γ by the NK cells and elevated its functional capability to differentiate tumors. Monocytes from cancer patients were found to express lower CD16 receptors, providing a potential mechanism for their lack of ability to trigger secretion of functional IFN-γ. In addition to in vitro studies, we also conducted in vivo studies in which cancer patients were given oral supplementation of AJ2 and the function of NK cells were studied. Oral ingestion of AJ2 improved the secretion of IFN-γ by patient derived NK cells and resulted in the better functioning of NK cells in cancer patients. Thus, our studies indicate that for successful NK cell immunotherapy, not only the defect in NK cells but also those in monocytes should be corrected. In this regard, AJ2 probiotic bacteria may serve to provide a potential adjunct treatment strategy.
Natural killer (NK) cells are the key immune effectors with the ability to mediate selection and differentiation of a number of different cancer stem cells/undifferentiated tumors via lysis, and secreted or membrane-bound interferon (IFN)-γ and tumor necrosis factor (TNF)-α, respectively, leading to curtailment of tumor growth and metastasis. In this review, we present an overview of our recent findings on the biology and significance of NK cells in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in humanized-BLT mice and in cancer patients. In addition, we present current advances in NK cell expansion and therapeutic delivery, and discuss the utility of allogeneic supercharged NK cells in the treatment of cancer patients. Moreover, we discuss the potential loss of NK cell numbers and function at the neoplastic and pre-neoplastic stages of tumorigenesis in induction and progression of pancreatic cancer. Therefore, because of their indispensable role in targeting cancer stem-like/undifferentiated tumors, NK cells should be placed high in the armamentarium of tumor immunotherapy. A combination of allogeneic supercharged NK cells with other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, CAR NK cells, and chemotherapeutic and radiotherapeutic strategies can be used for the ultimate goal of tumor eradication. Natural killer (NK) cells are the key immune effectors with the ability to mediate selection and differentiation of a number of different cancer stem cells/undifferentiated tumors via lysis, and secreted or membrane-bound interferon (IFN)-γ and tumor necrosis factor (TNF)-α, respectively, leading to curtailment of tumor growth and metastasis. In this review, we present an overview of our recent findings on the biology and significance of NK cells in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in humanized-BLT mice and in cancer patients. In addition, we present current advances in NK cell expansion and therapeutic delivery, and discuss the utility of allogeneic supercharged NK cells in the treatment of cancer patients. Moreover, we discuss the potential loss of NK cell numbers and function at the neoplastic and pre-neoplastic stages of tumorigenesis in induction and progression of pancreatic cancer. Therefore, because of their indispensable role in targeting cancer stem-like/undifferentiated tumors, NK cells should be placed high in the armamentarium of tumor immunotherapy. A combination of allogeneic supercharged NK cells with other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, CAR NK cells, and chemotherapeutic and radiotherapeutic strategies can be used for the ultimate goal of tumor eradication. Natural killer (NK) cells develop in bone marrow and are known to regulate innate and adaptive immunity.1Fang F. Xiao W. Tian Z. NK cell-based immunotherapy for cancer.Semin. Immunol. 2017; 31: 37-54Crossref PubMed Scopus (129) Google Scholar,2Freud A.G. Mundy-Bosse B.L. Yu J. 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Human circulating and tissue-resident CD56bright natural killer cell populations.Front. Immunol. 2016; 7: 262Crossref PubMed Scopus (83) Google Scholar NK cells may lose the ability to mediate cytotoxicity or secrete interferon (IFN)-γ, thereby giving rise to the third stage of NK cell maturation. Finally, NK cells may undergo apoptosis, giving rise to stage 4.18Kaur K. Cook J. Park S.H. Topchyan P. Kozlowska A. Ohanian N. Fang C. Nishimura I. Jewett A. Novel strategy to expand super-charged NK cells with significant potential to lyse and differentiate cancer stem cells: differences in NK expansion and function between healthy and cancer patients.Front. Immunol. 2017; 8: 297Crossref PubMed Scopus (19) Google Scholar In many cancer patients, the numbers and frequencies of stage 3 and 4 NK cells increase substantially, leading to ineffective NK cell-mediated functions.19Shurin M.R. Umansky V. Malyguine A. Hurwitz A.A. Apte R.N. Whiteside T. Jewett A. Thanavala Y. Murphy W.J. 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Augmented IFN-γ and TNF-α induced by probiotic bacteria in NK cells mediate differentiation of stem-like tumors leading to inhibition of tumor growth and reduction in inflammatory cytokine release; regulation by IL-10.Front. Immunol. 2015; 6: 576Crossref PubMed Scopus (24) Google Scholar,50Kaur K. Topchyan P. Kozlowska A.K. Ohanian N. Chiang J. Maung P.O. Park S.H. Ko M.W. Fang C. Nishimura I. Jewett A. Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs.OncoImmunology. 2018; 7: e1426518Crossref PubMed Scopus (21) Google Scholar,51Kaur K. Kozlowska A.K. Topchyan P. Ko M.W. Ohanian N. 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Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs.OncoImmunology. 2018; 7: e1426518Crossref PubMed Scopus (21) Google Scholar We have reported previously that split-anergized NK cells, either paraformaldehyde fixed or their supernatants, trigger differentiation of CSCs/undifferentiated tumors primarily via secreted and membrane-bound forms of IFN-γ and TNF-α, with IFN-γ having a more dominant role. NK cell-induced differentiation of stem-like/poorly differentiated tumors was also shown to decrease the rate of tumor growth and induce resistance of tumor cells to NK cell-mediated cytotoxicity.27Tseng H.C. Cacalano N. Jewett A. Split anergized natural killer cells halt inflammation by inducing stem cell differentiation, resistance to NK cell cytotoxicity and prevention of cytokine and chemokine secretion.Oncotarget. 2015; 6: 8947-8959Crossref PubMed Scopus (22) Google Scholar,44Bui V.T. Tseng H.C. Kozlowska A. Maung P.O. Kaur K. Topchyan P. Jewett A. Augmented IFN-γ and TNF-α induced by probiotic bacteria in NK cells mediate differentiation of stem-like tumors leading to inhibition of tumor growth and reduction in inflammatory cytokine release; regulation by IL-10.Front. Immunol. 2015; 6: 576Crossref PubMed Scopus (24) Google Scholar,47Tseng H.C. Bui V. Man Y.G. Cacalano N. Jewett A. Induction of split anergy conditions n
Background and Aim: Use of glass fiber posts is of widespread acceptance in restoring root canal treated teeth, but studies concerning the most proper length of the post to provide the utmost fracture resistance are inadequate. The aim of this study was to evaluate the effect of glass fiber post length on fracture resistance of root canal treated central incisors. Materials and Methods: This experimental study was carried out on 40 maxillary central incisors in 4 groups of 10 each. RDT posts and cement was used in this experimental study with the lengths of 6, 8, 10, and 12 mm in the study groups. The samples were debrided and decoronated at the CEJ levels and endodontically treated using step-back technique. RDT drills were used for post space preparation. Then, the root canal walls were etched and the posts cemented in place. The composite cores were then prepared at the height of 5 mm and samples mounted 2mm down to their CEJ levels within acrylic blocks. An impression material (Impregum, 3M, ESPE) with a thickness of 0.2mm was used to simulate PDL around the samples. The samples were subjected to compressive forces at a 135-degree angle to their long axes using a Universal Testing Machine. Data pertaining to the fracture of the samples were analyzed using ANOVA and Tukey statistical tests. Results: The maximum resistance to fracture was recorded in 8-and 10-mm-long posts and the minimum was observed in the lengths of 6 and 12 mm. Statistical tests showed a significant difference between 8- and 10-mm-long posts with those having lengths of 6 and 12 mm in terms of fracture resistance. There was no significant difference between 8- and 10-mm-long posts as well as 6- and 12-mm-long ones. Conclusion: It can be concluded that the length of post is influential in the fracture resistance of the root so that the maximal resistance can be obtained in 8 to 10 mm of length and such lengths can be recommended for non-metal posts.
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