Research Spotlight

Aminoshariae, A., Azarpazhooh, A., Diogenes, A.R., Fouad, A.F., Glickman, G.N., Kishen, A., Letra, A.M., Levin, L., Roda, R.S., Setzer, F.C., Tay, F.R. and Hargreaves, K.M. (2021). “Insights into the April 2021 Issue of the Journal of Endodontics.” J Endod.

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Welcome to the April 2021 issue of the Journal of Endodontics (JOE). Here we share some of our favorite articles that are published in this issue of the journal. We hope you look forward to reading these and other articles in JOE. [Epub ahead of print].

Aminoshariae, A., Azarpazhooh, A., Diogenes, A.R., Fouad, A.F., Glickman, G.N., Kishen, A., Letra, A.M., Levin, L., Roda, R.S., Setzer, F.C., Tay, F.R. and Hargreaves, K.M. (2021). “Insights Into the March 2021 Issue of the JOE.” J Endod 47(3): 343-344.

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Welcome to the March issue of the JOE. Here, we share some of our favorite articles that are published in this issue of the Journal. We hope you look forward to reading these and other articles in the JOE.

Wu, X., Cheng, Y.L., Matthen, M., Yoon, A., Schwartz, G.K., Bala, S., Taylor, A.M. and Momen-Heravi, F. (2021). “Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion.” J Exp Clin Cancer Res 40(1): 70.

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BACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.

Li, J., Qi, D., Hsieh, T.C., Huang, J.H., Wu, J.M. and Wu, E. (2021). “Trailblazing perspectives on targeting breast cancer stem cells.” Pharmacol Ther Jan 7;223:107800. [Epub ahead of print]. 107800.

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Breast cancer (BCa) is one of the most prevalent malignant tumors affecting women’s health worldwide. The recurrence and metastasis of BCa have made it a long-standing challenge to achieve remission-persistent or disease-undetectable clinical outcomes. Cancer stem cells (CSCs) possess the ability to self-renew and generate heterogeneous tumor bulk. The existence of CSCs has been found to be vital in the initiation, metastasis, therapy resistance, and recurrence of tumors across cancer types. Because CSCs grow slowly in their dormant state, they are insensitive to conventional chemotherapies; however, when CSCs emerge from their dormant state and become clinically evident, they usually acquire genetic traits that make them resistant to existing therapies. Moreover, CSCs also show evidence of acquired drug resistance in synchrony with tumor relapses. The concept of CSCs provides a new treatment strategy for BCa. In this review, we highlight the recent advances in research on breast CSCs and their association with epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs), plasticity of tumor cells, tumor microenvironment (TME), T-cell modulatory protein PD-L1, and non-coding RNAs. On the basis that CSCs are associated with multiple dysregulated biological processes, we envisage that increased understanding of disease sub-classification, selected combination of conventional treatment, molecular aberration directed therapy, immunotherapy, and CSC targeting/sensitizing strategy might improve the treatment outcome of patients with advanced BCa. We also discuss novel perspectives on new drugs and therapeutics purposing the potent and selective expunging of CSCs.

Wall, A.E. (2021). “Why is self-advocacy a barrier to living donor kidney transplantation?” Am J Surg Feb 4;S0002-9610(21)00069-6. [Epub ahead of print].

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Living donor kidney transplantation (LDKT) offers patients with end stage renal disease an opportunity to skip the long waiting list for deceased donor grafts and get the highest quality kidney graft in terms of both patient and graft survival. LDKT is truly life-saving as one in five patients die within the first year and two out of three die within 5 years of initiating dialysis. Despite the huge advantages associated with living donor kidney transplantation (LDKT), fewer than 20,000 are performed each year in the US. Barriers to LDKT include both a lack of knowledge about LDKT and a lack of knowledge about how to ask someone to be a kidney donor. [No abstract; excerpt from Editorial].