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Keren Cohen Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Uri Abadi Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Aleck Hercbergs Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA

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Paul J Davis Department of Medicine, Albany Medical College, Albany, New York, USA

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Martin Ellis Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Osnat Ashur-Fabian Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Multiple myeloma (MM) is a plasma cell malignancy in which involvement of the thyroid hormone-integrin αvβ3 pathway was shown, and pharmacologic inhibition of this pathway is a rational approach to disease management. A thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), which inhibits l-thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3) binding to αvβ3 integrin, was studied in five MM cell lines and primary bone marrow (BM) MM cells. Tetrac inhibited MM cell proliferation (absolute cell number/viability) and induced caspase-dependent apoptosis (annexin-V/PI and cell cycle). Activation of caspase-9 and caspase-3 was further demonstrated. Moreover, DNA damage markers, ataxia-telangiectasia-mutated (ATM) kinase, poly ADP-ribose polymerase (PARP-1) and histone γH2AX were induced by tetrac. The various tetrac-initiated effects were attenuated by Arg-Gly-Asp (RGD) peptide, suggesting integrin involvement. Primary BM mononuclear cells were harvested from MM patients (n = 39) at various disease stages. Tetrac-induced apoptosis (12/17 samples) and sensitized the cytotoxic action of bortezomib (6/9 samples). Lastly, expression of plasma membrane integrin αvβ3 was shown not only in the malignant plasma clone, but also in other cell populations within the BM samples (n = 25). Tetrac is anti-proliferative and pro-apoptotic in MM and cells may offer a therapeutic approach for this disease.

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Eilon Krashin Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Barbara Silverman Israel National Cancer Registry, Ministry of Health, Gertner Institute, Sheba Medical Center, Tel Hashomer, Israel
School of Public Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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David M Steinberg Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

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Daniel Yekutieli Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

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Shmuel Giveon Clalit Health Services, Tel Aviv, Israel

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Offer Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel

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Aleck Hercbergs Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA

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Paul J Davis Department of Medicine, Albany Medical College, Albany, New York, USA

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Martin Ellis Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Osnat Ashur-Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1–5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

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