United States

Introduction: The influence of the immune system on follicular cell-derived thyroid cancer behavior has been suggested by various studies but this information has not been comprehensively translated into a prediction for thyroid cancer prognosis. We aimed to identify circulating immune cell profiles associated with thyroid cancer prognosis. This information would be a significant advance in the field of thyroid cancer management. Methods: We performed a single-center prospective cohort study of 32 follicular-cell derived thyroid cancer patients enrolled at the time of initial or subsequent surgery. We performed peripheral blood multi-parameter flow cytometry and collected relevant clinicopathologic, biochemical and radiologic data. We classified patients based on the AJCC TNM cancer stage, American Thyroid Association (ATA) initial risk of recurrence, and status of disease during follow-up. Results: On initial immunophenotyping, patients with aggressive/advanced thyroid cancer (ATA high risk vs. intermediate/low risk; AJCC stage 3/4 vs. 1/2; recurrence or distant metastases vs. no evidence of disease during follow-up) demonstrated increased circulating monocytes and granulocytes but decreased all lymphocytes, T cells (specifically CD4+ and gamma delta) and natural killer (NK) T-like cells. Further immunophenotyping revealed that aggressive/advanced thyroid cancer had increased circulating CD4+CD45+RO effector memory but decreased CD4+CD45+RA central memory T cells and increased regulatory T cells. Stage 3/4 thyroid cancer patients additionally had increased circulating CD33+HLADR- myeloid-derived suppressor cells (MDSCs) as compared to stage1/2. Conclusions: Aggressive thyroid cancer at presentation (AJCC stage, ATA risk category) or during follow-up (distant metastases) is characterized by a circulating immunophenotype comprising of increased immune suppressor cells (regulatory T cells, MDSCs, effector memory T cells) but decreased immune activator cells (CD4+ T cells, gamma delta T cells, NK T-like cells, central memory T cells) as compared to less aggressive thyroid cancer. This circulating immunophenotype may serve as a biomarker for cancer prognosis and guide the selection and development of novel immunotherapies for advanced thyroid cancer.?? 

ENDO 2021

Aggressive Thyroid Cancer is Associated with Suppressor Circulating Immunophenotype

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

technical paper

A Novel Role of Nuclear and Membrane Receptor on Isoflavones-Induced Neuritogenesis and Synaptogenesis

Obesity-induced chronic adipose tissue inflammation is a significant risk factor for metabolic and cardiovascular disease (CVD), which affects 30.3 million adults in the United States. Interaction of adipocytes with hormonal, metabolic and immune systems play an integral role in the underlying pathophysiological mechanisms that leads to development of obesity-related complications. Despite this association, the mechanisms that coordinate the inflammatory mediators in causing adipose tissue inflammation are not well understood. Glucocorticoids (GC) are well known for their potent anti-inflammatory actions; however, the mechanism by which GC coordinate the inflammatory response of adipocytes are unknown. From our genome-wide microarray data derived from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice, we found that GR inactivation leads to a significant increase in pro-inflammatory gene in white adipose tissue (WAT). Additionally, WAT isolated from AdipoGRKO mice showed significant increase in immune cell infiltration, which correlates with our gene expression data. Among the top up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (Cxcr2), which is a powerful mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of Cxcr2 in adipocytes and suggested the contribution of Cxcr2 signaling in adipocyte development, its role in integrating adipose tissue inflammatory response is unknown. This led us to hypothesize that GR is critical to repress Cxcr2 gene expression and its pro inflammatory effects in adipocytes. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of Cxcr2 mRNA and protein levels. Furthermore, these effects are mediated by GR acting directly to repress Cxcr2 gene expression. Systemic administration of corticosterone significantly altered Cxcr2 expression in adipose tissue compared to untreated mice further supporting our results. Together our findings suggest that administration of glucocorticoids could inhibit adipose tissue inflammation and alleviate the comorbidities that arise from inflamed adipose tissue.?? 

Inhibition of Cxcr2 by Glucocorticoids in Adipose Tissue

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The Worldwide Landscape of Variants in the Androgen Receptor Gene Related to the Androgen Insensitivity Syndrome: An Integrative Analysis

Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in ER+ mammary intraductal (MIND) xenografts. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cells that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance in ER+ breast cancer.?? 

Steroid Receptor Co-Activators Regulate Metabolic Kinases to Drive Therapy Resistant ER+ Breast Cancer

Prohibitn-1 Transgenic Mice Revealed an Important Role of Prohibitin in Testicular Steroidogenesis

Diabetes Mellitus What Has Changed in the Past 30 Years?

Advances in Monitoring and Delivering InsulinMeters, CGM, Pens, Pumps, Inhaled Transplantation

Clinical Research 101

A (Brief) Introduction to Drug Regulation Before, During, (and Soon) After COVID

https://d3smihljt9218e.cloudfront.net/transcript/25863/subtitle/d70bd40e8a87ff7cef71be488c63caeb.vtt

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Aggressive Thyroid Cancer is Associated with Suppressor Circulating Immunophenotype

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A Novel Role of Nuclear and Membrane Receptor on Isoflavones-Induced Neuritogenesis and Synaptogenesis

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