Sequential Complications of Hypercalcemia, Necrotizing Granulomatous Vasculitis, and Aplastic Anemia Occurring in One Patient with Angioimmunoblastic T-cell Lymphoma.

In this case report of a patient with angioimmunoblastic T-cell lymphoma (AITL), we describe the occurrence of three sequential complications that have been reported uncommonly in this disease subtype. Firstly, the patient developed hypercalcemia due to elevated 1,25-didydroxyvitamin D. Although hypercalcemia in AITL is not rare (1-2% incidence), this case was unusual in that the complication developed when disease appeared stable and symptomatically, he was doing well otherwise. Hypercalcemia surprisingly resolved a few months later at a time when his disease appeared to be progressing. A year later, the patient presented with digital ischemia necessitating partial amputation of a finger. Pathological exam revealed granulomatous vasculitis of small and medium arterioles with infiltrating malignant T lymphocytes. Although skin manifestations are common in AITL, necrotizing granulomatous vasculitis with accompanying tumor cells leading to severe digital ischemia appears rare. Subsequently the patient developed profound pancytopenia with bone marrow confirming severe aplastic anemia. To our knowledge only one other case of aplastic anemia has been reported in a patient with AITL. We discuss the diagnostic and management considerations involved in this patient care and review similar reported cases.

Vitamin D3 decreases glycolysis and invasiveness, and increases cellular stiffness in breast cancer cells.

Breast cancer is one of the major causes of death in the USA. Cancer cells, including breast, have high glycolysis rates to meet their energy demands for survival and growth. Vitamin D3 (VD3) is important for many important physiological processes such as bone mineralization, but its anticancer role is yet to be proven. We find that VD3 treatment significantly down-regulates glycolytic enzymes and genes and decreases glucose uptake - for both lowly metastatic MCF-7 and highly metastatic MDA-MB-231 (MB231) breast cancer cells. VD3 also significantly decreases cell viability by inducing apoptosis - consistent with decreased expression of mammalian target of rapamycin (mTOR), which regulates glycolysis and cancer cell survival, and increases 5' adenosine monophosphate-activated protein kinase (AMPK) activation. These changes accompany a significant reduction of cell migration and increased cell stiffness, presumably a consequence of reversal of the epithelial to mesenchymal transition resulting in increased E-cadherin, and F-actin, and reduced vimentin expression. High levels of cytoskeletal and cortical F-actin may cause high cell stiffness. VD3-induced mechanical changes are stronger in highly metastatic MB231 than in lowly metastatic MCF-7 cells. Our results suggest therapeutic and preventive roles of VD3 in breast cancer.

The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer.

Breast cancer​ is one of the most commonly diagnosed cancers in women. Accumulating evidence suggests that cholesterol plays an important role in the development of breast cancer. Even though the mechanistic link between these two factors is not well understood, one possibility is that dysregulated cholesterol metabolism may affect lipid raft and membrane fluidity and can promote tumor development. Current studies have shown oxysterol 27-hydroxycholesterol (27-HC) as a critical regulator of cholesterol and breast cancer pathogenesis. This is supported by the significantly higher expression of CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1) in breast cancers. This enzyme is responsible for 27-HC synthesis from cholesterol. It has been shown that 27-HC can not only increase the proliferation of estrogen receptor (ER)-positive breast cancer cells but also stimulate tumor growth and metastasis in several breast cancer models. This phenomenon is surprising since 27-HC and other oxysterols generally reduce intracellular cholesterol levels by activating the liver X receptors (LXRs). Resolving this paradox will elucidate molecular pathways by which cholesterol, ER, and LXR are connected to breast cancer. These findings will also provide the rationale for evaluating pharmaceutical approaches that manipulate cholesterol or 27-HC synthesis in order to mitigate the impact of cholesterol on breast cancer pathophysiology. In addition to cholesterol, epigenetic changes including non-coding RNAs, and microRNAs, DNA methylation, and histone modifications, have all been shown to control tumorigenesis. The purpose of this review is to discuss the link between altered cholesterol metabolism and epigenetic modification during breast cancer progression.