Zero to one: normal derived human ER+ cells in culture-proliferating

Cell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer

Zero to one:normal derived human ER+ cells in culture-proliferating

Cell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer

Improving health-related quality of life in Crohn's disease patients with cognitive behavioral therapy

BACKGROUND: The burden of Crohn’s Disease (CD) on patients’ functional status, interpersonal relationships, and self-image is well documented. Additionally, recent advances in the understanding of the gut-brain axis have alluded to the potential role of psychological treatments in the reduction of CD activity. More recent consensus guidelines for the treatment of this disease advocate for addressing the psychosocial needs of CD patients, however the efficacy of cognitive behavioral therapy (CBT) in this patient population is unclear. Prior studies have found mixed results, but have been hindered by poorly targeted study populations. METHODS: The proposed study aims to explore the use of CBT in patients with CD utilizing improved study population selection. This will be a randomized controlled trial which will assess the effect of CBT on health-related quality of life (HRQOL) and disease activity in patients with moderate to severe CD. DISCUSSION: This study will help determine if CBT is an effective adjuvant treatment modality to the current medical management of CD. It would have far-reaching implications, resulting in decreased sequelae of CD and improved HRQOL

Comparison of Echocardiographic Outcomes Following Transcatheter Aortic Valve Replacement With Edwards S3 23 MM Versus Medtronic Evolut 26 MM Valves

Background Patients with small aortic valve annulus (SAVA) undergoing TAVR are prone to higher post TAVR trans-valve gradients. In many such patients, the choice of TAVR valve commonly involves choosing between the Edwards S3 23 mm (ES23) versus the Medtronic Evolut 26 mm (ME26). The supraannular design of the Evolut has been touted as providing superior hemodynamics in SAVA. We sought to compare performance of these two valves in SAVA, particularly in regard to occurrence of elevated trans-valve gradients. Methods We queried the Providence St Joseph Health STS/ACC TVT Registry database for patients undergoing TAVR for SAVA with either the ES23 or ME26 between 2015Q3 and 2018Q1 at 11 hospitals in six states. Post TAVR echo results at 1 month and at 1 year were examined. High gradient was defined as mean gradient of ≥20 mmHg. Results Using the above criteria, we identified 608 patients treated with ES23 and 155 treated with ME26 (68% R/32% PRO). Baseline clinical (87% female) and echocardiographic characteristics were similar. Conclusion Patients with SAVA undergoing TAVR treated with ES23 had \u3e70% higher mean gradient compared to ME26. High gradients (≥20 mmHg) were noted in 10% of ES23 valves at 1 month that increased to 16% at 1 year (rare at either time with ME26). These findings may have important clinical implications in the occurrence of patient prosthesis mismatch and possibly valve durability

Establishment of a normal-derived estrogen receptor-positive cell line comparable to the prevailing human breast cancer subtype

Understanding human cancer increasingly relies on insight gained from subtype specific comparisons between malignant and non-malignant cells. The most frequent subtype in breast cancer is the luminal. By far the most frequently used model for luminal breast cancer is the iconic estrogen receptor-positive (ER(pos)) MCF7 cell line. However, luminal specific comparisons have suffered from the lack of a relevant non-malignant counterpart. Our previous work has shown that transforming growth factor-β receptor (TGFβR) inhibition suffices to propagate prospectively isolated ER(pos) human breast luminal cells from reduction mammoplasties (HBEC). Here we demonstrate that transduction of these cells with hTERT/shp16 renders them immortal while remaining true to the luminal lineage including expression of functional ER (iHBEC(ERpos)). Under identical culture conditions a major difference between MCF7 and normal-derived cells is the dependence of the latter on TGFβR inhibition for ER expression. In a breast fibroblast co-culture model we further show that whereas MCF7 proliferate concurrently with ER expression, iHBEC(ERpos) form correctly polarized acini, and segregate into proliferating and ER expressing cells. We propose that iHBEC(ERpos) may serve to shed light on hitherto unappreciated differences in ER regulation and function between normal breast and breast cancer

A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study

Aims Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size. Methods and results In 454 patients undergoing PCI, acetylcholine (10−6 to 10−4 M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30-60 mg/day and followed for 18-24 months. Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns. Conclusion The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volum

Propagation of oestrogen receptor-positive and oestrogen-responsive normal human breast cells in culture

Investigating the susceptibility of oestrogen receptor-positive (ER(pos)) normal human breast epithelial cells (HBECs) for clinical purposes or basic research awaits a proficient cell-based assay. Here we set out to identify markers for isolating ER(pos) cells and to expand what appear to be post-mitotic primary cells into exponentially growing cultures. We report a robust technique for isolating ER(pos) HBECs from reduction mammoplasties by FACS using two cell surface markers, CD166 and CD117, and an intracellular cytokeratin marker, Ks20.8, for further tracking single cells in culture. We show that ER(pos) HBECs are released from growth restraint by small molecule inhibitors of TGFβ signalling, and that growth is augmented further in response to oestrogen. Importantly, ER signalling is functionally active in ER(pos) cells in extended culture. These findings open a new avenue of experimentation with normal ER(pos) HBECs and provide a basis for understanding the evolution of human breast cancer