The capture of circulating tumor cells (CTCs) in shear flow is studied systematically by driving suspensions of breast cancer cells, with different EpCAM receptor expression levels, through microchannels functionalized with EpCAM antibody ligands at various densities. The dependence of cell capture efficiency on flow rate is established and can be described by an exponential function; a characteristic flow rate immerges as the most dominant parameter affecting the capture efficiency. Utilizing this characteristic flow rate as a scaling factor, all measured capture efficiencies for the tested receptor and ligand densities can be expressed using a single exponential formula. The effect of both ligand and receptor densities on the characteristic flow rate is found to be a product of two independent cumulative distributions.
The initial conditions for morphogenesis trigger a cascade of events that ultimately dictate structure and functions of tissues and organs. Here we report that surface nanopatterning can control the initial assembly of focal adhesions, hence guiding human mesenchymal stem cells (hMSCs) through the process of self-organization and differentiation. This process self-sustains, leading to the development of macroscopic tissues with molecular profiles and microarchitecture reminiscent of embryonic tendons. Therefore, material surfaces can be in principle engineered to set off the hMSC program toward tissuegenesis in a deterministic manner by providing adequate sets of initial environmental conditions.
Abstract Background: In pts with HR-positive metastatic breast cancer, endocrine resistance is a major clinical problem. Ganetespib is a small molecule inhibitor of heat shock protein 90 (HSP90), a molecular chaperone protein that regulates post-translational folding of numerous client proteins including estrogen and progesterone receptor. In preclinical HR-positive breast cancer models, ganetespib impairs endocrine resistance and reduces heterogeneity in the disease control achievable by hormonal therapies. Trial Design and Eligibility: This is a randomized phase II study designed to evaluate the efficacy of ganetespib in combination with fulvestrant compared to fulvestrant alone. Pts with endocrine-resistant, HR-positive metastatic breast cancer and up to 1 prior line of metastatic chemotherapy are eligible. Endocrine resistance is defined as relapse while on or within 1 year of completion of adjuvant endocrine therapy (ET) or progression through at least one line of ET for advanced disease. Patients are treated with fulvestrant 500 mg IM on Cycle 1 Day 1 (C1D1) and C1D15, C2D1, and D1 of each subsequent 28-day cycle. Ganetespib is administered at a starting dose of 200 mg/m2 IV on Days 1, 8, and 15 of each cycle. Pts undergo optional research biopsies at baseline and time of progression. Pts with accessible disease undergo a required research biopsy on C2D9. Circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMCs) are collected at baseline, C2D8, C2D9, and time of progression. Pts who progress on fulvestrant may cross over to the combination. Aims: The primary endpoint is progression-free survival. Secondary endpoints include safety and tolerability, objective response rate by RECIST 1.1, clinical benefit rate, and overall survival. Correlative aims include comparison of biomarkers on the C2D9 biopsy in pts treated with fulvestrant alone versus the combination of fulvestrant plus ganetespib, analysis of CTCs and pharmacodynamic markers in PMBCs. Statistical Methods: Pts will be randomized 1:2 to receive fulvestrant alone or the combination of fulvestrant plus ganetespib. The total accrual goal is 71 pts. The expected accrual rate is 3.5-4.5 pts per month over a period of ∼20 months; it is anticipated at ∼15% of pts may be censored for PFS, with similar probability on both arms. There will be 80% power to detect a prolongation of true median PFS from 4.0 months to 8.0 months, using a one-sided 0.05 log-rank test. Acrrual: To date, 15 of 71 planned pts have been enrolled. Funding: The trial is supported by a grant from the Susan G. Komen foundation and funding from Synta Pharmaceuticals. Contact information: nlin@partners.org. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-05.
Abstract Background: Breast cancer is the leading cause of life-threatening malignancy affecting women and the second leading cause of female cancer death in the United States. Weekly paclitaxel, alone or in combination with other chemotherapies, has proven to be an effective and well-tolerated therapy for patients with metastatic disease. Due to the tumor's dependence on vascularization for progression, survival and dissemination, targeting a tumor's vascular network is an important additional cancer management strategy. Bavituximab, a monoclonal antibody developed by Peregrine Pharmaceuticals against phosphatidylserine (PS), is a vascular disrupting agent designed to selectively attack tumor blood vessels already in existence. Under normal conditions, PS is localized to the internal surface of the plasma membrane. However, PS is preferentially localized on the outer surface of vascular endothelial cells in tumors, possibly due to stress conditions in the tumor microenvironment. Bavituximab is able to localize and bind specifically to PS in tumor vessels in a α2-glycoprotein 1 dependent manner, mediating the binding of host effector cells to the tumor vascular endothelium. This leads to vessel damage, vascularity reduction, necrosis, and growth retardation within the tumor. Microparticles are vesicles that are released from cells after activation, stress, death, or malignant transformation. Elevated levels of microparticles derived from platelets, endothelial cells, and/or leukocytes have been associated with several disease states, including cancer, however, the effect of anti-angiogenic or vascular disrupting agents on microparticle production is unclear. We investigated microparticle formation in our patients at baseline, in response to Paclitaxel chemotherapy, and after addition of Bavituximab. Patients and Methods: We initiated a phase I clinical trial in patients with Her-2 negative metastatic breast cancer treated with paclitaxel (80 mg/m2)on a weekly schedule for 3 out of 4 weeks, and weekly bavituximab (3 mg/kg) for 4 out of 4 weeks. Each cycle was defined as 4 weeks of therapy. Microparticles were isolated from peripheral blood and examined by flow cytometric phenotyping. Leukocyte, endothelial cell, and activated platelet microparticles were quantified and longitudinal trends analyzed. Five patients have been enrolled to date with additional patients accruing. At presentation, the longitudinal trends in microparticle formation from platelets, endothelial cells, and leukocytes will be presented in response to weekly Paclitaxel versus combined Paclitaxel and Bavituximab therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4404. doi:1538-7445.AM2012-4404
We propose a sparsity-based denoising algorithm for digital holography retrieved wrapped phase maps (WPMs) mod 2π by using a modified version of the SPADEDH (SPArsity DEnoising of Digital Holograms) algorithm, proposed in [1]. We test the proposed method on both simulated wrapped phase reconstructions and experimental wrapped phase maps obtained by digital holograms of living cells. Finally, we also show that the proposed algorithm can be used as a helper for the typical local phase unwrapping algorithms.
Background The independent prognostic impact of diabetes mellitus ( DM ) and prediabetes mellitus (pre‐ DM ) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐ DM on survival outcomes in the GISSI ‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial. Methods and Results We assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI ‐ HF trial, who were stratified by presence of DM (n=2852), pre‐ DM (n=2013), and non‐ DM (n=2070) at baseline. Compared with non‐ DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐ DM patients and those with pre‐ DM . Cox regression analysis showed that DM , but not pre‐ DM , was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI , 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI , 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI , 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI , 1.01–1.29, respectively). Conclusions Presence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00336336.
Abstract Introduction: Carbonic anhydrase-IX (CAIX) facilitates the reversible hydration of carbon dioxide to bicarbonate and protons, a process integral to maintaining pH differences across the cancer cell plasma membrane. CAIX is regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha) and is essential for the elimination of acid loads generated by glycolysis. High CAIX expression is associated with poor prognosis and chemoresistance in breast cancer patients (pts) (1-3). To explore the role of CAIX as a possible biomarker for predicting breast cancer therapies, we measured plasma CAIX levels in response to various chemotherapy regimens, including anti-angiogenics, in several breast cancer clinical trials. Methods: Circulating plasma CAIX was quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (R & D Systems). We evaluated the plasma stability of CAIX by quantifying levels within 1 hour as well as at 24 and 48 hours post phlebotomy in healthy controls (n = 10). We also evaluated the ideal anticoagulant for sample collection and stability of CAIX levels over time in healthy controls. For our analysis in breast cancer pts, we quantified plasma CAIX levels in two populations treated on chemotherapeutic clinical trials: 1) locally advanced breast cancer (LABC) pts treated in the neoadjuvant setting with paclitaxel in combination with sunitinib followed by anthracycline (AC) based chemotherapy (n = 63); 2) metastatic breast cancer (MBC) pts treated with systemic chemotherapy with either irinotecan + etoposide; or paclitaxel + a novel immunomodulatory agent (n = 22). Results: In healthy control subjects, plasma levels of CAIX were stable at all time points tested (within1 hour, 24 hrs, 48 hours post phlebotomy) with no significant change on repeat testing at 6 months. Average baseline plasma CAIX levels were lowest in normal controls (20.5 pg/ml) compared to pts with LABC (34.1 pg/ml) or MBC (90.7 pg/ml) (p = <0.001). In pts with LABC, CAIX rose significantly in response to paclitaxel/sunitinib (TS) therapy (p = 0.01) but not further with anthracycline based therapy (p = 0.37). The rise in response to TS was primarily in pts with baseline levels below the median. In pts with MBC treated with cytotoxic chemotherapies (without an anti-angiogenic) CAIX levels did not change in response to therapy. Discussion: Plasma CAIX is a robust biomarker that is stable at room temperature in plasma for at least 48hrs and over time in healthy controls. Plasma CAIX levels are elevated in pts with MBC when compared to those with LABC or normal controls. CAIX levels rise in response to anti-angiogenic therapy but not in response to cytotoxic chemotherapy. Our results suggest CAIX may be a robust and easily measured pharmacodynamic biomarker of anti-angiogenic induced hypoxia and HIF-1 alpha upregulation. 1. Potter CP and Harris AL. Br J Cancer. 89:2-7, 2003. 2. Betof AS, Rabbani ZN, Hardee ME, et al. BJ Cancer. 106:916-922, 2012. 3. Generali D, Fox Berruti A, et al. Endocrine-Related Cancer. 13:921-30, 2006. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-03-01.
