Fibulin-2 is required for basement membrane integrity of mammary epithelium

Fibulin-2 (FBLN2) is a secreted extracellular matrix glycoprotein which has been associated with tissue development and remodelling. In the mouse mammary gland, FBLN2 can be detected during ductal morphogenesis in cap cells and myoepithelial cells at puberty and early pregnancy, respectively. In an attempt to assign its function, we knocked down Fbln2 in the mouse mammary epithelial cell line EpH4. FBLN2 reduction led to an increase in the size of spheroidal structures when compared to scrambled control shRNA-transduced cells plated on Matrigel matrix. This phenotype was associated with a disruption of the collagen IV sheath around the epithelial spheroids and downregulation of integrin β1, suggesting a role for FBLN2 in stabilizing the basement membrane (BM). In contrast to mice, in normal adult human breast tissue, FBLN2 was detected in ductal stroma, and in the interlobular stroma, but was not detectable within the lobular regions. In tissue sections of 65 breast cancers FBLN2 staining was lost around malignant cells with retained staining in the neighbouring histologically normal tissue margins. These results are consistent with a role of FBLN2 in mammary epithelial BM stability, and that its down-regulation in breast cancer is associated with loss of the BM and early invasion

Fibulin-2 is required for basement membrane integrity of mammary epithelium

Fibulin-2 (FBLN2) is a secreted extracellular matrix glycoprotein which has been associated with tissue development and remodelling. In the mouse mammary gland, FBLN2 can be detected during ductal morphogenesis in cap cells and myoepithelial cells at puberty and early pregnancy, respectively. In an attempt to assign its function, we knocked down Fbln2 in the mouse mammary epithelial cell line EpH4. FBLN2 reduction led to an increase in the size of spheroidal structures when compared to scrambled control shRNA-transduced cells plated on Matrigel matrix. This phenotype was associated with a disruption of the collagen IV sheath around the epithelial spheroids and downregulation of integrin β1, suggesting a role for FBLN2 in stabilizing the basement membrane (BM). In contrast to mice, in normal adult human breast tissue, FBLN2 was detected in ductal stroma, and in the interlobular stroma, but was not detectable within the lobular regions. In tissue sections of 65 breast cancers FBLN2 staining was lost around malignant cells with retained staining in the neighbouring histologically normal tissue margins. These results are consistent with a role of FBLN2 in mammary epithelial BM stability, and that its down-regulation in breast cancer is associated with loss of the BM and early invasion

Matching Drivers to Riders: A Two-Stage Robust Approach

Matching demand (riders) to supply (drivers) efficiently is a fundamental problem for ride-hailing platforms who need to match the riders (almost) as soon as the request arrives with only partial knowledge about future ride requests. A myopic approach that computes an optimal matching for current requests ignoring future uncertainty can be highly sub-optimal. In this paper, we consider a two-stage robust optimization framework for this matching problem where future demand uncertainty is modeled using a set of demand scenarios (specified explicitly or implicitly). The goal is to match the current request to drivers (in the first stage) so that the cost of first stage matching and the worst-case cost over all scenarios for the second stage matching is minimized. We show that this two-stage robust matching is NP-hard under both explicit and implicit models of uncertainty. We present constant approximation algorithms for both models of uncertainty under different settings and show they improve significantly over standard greedy approaches

Financial conservatism, firm value and international business risk: Evidence from emerging economies around the global financial crisis

The increase in debt-free or under-levered firms (financial conservatism) is one of the most recent stylized puzzles that cannot be explained within the context of extant capital structure theories. In this paper, we exploit the 2008–09 contractions in credit supply in a quasi-natural experiment to examine whether financial conservatism affects firm value. Using a large sample of firms from seven African countries over the period 2003–2012, we find strong evidence that financial conservatism mitigates the adverse effect of contractions in credit supply on firm value for both local and international firms. Our results suggest that financial conservatism is an effective strategy for managing risks arising from contractions in credit supply and international business exposure. These findings provide novel empirical evidence on the value relevance of financial conservatism which shields firms from the adverse and far-reaching effects of contractions in credit supply

Metastasis-associated in colon cancer 1 is an independent prognostic biomarker for survival in klatskin tumor patients

Curative treatment of intrahepatic cholangiocarcinoma (ICC) and hilar cholangiocarcinoma (Klatskin tumors) is limited to surgical resection or orthotopic liver transplantation. However, not all patients benefit from a surgical approach and suffer from early tumor recurrence. Response to chemotherapy is generally poor and, until today, no targeted therapy could be established. Metastasis-associated in colon cancer 1 (MACC1) is a recently discovered regulator of the hepatocyte growth factor (HGF)/Met/mitogen-activated protein kinase pathway, which induces proliferation, migration, and invasion in cell culture, as well as metastasis in mice. MACC1 expression shows a significant correlation with Met expression in colon cancer tissue and is highly prognostic for occurrence of distant metastasis and survival in colon cancer patients. Thus, we aimed to measure the expression of MACC1, Met, and HGF messenger RNA in microdissected tumor tissue and corresponding normal liver tissue of 156 patients with Klatskin tumors (n = 76) and ICC (n = 80) using real-time quantitative reverse-transcriptase polymerase chain reaction. We used immunohistochemical staining to validate the results. MACC1 expression in tumor tissue of both tumor entities was significantly higher than in corresponding normal liver tissue (P < 0.001). Klatskin tumor patients with a history of tumor recurrence had significantly higher MACC1 expression than those without tumor recurrence (P = 0.005). Uni- und multivariate survival analysis showed that Klatskin tumor patients with high MACC1 had a significantly shorter overall (OS) and disease-free survival (DFS; P = 0.001 and P < 0.001, respectively). The multivariate analysis confirmed MACC1 to be an independent factor for overall survival in Klatskin tumor patients (hazard ratio: 2.777; 95% confidence interval: 1.389-5.555; P = 0.004). Conclusion: Our study identified MACC1 as a highly prognostic biomarker for OS and DFS in Klatskin tumor patients. MACC1 expression could become an important diagnostic tool and might be a candidate for targeted therapy

Sensitivity Analysis and Potential Uses of a Novel Gamma Interferon Release Assay for Diagnosis of Tuberculosis

Sputum smears for acid-fast bacilli (AFB) are the primary methods for diagnosis of tuberculosis (TB) in many countries. The tuberculin skin test (TST) is the primary method for diagnosis of latent TB infection (LTBI) worldwide. The poor sensitivity of the former and the poor specificity of the latter warrant the development of new tests and strategies to enhance diagnostic capabilities. We evaluated the sensitivity of an “in-tube” gamma interferon release assay (IGRA) using TB-specific antigens in comparison to the TST and the sputum smear for AFB in TB cases in South Africa. The sensitivity of the IGRA for TB was considered a surrogate of sensitivity in LTBI. Among 154 patients with a positive culture for Mycobacterium tuberculosis, the sensitivity of the IGRA for the diagnosis of TB varied by clinical subgroup from 64% to 82%, that of the TST varied from 85% to 94%, and that of two sputum smears for AFB varied from 35% to 53%. The sensitivity of the IGRA in human immunodeficiency virus (HIV)-infected TB cases was 81%. HIV-infected TB patients were significantly more likely to have indeterminate IGRA results and produced quantitatively less gamma interferon in response to TB-specific antigens than HIV-negative TB patients. The overall sensitivity of the TST in all TB cases was higher than that of the IGRA (90% versus 76%, respectively). The combined sensitivities of the TST plus IGRA and TST plus a single sputum smear were 96% and 93%, respectively. The TST combined with IGRA or with a single sputum smear may have a role in excluding the diagnosis of TB in some settings

Chronic ethanol attenuates centrally-mediated hypotension elicited via alpha-2-adrenergic, but not I1-imidazoline, receptor activation in female rats

Aims—This study dealt with the effect of chronic ethanol administration on hemodynamic responses elicited by α2-adrenergic (α-methyldopa) or I1-imidazoline (rilmenidine) receptor activation in telemetered female rats. Main methods—The effects of α-methyldopa or rilmenidine on blood pressure (BP), heart rate (HR) and their variability were investigated in rats that received liquid diet without or with ethanol (5% w/v) for 12 weeks. To evaluate the effect of each drug on cardiovascular autonomic control (BP and HR variability) in the absence or presence of ethanol, three time-domain indices of hemodynamic variability were measured: (i) standard deviation of mean arterial pressure (SDMAP), (ii) standard deviation of beat-to-beat intervals, and (iii) root mean square of successive differences in R-R intervals. Key findings—In liquid diet-fed control rats, i.p. rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg) reduced BP along with decreases and increases, respectively, in HR. Both drugs had no effect on HR variability but reduced BP variability (SDMAP), suggesting a reduced vasomotor sympathetic tone. Ethanol feeding attenuated reductions in BP and SDMAP evoked by α-methyldopa but not by rilmenidine. Significance—We conclude that chronic ethanol preferentially compromises α2- but not I1- receptor-mediated hypotension in female rats probably via modulation of vasomotor sympathetic activity. These findings highlight the adequacy of rilmenidine use to lower BP in hypertensive alcoholic females

Two-divisibility of the coefficients of certain weakly holomorphic modular forms

We study a canonical basis for spaces of weakly holomorphic modular forms of weights 12, 16, 18, 20, 22, and 26 on the full modular group. We prove a relation between the Fourier coefficients of modular forms in this canonical basis and a generalized Ramanujan tau-function, and use this to prove that these Fourier coefficients are often highly divisible by 2.Comment: Corrected typos. To appear in the Ramanujan Journa

The monocyte, a maestro in the tumor microenvironment (TME) of breast cancer

Breast cancer (BC) is well-known for being a leading cause of death worldwide. It is classified molecularly into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These subtypes differ in their prognosis; thus, understanding the tumor microenvironment (TME) makes new treatment strategies possible. The TME contains populations that exhibit anti-tumorigenic actions such as tumor-associated eosinophils. Moreover, it contains pro-tumorigenic populations such as tumor-associated neutrophils (TANs), or monocyte-derived populations. The monocyte-derived populations are tumor-associated macrophages (TAMs) and MDSCs. Thus, a monocyte can be considered a maestro within the TME. Moreover, the expansion of monocytes in the TME depends on many factors such as the BC stage, the presence of macrophage colony-stimulating factor (M-CSF), and the presence of some chemoattractants. After expansion, monocytes can differentiate into pro-inflammatory populations such as M1 macrophages or anti-inflammatory populations such as M2 macrophages according to the nature of cytokines present in the TME. Differentiation to TAMs depends on various factors such as the BC subtype, the presence of anti-inflammatory cytokines, and epigenetic factors. Furthermore, TAMs and MDSCs not only have a role in tumor progression but also are key players in metastasis. Thus, understanding the monocytes further can introduce new target therapies

Numerical Implementation of the QuEST Function

This paper deals with certain estimation problems involving the covariance matrix in large dimensions. Due to the breakdown of finite-dimensional asymptotic theory when the dimension is not negligible with respect to the sample size, it is necessary to resort to an alternative framework known as large-dimensional asymptotics. Recently, Ledoit and Wolf (2015) have proposed an estimator of the eigenvalues of the population covariance matrix that is consistent according to a mean-square criterion under large-dimensional asymptotics. It requires numerical inversion of a multivariate nonrandom function which they call the QuEST function. The present paper explains how to numerically implement the QuEST function in practice through a series of six successive steps. It also provides an algorithm to compute the Jacobian analytically, which is necessary for numerical inversion by a nonlinear optimizer. Monte Carlo simulations document the effectiveness of the code.Comment: 35 pages, 8 figure