Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin

Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering β-catenin and thus antagonizing β-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin–negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the β-catenin–binding domain of the E-cadherin cytoplasmic tail but not through the p120ctn-binding domain. β-catenin depletion also results in invasion suppression. However, alteration in the β-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other β-catenin–binding proteins

Effective Dynamic Range in Measurements with Flash Analog-to-Digital Convertor

Flash Analog to Digital Convertor (FADC) is frequently used in nuclear and particle physics experiments, often as the major component in big multi-channel systems. The large data volume makes the optimization of operating parameters necessary. This article reports a study of a method to extend the dynamic range of an 8-bit FADC from the nominal $\rm{2^8}$ value. By comparing the integrated pulse area with that of a reference profile, good energy reconstruction and event identification can be achieved on saturated events from CsI(Tl) crystal scintillators. The effective dynamic range can be extended by at least 4 more bits. The algorithm is generic and is expected to be applicable to other detector systems with FADC readout.Comment: 19 pages, 1 table, 10 figure

Hepatocyte growth factor enhances proteolysis and invasiveness of human nasopharyngeal cancer cells through activation of PI3K and JNK

AbstractThe hepatocyte growth factor (HGF) receptor, Met, is frequently overexpressed in nasopharyngeal cancer (NPC). Here, we showed for the first time that human NPC cells with high Met expression were more sensitive to the cell motility and invasion effect of HGF. The downregulation of Met by small interfering RNA decreased tumor cell invasion/migration. HGF significantly increased matrix metalloproteinase-9 production. This was inhibited by blocking phosphatidylinositide 3-kinase (PI3K) and c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling pathways. We also demonstrated that PI3K induced activation of JNK, with Akt as a potential point of this cross-talk. These results provide new insights into the molecular mechanism responsible for NPC progression and metastasis

Pulse Shape Discrimination Techniques in Scintillating CsI(Tl) Crystals

There are recent interests with CsI(Tl) scintillating crystals for Dark Matter experiments. The key merit is the capability to differentiate nuclear recoil (nr) signatures from the background $\beta / \gamma$-events due to ambient radioactivity on the basis of their different pulse shapes. One of the major experimental challenges is to perform such pulse shape analysis in the statistics-limited domain where the light output is close to the detection threshold. Using data derived from measurements with low energy $\gamma$'s and nuclear recoils due to neutron elastic scatterings, it was verified that the pulse shapes between $\beta / \gamma$-events are different. Several methods of pulse shape discrimination are studied, and their relative merits are compared. Full digitization of the pulse shapes is crucial to achieve good discrimination. Advanced software techniques with mean time, neural network and likelihood ratios give rise to satisfactory performance, and are superior to the conventional Double Charge method commonly applied at higher energies. Pulse shape discrimination becomes effective starting at a light yield of about 20 photo-electrons. This corresponds to a detection threshold of about 5 keV electron-equivalence energy, or 40$-$50 keV recoil kinetic energy, in realistic experiments.Comment: 20 pages, 7 figure

Measurement of the Intrinsic Radiopurity of Cs-137/U-235/U-238/Th-232 in CsI(Tl) Crystal Scintillators

The inorganic crystal scintillator CsI(Tl) has been used for low energy neutrino and Dark Matter experiments, where the intrinsic radiopurity is an issue of major importance. Low-background data were taken with a CsI(Tl) crystal array at the Kuo-Sheng Reactor Neutrino Laboratory. The pulse shape discrimination capabilities of the crystal, as well as the temporal and spatial correlations of the events, provide powerful means of measuring the intrinsic radiopurity of Cs-137 as well as the U-235, U-238 and Th-232 series. The event selection algorithms are described, with which the decay half-lives of Po-218, Po-214, Rn-220, Po-216 and Po-212 were derived. The measurements of the contamination levels, their concentration gradients with the crystal growth axis, and the uniformity among different crystal samples, are reported. The radiopurity in the U-238 and Th-232 series are comparable to those of the best reported in other crystal scintillators. Significant improvements in measurement sensitivities were achieved, similar to those from dedicated massive liquid scintillator detector. This analysis also provides in situ measurements of the detector performance parameters, such as spatial resolution, quenching factors, and data acquisition dead time.Comment: 28 pages, 12 figure

Macrostate Data Clustering

We develop an effective nonhierarchical data clustering method using an analogy to the dynamic coarse graining of a stochastic system. Analyzing the eigensystem of an interitem transition matrix identifies fuzzy clusters corresponding to the metastable macroscopic states (macrostates) of a diffusive system. A "minimum uncertainty criterion" determines the linear transformation from eigenvectors to cluster-defining window functions. Eigenspectrum gap and cluster certainty conditions identify the proper number of clusters. The physically motivated fuzzy representation and associated uncertainty analysis distinguishes macrostate clustering from spectral partitioning methods. Macrostate data clustering solves a variety of test cases that challenge other methods.Comment: keywords: cluster analysis, clustering, pattern recognition, spectral graph theory, dynamic eigenvectors, machine learning, macrostates, classificatio

New insights into the role of soluble E-cadherin in tumor angiogenesis

A key to successful metastasis is the formation of new vasculature, known as angiogenesis. Therefore, it is of great interest to unravel the underlying molecular mechanisms of tumor angiogenesis. Cadherins are a major class of cell surface receptors. The loss of cadherins, especially E-cadherin, is a well-established marker for tumor metastasis. Loss of E-cadherin is also a defining characteristic of several carcinomas, such as lobular carcinoma of the breast, and de-differentiated endometrioid carcinoma of the endometrium and ovary, which are known to be associated with more aggressive tumor behavior. Although E-cadherin is synthesized as a transmembrane molecule, its extracellular domain can be enzymatically cleaved off and released as a soluble E-cadherin (sE-cad), and this accounts for the loss of E-cadherin function or expression that has been implicated in tumor progression and metastasis. Importantly, sE-cad is present at high levels in the serum and malignant ascites of ovarian carcinoma patients. Nevertheless, little is known about how this essential protein dictates metastasis. Hitherto, many studies have given attention only to the dominant negative role of the loss of E-cadherin in weakening cell-cell adhesion, however, it is not known if sE-cad has biological activity in itself. In addition, the release mechanism of sE-cad has remained elusive. Here we show for the first time that sE-cad is a pivotal regulator of angiogenesis. We further show that exosomes are a novel major platform for the cleavage and release of sE-cad in vitro, in vivo and in patients’ derived samples (Nat Commun, 9: 2270)

Use of traditional and complementary medicine as self-care strategies in community health centers

In China, Community Health Centers (CHCs) are major providers of primary care services, but their potential in empowering patients’ self-management capacity has not been assessed. This study aims to describe self-care practice patterns amongst CHC attendees in urban China. In this cross-sectional quantitative study, 3360 CHC patients from 6 cities within the Pearl Delta Region were sampled using multistage cluster sampling. Thirty-seven per cent had used with over-the-counter Chinese herbal medicines (OTC CHMs) in the past year and majority of respondents found OTC CHMs effective. OTC CHMs were more popular amongst those who needed to pay out of pocket for CHC services. Less than 10% used vitamins and minerals, and those with a lower socioeconomic background have a higher propensity to consume. Although doubts on their usefulness are expressed, their use by the vulnerable population may reflect barriers to access to conventional health care, cultural affinity, or a defense against negative consequences of illnesses. About 25% performed physical exercise, but the prevalence is lower amongst women and older people. Taiji seems to be an alternative for these populations with promising effectiveness, but overall only 6% of CHC attendees participated. These results suggest that CHCs should start initiatives in fostering appropriate use of OTC CHM, vitamins, and minerals. Engaging community pharmacists in guiding safe and effective use of OTC CHM amongst the uninsured is essential given their low accessibility to CHC services. Prescription of Taiji instead of physical exercises to women and older people could be more culturally appropriate, and the possibility of including this as part of the CHC services worth further exploration

Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress

One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics

First detection of Babesia sp. in Bornean sun bear (Helarctos malayanus euryspilus Horsfield) in Sabah, Malaysia

The Bornean sun bear, a subspecies of the endangered Malayan sun bear, resides only on Borneo Island and little is known about diseases or parasites that may impact their health. In 2019, blood and ticks were collected from 46 captive bears held at the Bornean Sun Bear Conservation Centre in Sabah, Malaysia during annual health examinations in response to previous blood smear analysis that revealed presumptive haemoparasites in more than half the resident bears. Polymerase chain reaction detected a unique Babesia sp. in one of the bears. Disease surveillance of mosquitoes trapped along the outer perimeter of the bears’ outdoor enclosure did not reveal any malaria parasites. This research marks the first documented case in Bornean sun bears of both a Babesia sp. and the Ixodes tick Haemaphysalis nr koningsbergeri. More research on incriminating the vector and the effects of Babesia infection on the health of Bornean sun bears is needed. Due to the zoonotic nature of babesiosis, mitigative actions should be taken to protect any humans that work with or come into close contact with these captive bears or their enclosures