A New Tumor Suppressor That Regulates Tissue Architecture

Pathologists use loss of normal tissue architecture as a key criterion to identify and categorize disease states. Epithelia in all glandular structures in vivo have a characteristic organization where they line a central lumen and are involved in absorptive and/or secretory functions. Under some physiological conditions—such as pregnancy, wound healing, and the periodic tissue remodeling that occurs in tissues such as colon—there is a significant increase in the rate of cell proliferation. Although the proliferation rate in these physiological conditions is higher than that seen under disease states, the overall tissue size and structure are maintained. Such maintenance of size/structure occurs because the increased proliferation is tightly coupled with tissue morphogenesis programs, resulting in remodeling of normal tissue architecture

Autocrine prolactin: an emerging market for homegrown (prolactin) despite the imports

Prolactin (PRL) is a peptide hormone that is produced by the pituitary gland and is known to regulate lactogenic differentiation. There is a significant body of evidence that points to autocrine production of prolactin and activation of an autocrine/paracrine signaling pathway to regulate cell proliferation and migration and inhibition of cell death. This perspective highlights the recent study in the October 1, 2012, issue of Genes & Development by Chen and colleagues (pp. 2154-2168) that describes a mechanism for autocrine prolactin production and places the finding in the context of a role for prolactin in breast development and cancer

Antibiotics to improve recovery following tonsillectomy: a systematic review.

OBJECTIVE: To determine if antibiotics improve recovery following tonsillectomy. STUDY DESIGN: DATA SOURCES: Electronic databases Medline, Embase, and Cochrane Controlled Trials Register were searched using relevant search terms. Additional trials, if any, were retrieved by searching the references from all identified trials, reviews, correspondences, editorials, and conference proceedings. No language restriction was applied. STUDY SELECTION: Systematic review of trials in which antibiotic was administered as a study medication intraoperatively and/or postoperatively, in children or adults undergoing tonsillectomy or adenotonsillectomy. Only randomized, placebo-controlled, double-blind trials attaining preset quality scores were included. Outcomes analyzed: 1) pain, need for analgesia, fever, halitosis, and return to normal diet and activities; 2) secondary hemorrhage using 2 parameters-significant hemorrhage (ie, warranting readmission, blood transfusion, or return to theatre for hemostasis) and total hemorrhage; and 3) adverse events. RESULTS: Five trials met the eligibility criteria. Antibiotics significantly reduced the number of subjects manifesting fever (relative risk [RR]: 0.62, 95% confidence interval [CI]: 0.45, 0.85) and duration of halitosis (-1.94 [-3.57, -0.30] days), and marginally reduced the time taken to resume normal activity (-0.63 [-1.12, -0.14] days), but had no significant effect in reducing pain scores (-0.01 [-0.60, 0.57]) or need for analgesia. Similarly, there was no significant difference in the time taken to resume normal diet or incidence of significant and total hemorrhage, although data was underpowered to detect differences for these outcomes. In the antibiotic group 4 patients developed an adverse reaction (3 cases of rash and 1 case of oropharyngeal candidiasis), while in the control group 1 patient had an adverse reaction (rash). The RR of antibiotic-related adverse events was 2.45 (0.45, 13.31). CONCLUSION: Antibiotics appear to be effective in reducing some, but not all, morbid outcomes following tonsillectomy, and may increase the risk of adverse events. Further trials are needed to better define the role of antibiotics in facilitating post-tonsillectomy recovery. EBM RATING: A-1a

A Brake Becomes an Accelerator: PTP1B-A New Therapeutic Target for Breast Cancer

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer

ErbB receptors and cell polarity: New pathways and paradigms for understanding cell migration and invasion

The ErbB family of receptor tyrosine kinases is involved in initiation and progression of a number of human cancers, and receptor activation or overexpression correlates with poor patient survival. Research over the past two decades has elucidated the molecular mechanisms underlying ErbB-induced tumorigenesis, which has resulted in the development of effective targeted therapies. ErbB-induced signal transduction cascades regulate a wide variety of cell processes, including cell proliferation, apoptosis, cell polarity, migration and invasion. Within tumors, disruption of these core processes, through cooperative oncogenic lesions, results in aggressive, metastatic disease. This review will focus on the ErbB signaling networks that regulate migration and invasion and identify a potential role for cell polarity pathways during cancer progression

A Note on waves Generated at a Liquid Solid Interface-II (Viscous Effects)

This paper, being a continuation of a previous note of the same title, deals with the effect of viscosity on the interface waves propagated in a liquid layer overlying a generalized thermoelastic solid halfspace. This note extends the results of Harinath and has applications to defence science and geophysical problems. The problem considered has more relevance to the physical situations encountered in reality than its elastic counterpart. In other words, generalized thermoelasticity fits into the realistic situation better than classical elasticity or coupled thermoelasticity. The details pertaining to the non viscous effects of liquid layer overlying a perfectly elastic halfspace may be found in the treatise by Ewing, Jardetzky and Press those of coupled thermoelasticity in the treatise by Nowacki and details of wave propagation problems in generalized thermoelasticity in the concise paper by Harinath. The stress strain relations used for a viscous fluid may be found in Pipkin, with slight modifications, without any loss in generality. Most of the results obtained here are new

Shc is required for ErbB2-induced inhibition of apoptosis but is dispensable for cell proliferation and disruption of cell polarity

Amplification and overexpression of ErbB2 strongly correlates with aggressive breast cancers. A deeper understanding of pathways downstream of ErbB2 signaling that are required for the transformation of human mammary epithelial cells will identify novel strategies for therapeutic intervention in breast cancer. Using an inducible activation of ErbB2 autophosphorylation qsite mutants and the MCF-10A three-dimensional (3D) culture system, we investigated pathways used by ErbB2 to transform the epithelia. We report that ErbB2 induces cell proliferation and loss of 3D organization by redundant mechanisms, whereas it disrupts apical basal polarity and inhibits apoptosis using Tyr 1201 and Tyr 1226/7, respectively. Signals downstream of Tyr 1226/7 were also sufficient to confer paclitaxel resistance. The Tyr 1226/7 binds Shc, and the knockdown of Shc blocks the ability of ErbB2 to inhibit apoptosis and mediate paclitaxel resistance. Tyr 1226/7 is known to activate the Ras/Erk pathway; however, paclitaxel resistance did not correlate with the activation of Erk or Akt, suggesting the presence of a novel mechanism. Thus, our results show that targeting pathways used by ErbB2 to inhibit cell death is a better option than targeting cell proliferation pathways. Furthermore, we identify a novel function for Shc as a regulator of apoptosis and drug resistance in human mammary epithelial cells transformed by ErbB2. Oncogene (2010) 29, 174-187; doi:10.1038/onc.2009.312; published online 12 October 200

Reinforcement learning based path planning of multiple agents of SwarmItFIX robot for fixturing operation in sheetmetal milling process

SwarmItFIX (self-reconfigurable intelligent swarm fixtures) is a multi-agent setup mainly used as a robotic fixture for large Sheet metal machining operations. A Constraint Satisfaction Problem (CSP) based planning model is utilized currently for computing the locomotion sequence of multiple agents of the SwarmItFIX. But the SwarmItFIX faces several challenges with the current planner as it fails on several occasions. Moreover, the current planner computes only the goal positions of the base agent, not the path. To overcome these issues, a novel hierarchical planner is proposed, which employs Monte Carlo and SARSA TD based model-free Reinforcement Learning (RL) algorithms for the computation of locomotion sequences of head and base agents, respectively. These methods hold two distinct features when compared with the existing methods (i) the transition model is not required for obtaining the locomotion sequence of the computational agent, and (ii) the state-space of the computational agent become scalable. The obtained results show that the proposed planner is capable of delivering optimal makespan for effective fixturing during the sheet metal milling process

Rotational motion during three-dimensional morphogenesis of mammary epithelial acini relates to laminin matrix assembly

Our understanding of the mechanisms by which ducts and lobules develop is derived from model organisms and three-dimensional (3D) cell culture models wherein mammalian epithelial cells undergo morphogenesis to form multicellular spheres with a hollow central lumen. However, the mechanophysical properties associated with epithelial morphogenesis are poorly understood. We performed multidimensional live-cell imaging analysis to track the morphogenetic process starting from a single cell to the development of a multicellular, spherical structure composed of polarized epithelial cells surrounding a hollow lumen. We report that in addition to actively maintaining apicobasal polarity, the structures underwent rotational motions at rates of 15-20 μm/h and the structures rotated 360° every 4 h during the early phase of morphogenesis. Rotational motion was independent of the cell cycle, but was blocked by loss of the epithelial polarity proteins Scribble or Pard3, or by inhibition of dynein-based microtubule motors. Interestingly, none of the structures derived from human cancer underwent rotational motion. We found a direct relationship between rotational motion and assembly of endogenous basement membrane matrix around the 3D structures, and that structures that failed to rotate were defective in weaving exogenous laminin matrix. Dissolution of basement membrane around mature, nonrotating acini restored rotational movement and the ability to assemble exogenous laminin. Thus, coordinated rotational movement is a unique mechanophysical process observed during normal 3D morphogenesis that regulates laminin matrix assembly and is lost in cancer-derived epithelial cells