Transformation of human melanocytes and mechanisms of melanoma metastasis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Includes bibliographical references.While a fundamental feature of human melanoma is its tendency to metastasize to numerous organs throughout the body, very few animal models recapitulate this essential aspect of the disease. In the work described, it is demonstrated that human dermal melanocytes, transformed by the introduction of the SV40ER, hTERT, and RasG12V genes, form primary tumors that are invasive and highly metastatic to secondary sites in the body. Moreover, the anatomical sites of metastasis exhibited by the melanoma cells created in this manner are analogous to those observed in human patients. The introduction of an identical set of genes into human epithelial and fibroblast cell types results in localized tumor formation in the absence of metastasis. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes but not in other cell types. Analysis of microarray data from human nevi reveals that Slug, a master regulator of neural crest cell specification and migration, correlates in its expression pattern with other genes that are important for neural crest cell migration during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present prior to neoplastic transformation can play a pivotal role in governing melanoma's progression.by Piyush B. Gupta.Ph.D

A case of telescoping of bowel during sailing

Intussusceptions as an entity is more common in children than adults in whom it is almost always secondary to some associated pathology. Moreover, the presentation is subacute or chronic in nature and all classical features of intussusceptions are rarely present together that makes the diagnosis more challenging. Here we presented a case of ileo-ileal intussusception in an adult male. Obligation of early diagnosis, initial management is unique in such cases. It also focuses on importance of availability of the imaging facilities in management of acute abdomen so as to assist in timely diagnosis as well as the definitive management of intussusceptions.

Sciatic Nerve Injection Palsy in Children

How to Cite This Article: Harsh V, Chengazhacherril R.B, SharmaK, Kalakoti P, Gupta U, Ahmad W, Kumar A. Sciatic Nerve Injection Palsy in Children. Iran J Child Neurol. Autumn 2016; 10(4):86-87. Letter to Editor Pls see PDF file. References1. Toopchizadeh V, Barzegar M, Habibzadeh A. Sciatic Nerve Injection Palsy in Children, Electrophysiologic Pattern and Outcome: A Case Series Study. Iran J Child Neurol 2015 Summer;9(3):69-72.2. Sunderland S. Miscellaneous causes of nerve injury. London: Churcill Livingstone; 1991.3. Lehmann HC, Zhang J, Mori S, Sheikh KA. Diffusion tensor imaging to assess axonal regeneration in peripheral nerves. Exp Neurol 2010;223(1):238-44.4. Takagi T, Nakamura M, Yamada M, Hikishima K, Momoshima S, Fujiyoshi K, et al. Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography. NeuroImage 2009 ;44(3):884-92.5. Barry JM, Harsh V, Kumar A, Patil S. Injection nerve palsy: What’s to blame? J Neurosci Rural Pract 2013;4:481.6. Greensmith JE, Murray WB. Complications of regional anesthesia. Current opinion in anaesthesiology. 2006;19(5):531-7.7. Barry JM, Harsh V, Patil S. Are our intramuscular injections nerve-friendly? What are we missing? Simple techniques to prevent, recognize and manage nerve injection injuries. Int J Stud Res 2014;4(2):25-8

The Hippo Transducer TAZ Interacts with the SWI/SNF Complex to Regulate Breast Epithelial Lineage Commitment

Lineage-committed cells of many tissues exhibit substantial plasticity in contexts such as wound healing and tumorigenesis, but the regulation of this process is not well understood. We identified the Hippo transducer WWTR1/TAZ in a screen of transcription factors that are able to prompt lineage switching of mammary epithelial cells. Forced expression of TAZ in luminal cells induces them to adopt basal characteristics, and depletion of TAZ in basal and/or myoepithelial cells leads to luminal differentiation. In human and mouse tissues, TAZ is active only in basal cells and is critical for basal cell maintenance during homeostasis. Accordingly, loss of TAZ affects mammary gland development, leading to an imbalance of luminal and basal populations as well as branching defects. Mechanistically, TAZ interacts with components of the SWI/SNF complex to modulate lineage-specific gene expression. Collectively, these findings uncover a new role for Hippo signaling in the determination of lineage identity through recruitment of chromatin-remodeling complexes

Increased epigenetic age in normal breast tissue from luminal breast cancer patients

BACKGROUND: Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. RESULTS: Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the "Epigenetic Clock," a published biomarker of aging based on a defined set of 353 CpGs in the human genome. The resulting age estimate, DNA methylation age, was related to chronological age and to breast cancer status. The DNAmAge of normal breast tissue was strongly correlated with chronological age (r = 0.712, p < 0.001). Compared to unaffected peers, breast cancer patients exhibited significant age acceleration in their normal breast tissue (p = 0.002). Multivariate analysis revealed that epigenetic age acceleration in the normal breast tissue of subjects with cancer remained significant after adjusting for clinical and demographic variables. Additionally, smoking was found to be positively correlated with epigenetic aging in normal breast tissue (p = 0.012). CONCLUSIONS: Women with luminal breast cancer exhibit significant epigenetic age acceleration in normal adjacent breast tissue, which is consistent with an analogous finding in malignant breast tissue. Smoking is also associated with epigenetic age acceleration in normal breast tissue. Further studies are needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of incident breast cancer and whether this mediates the risk of chronological age on breast cancer risk

Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation

Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis

A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection

available in PMC 2010 June 28.During the course of a viral infection, viral proteins interact with an array of host proteins and pathways. Here, we present a systematic strategy to elucidate the dynamic interactions between H1N1 influenza and its human host. A combination of yeast two-hybrid analysis and genome-wide expression profiling implicated hundreds of human factors in mediating viral-host interactions. These factors were then examined functionally through depletion analyses in primary lung cells. The resulting data point to potential roles for some unanticipated host and viral proteins in viral infection and the host response, including a network of RNA-binding proteins, components of WNT signaling, and viral polymerase subunits. This multilayered approach provides a comprehensive and unbiased physical and regulatory model of influenza-host interactions and demonstrates a general strategy for uncovering complex host-pathogen relationships.National Institutes of Health (U.S.) (grant U01 AI074575)National Institutes of Health (U.S.) (grant U54 AI057159)National Institutes of Health (U.S.) (NIH New Innovator Award)Ford Foundation (Predoctoral Fellowship)Ellison Medical FoundationNational Institutes of Health (U.S.) (NIH grant R01 HG001715)National Institutes of Health (U.S.) (grant P50 HG004233)National Institutes of Health (U.S.) (PIONEER award)Howard Hughes Medical InstituteBurroughs Wellcome Fund (Career Award at the Scientific Interface)Alfred P. Sloan Foundatio

Electrochemically synthesized polymers in molecular imprinting for chemical sensing

This critical review describes a class of polymers prepared by electrochemical polymerization that employs the concept of molecular imprinting for chemical sensing. The principal focus is on both conducting and nonconducting polymers prepared by electropolymerization of electroactive functional monomers, such as pristine and derivatized pyrrole, aminophenylboronic acid, thiophene, porphyrin, aniline, phenylenediamine, phenol, and thiophenol. A critical evaluation of the literature on electrosynthesized molecularly imprinted polymers (MIPs) applied as recognition elements of chemical sensors is presented. The aim of this review is to highlight recent achievements in analytical applications of these MIPs, including present strategies of determination of different analytes as well as identification and solutions for problems encountered