TRANSCRIPTIONAL REGULATION OF GENES ASSOCIATED WITH DRUG RESISTANCE AND GROWTH OF PANCREATIC CANCER CELLS BY MUCIN 1

th Pancreatic ductal adenocarcinoma (PDA) is the 4 leading cause of cancer-related deaths in the US. An understanding of the molecular pathogenesis of PDA is of utmost importance to be able to improve the current or design new targeted therapies for treatment of PDA. MUC1 (CD227), a membrane tethered mucin glycoprotein is overexpressed in >60% of human pancreatic cancers and 80% of PDA and is associated with poor prognosis, enhanced metastasis, and chemoresistance in PDA. The objective of thesis was to delineate the mechanism by which MUC1 induces drug resistance, and promotes invasion and proliferation in PDA. We report here for the first time that MUC1 contributes to drug resistance in pancreatic cancer (PC) via upregulating the expression of ABC transporters that reduces intracellular drug concentration inside the cancer cells. We found that MUC1 high PC cells exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison to cells that express low levels of MUC1. This chemo resistance is attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein, encoded by the ABCC1 gene is significantly higher in the MUC1-high PDA cells. In human PDA cell lines, MUC1 upregulates MRP1 via an Akt dependent pathway, whereas, in mouse cells, MUC1 mediated MRP1 upregulation is via an Akt independent mechanism. However, in both mouse and human cell lines, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PDA cells and thus confer drug resistance. We also report that human and mouse PDA cell lines expressing high levels of endogenous MUC1 also express high levels of Cox-2 compared to MUC1 null cells. Further, in both mouse and human cell lines, MUC1 upregulates expression of Cox- 2/COX-2 gene via an NF-kB dependent mechanism. In MUC1 positive PDA cell lines, MUC1 and NF-kB binds to the 5?UTR of Cox-2/COX-2 gene around the NFkB response element (within 500bp upstream of TSS), which is not observed in MUC1 null PDA cells. The increased expression of Cox-2 gives the MUC1 positive PDA cell lines a growth and/or invasive advantage. Lastly, we report that MUC1 modulates TGF-ß signaling axis causing TGF-ß1 to act as a tumor promoter in MUC1 high cells and acting as a tumor suppressor in MUC1 null cells. The difference in TGF-ß1 functioning could be partly attributed to difference in the expression profile of the TGF-ßRI and TGF-ßRII and activation of the downstream signaling cascades

Web 2.0 technologies for effective knowledge management in organizations: a qualitative analysis

A new generation of Internet-based collaborative tools, commonly known as Web 2.0, has increased in popularity, availability, and power in the last few years (Kane and Fichman, 2009). Web 2.0 is a set of Internet-based applications that harness network effects by facilitating collaborative and participative computing (O'Reilly, 2006). Conceptually, Web 2.0--with its ability to combine traditional KM tools' features with social computing, where knowledge is evolved through social interactions (Parameswaran, 2007)--has been identified as an effective KM paradigm (Fitch, 2007; Mindel and Verma, 2006).With such a capability, Web 2.0 technology has the potential to address many of the KM challenges that organizations face (Minocha and Thomas, 2007; Wagner, 2006). While Web 2.0 has gained widespread popularity at the consumer level, it is still not well-understood how Web 2.0 can be effectively used for KM by enterprises. In our research, we address this critical gap in the literature by using a multiple-case research design. This dissertation examines how IT organizations use Web 2.0 technologies for Knowledge Management (KM) at the individual, project, and group level. We also investigate how the use of Web 2.0 technology for KM affects organization, group, project, and individual level outcomes. Using multiple case research design, this research provides examples of effective use of Web 2.0 for KM at the individual, project, group, and organization level. Using empirical data, this research also establishes a relationship between the uses of Web 2.0 for KM and its effects on individual, project, group, and organization levels. The extant literature has yet to examine such relationships

A history of Burlington Industries, Inc.

It was the purpose of this paper to describe the founding, building up, and maintaining of Burlington Industries, Incorporated, as a corporation primarily engaged in the manufacture, conversion, and sale of textiles. The attempt was begun with no preconceptions, except the assumption that Burlington Industries has been a major textile firm for about two decades. The main problem faced in the course of writing the paper was the difficulty of locating sources. Most of the existing published sources were too brief, others were either too verbose or slanted. One main source, the personal notebook of J. Spencer Love, was not available. Once the sources were located, an effort was made to separate the opinions from the facts; and on the basis of these facts, a chronological history of the corporation was written. Opinions occur occasionally, but only to facilitate the writing of the paper according to the original plan. Information was often obtained from direct interviews with persons acquainted with the subject, but such information was always complemented by written sources, so that references to oral interviews were omitted

Brains of verbal memory specialists show anatomical differences in language, memory and visual systems

Abstract We studied a group of verbal memory specialists to determine whether intensive oral text memory is associated with structural features of hippocampal and lateral-temporal regions implicated in language processing. Professional Vedic Sanskrit Pandits in India train from childhood for around 10 years in an ancient, formalized tradition of oral Sanskrit text memorization and recitation, mastering the exact pronunciation and invariant content of multiple 40,000–100,000 word oral texts. We conducted structural analysis of gray matter density, cortical thickness, local gyrification, and white matter structure, relative to matched controls. We found massive gray matter density and cortical thickness increases in Pandit brains in language, memory and visual systems, including i ) bilateral lateral temporal cortices and ii ) the anterior cingulate cortex and the hippocampus, regions associated with long and short-term memory. Differences in hippocampal morphometry matched those previously documented for expert spatial navigators and individuals with good verbal working memory. The findings provide unique insight into the brain organization implementing formalized oral knowledge systems

Does primary brachial plexus surgery alter palliative tendon transfer surgery outcomes in children with obstetric paralysis?

<p>Abstract</p> <p>Background</p> <p>The surgical management of obstetrical brachial plexus palsy can generally be divided into two groups; early reconstructions in which the plexus or affected nerves are addressed and late or palliative reconstructions in which the residual deformities are addressed. Tendon transfers are the mainstay of palliative surgery. Occasionally, surgeons are required to utilise already denervated and subsequently reinnervated muscles as motors. This study aimed to compare the outcomes of tendon transfers for residual shoulder dysfunction in patients who had undergone early nerve surgery to the outcomes in patients who had not.</p> <p>Methods</p> <p>A total of 91 patients with obstetric paralysis-related shoulder abduction and external rotation deficits who underwent a modified Hoffer transfer of the latissimus dorsi/teres major to the greater tubercle of the humerus tendon between 2002 and 2009 were retrospectively analysed. The patients who had undergone neural surgery during infancy were compared to those who had not in terms of their preoperative and postoperative shoulder abduction and external rotation active ranges of motion.</p> <p>Results</p> <p>In the early surgery groups, only the postoperative external rotation angles showed statistically significant differences (25 degrees and 75 degrees for total and upper type palsies, respectively). Within the palliative surgery-only groups, there were no significant differences between the preoperative and postoperative abduction and external rotation angles. The significant differences between the early surgery groups and the palliative surgery groups with total palsy during the preoperative period diminished postoperatively (p < 0.05 and p > 0.05, respectively) for abduction but not for external rotation. Within the upper type palsy groups, there were no significant differences between the preoperative and postoperative abduction and external rotation angles.</p> <p>Conclusions</p> <p>In this study, it was found that in patients with total paralysis, satisfactory shoulder abduction values can be achieved with tendon transfers regardless of a previous history of neural surgery even if the preoperative values differ.</p

Multiplex PCR technique could be an alternative approach for early detection of leprosy among close contacts - a pilot study from India

<p>Abstract</p> <p>Background</p> <p>Implementation of Multi drug Therapy (MDT) regimen has resulted in the decline of the total number of leprosy cases in the world. Though the prevalence rate has been declining, the incidence rate remains more or less constant and high in South East Asian countries particularly in India, Nepal, Bangladesh, Pakistan and Srilanka. Leprosy, particularly that of multibacillary type spreads silently before it is clinically detected. An early detection and treatment would help to prevent transmission in the community. Multiplex PCR (M-PCR) technique appears to be promising towards early detection among contacts of leprosy cases.</p> <p>Methods</p> <p>A total of 234 paucibacillary (PB) and 205 multibacillary (MB) leprosy cases were studied in a community of an endemic area of Bankura district of West Bengal (Eastern India). They were assessed by smear examination for acid-fast bacilli (AFB) and M-PCR technique. These patients were treated with Multidrug Therapy (MDT) as prescribed by WHO following detection. A total of 110 MB and 72 PB contacts were studied by performing M-PCR in their nasal swab samples.</p> <p>Results</p> <p>83.4% of MB patients were observed to be positive by smear examination for AFB and 89.2% by M-PCR. While 22.2% of PB patients were found to be positive by smear examination for AFB, 80.3% of these patients were positive by M-PCR. Among leprosy contacts (using M-PCR), 10.9% were found to be positive among MB contacts and 1.3% among PB contacts. Interestingly, two contacts of M-PCR positive MB cases developed leprosy during the period of two years follow up.</p> <p>Conclusion</p> <p>The M-PCR technique appears to be an efficient tool for early detection of leprosy cases in community based contact tracing amongst close associates of PB and MB cases. Early contact tracing using a molecular biology tool can be of great help in curbing the incidence of leprosy further.</p

Aptamers as molecular recognition elements for electrical nanobiosensors

Recent advances in nanotechnology have enabled the development of nanoscale sensors that outperform conventional biosensors. This review summarizes the nanoscale biosensors that use aptamers as molecular recognition elements. The advantages of aptamers over antibodies as sensors are highlighted. These advantages are especially apparent with electrical sensors such as electrochemical sensors or those using field-effect transistors

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity