Publications by authors named "Karin Bauer"

30 Publications

  • Page 1 of 1

Leveraging E-Learning Infrastructure in Times of Rapid Change: Use of the National STD Curriculum in the Era of COVID-19.

Sex Transm Dis 2021 May 1. Epub 2021 May 1.

University of Washington.

Abstract: The National STD Curriculum (NSTDC) is an e-learning platform. New registrations and learning group creations during March-April 2020 were compared to previous 12-month data. Substantial increases in registrations and learning groups demonstrate that the NSTDC was successfully leveraged to meet rapidly shifting training needs due to the COVID-19 pandemic.
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http://dx.doi.org/10.1097/OLQ.0000000000001462DOI Listing
May 2021

Potential for community based surveillance of febrile diseases: Feasibility of self-administered rapid diagnostic tests in Iquitos, Peru and Phnom Penh, Cambodia.

PLoS Negl Trop Dis 2021 Apr 26;15(4):e0009307. Epub 2021 Apr 26.

Tulane School of Public Health and Tropical Medicine, New Orleans, Lousiana, United States of America.

Rapid diagnostic tests (RDTs) have the potential to identify infectious diseases quickly, minimize disease transmission, and could complement and improve surveillance and control of infectious and vector-borne diseases during outbreaks. The U.S. Defense Threat Reduction Agency's Joint Science and Technology Office (DTRA-JSTO) program set out to develop novel point-of-need RDTs for infectious diseases and deploy them for home use with no training. The aim of this formative study was to address two questions: 1) could community members in Iquitos, Peru and Phnom Penh, Cambodia competently use RDTs of different levels of complexity at home with visually based instructions provided, and 2) if an RDT were provided at no cost, would it be used at home if family members displayed febrile symptoms? Test kits with written and video (Peru only) instructions were provided to community members (Peru [n = 202]; Cambodia [n = 50]) or community health workers (Cambodia [n = 45]), and trained observers evaluated the competency level for each of the several steps required to successfully operate one of two multiplex RDTs on themselves or other consenting participant (i.e., family member). In Iquitos, >80% of residents were able to perform 11/12 steps and 7/15 steps for the two- and five-pathogen test, respectively. Competency in Phnom Penh never reached 80% for any of the 12 or 15 steps for either test; the percentage of participants able to perform a step ranged from 26-76% and 23-72%, for the two- and five-pathogen tests, respectively. Commercially available NS1 dengue rapid tests were distributed, at no cost, to households with confirmed exposure to dengue or Zika virus; of 14 febrile cases reported, six used the provided RDT. Our findings support the need for further implementation research on the appropriate level of instructions or training needed for diverse devices in different settings, as well as how to best integrate RDTs into existing local public health and disease surveillance programs at a large scale.
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http://dx.doi.org/10.1371/journal.pntd.0009307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101991PMC
April 2021

Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia.

Leukemia 2021 Mar 30. Epub 2021 Mar 30.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34/CD38 fraction of the malignant clone. Whereas CD34/CD38 cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34/CD38 progenitors or the bulk of CD34 monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34/CD38 cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.
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http://dx.doi.org/10.1038/s41375-021-01227-zDOI Listing
March 2021

Degradation of BRD4 - a promising treatment approach not only for hematologic but also for solid cancer.

Am J Cancer Res 2021 1;11(2):530-545. Epub 2021 Feb 1.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna Austria.

Bromodomain (BRD) and extra-terminal (BET) proteins are epigenetic readers that regulate gene expression and promote cancer evolution. Pharmacological inactivation of BRD4 has recently been introduced as a promising anti-neoplastic approach that targets MYC oncogene expression. However, resistance against BRD4-targeting drugs has been described. We compared the efficacy of the small-molecule-type BET BRD inhibitor JQ1 with the recently developed BET protein degraders dBET1 and dBET6 in colon, breast, melanoma, ovarian, lung and prostate cancer cell lines. As determined by qPCR, all BRD4 targeting drugs dose-dependently decreased MYC expression, with dBET6 introducing the strongest downregulation of MYC. This correlated with the anti-proliferative activity of these drugs, which was at least one order of magnitude higher for dBET6 (IC 0.001-0.5 µM) than for dBET1 or JQ1 (IC 0.5-5 µM). Interestingly, when combined with commonly used cytotoxic therapeutics, dBET6 was found to promote anti-neoplastic effects and to counteract chemoresistance in most cancer cell lines. Moreover, JQ1 and both BET degraders strongly downregulated baseline and interferon-gamma induced expression of the immune checkpoint molecule PD-L1 in all cancer cell lines. Together, our data suggest that dBET6 outperforms first-generation BRD4 targeting drugs like dBET1 and JQ1, and decreases chemoresistance and immune resistance of cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868748PMC
February 2021

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues.

Stem Cells Transl Med 2020 11 13;9(11):1331-1343. Epub 2020 Jul 13.

Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienna, Vienna, Austria.

Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia-models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC-targeting antibodies or LSC-targeting immune cells. These therapies include, among others, new generations of LSC-eliminating antibody-constructs, checkpoint-targeting antibodies, bi-specific antibodies, and CAR-T or CAR-NK cell-based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment-induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell-based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance.
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http://dx.doi.org/10.1002/sctm.20-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581453PMC
November 2020

Evaluation of the National Sexually Transmitted Disease Curriculum: Reach, Utilization, and Engagement.

Sex Transm Dis 2020 06;47(6):412-418

From the Division of Allergy and Infectious Diseases, University of Washington.

Background: With increasing rates of sexually transmitted infections in the United States, there is a critical need to educate health professionals on the prevention, diagnosis, and treatment of sexually transmitted infections. The National Sexually Transmitted Disease Curriculum (NSTDC, https://www.std.uw.edu) is a free, online curriculum, funded by the Centers for Disease Control and Prevention. The purpose of this article is to evaluate the reach, utilization, and engagement of users with the curriculum.

Methods: Data on NSTDC utilization was collected for 24 months after the February 1, 2017 launch. For all users, Google Analytics was used to determine total number of users, geographic location, age and sex, and average session duration. For registered users, additional data analysis included work-role, demographics, and completion of self-study modules, check-on-learning questions, and question banks. User satisfaction was measured on a 5-point Likert scale.

Results: During the evaluation period, 136,270 individual users accessed the NSTDC, including 24,652 registered users. Among all registered users, 10,660 (43.2%) were registered nurses, 2810 (11.4%) physicians, 4942 (20.1%) Advanced Practice Nurses and Physician Assistants, and 6213 (25.2%) nonclinicians. Among registered users, 18,533 (75.2%) completed at least 1 module, 7898 (32.0%) completed all 7 modules, and 19,804 (80.4%) answered optional check-on-learning questions. Median satisfaction with the content was (5) very satisfied (interquartile range, 4-5).

Conclusions: The NSTDC is a free, guideline-based, online curriculum with novel dual functionality that has achieved extensive reach with a broad array of health professionals who engage deeply with the material. The wide usage of NSTDC demonstrates the need for high-quality, unbiased, free content in user-focused formats.
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http://dx.doi.org/10.1097/OLQ.0000000000001160DOI Listing
June 2020

Potential Use of Community-Based Rapid Diagnostic Tests for Febrile Illnesses: Formative Research in Peru and Cambodia.

PLoS Negl Trop Dis 2019 10 28;13(10):e0007773. Epub 2019 Oct 28.

University of California Fielding School of Public Health, Los Angeles, California, United States of America.

In 2012, the U.S. Defense Threat Reduction Agency Joint Science and Technology Office initiated a program to develop novel point-of-need diagnostic devices for surveillance of emerging infectious diseases including dengue, malaria, plague, and melioidosis. Prior to distribution of devices to observe their correct use among community members in Iquitos, Peru, and Phnom Penh, Cambodia, research was conducted to: 1) assess acceptability of use, including the motivation to use a rapid diagnostic test (RDT) before or instead of seeking care at a health facility, 2) explore comprehension of RDT use instructions, and 3) examine possible strategies for large scale RDT distribution and use at each site. In February 2014, 9 focus group discussions (FGD) with community members and 5 FGD with health professionals were conducted in Iquitos, and 9 FGD with community members and 9 in-depth interviews with health professionals in Phnom Penh. In both places, participants agreed to use the device themselves (involving finger prick) or could identify someone who could do so in their home or neighborhood. The main incentive to RDT use in both sites was the ability for device results to be used for care facilitation (post confirmatory tests), specifically reduced wait times to be seen or obtain a diagnosis. Comprehension of RDT use instructions was assessed in Iquitos by asking some participants to apply the device to research team members; after watching a short video, most steps were done correctly. In Phnom Penh, participants were asked to describe each step after reading the instructions; they struggled with comprehension. Health professionals' main concerns in both sites were their community's ability to accurately use the test, handle complicated instructions, and safety (i.e., disposal of lancets). Health system structure and ability to use home diagnostic devices varied in the two disease endemic sites, with substantial challenges in each, suggesting the need for different strategies for RDT large scale community use, and illustrating the value of formative research before deployment of novel technologies.
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http://dx.doi.org/10.1371/journal.pntd.0007773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837536PMC
October 2019

A kinase-independent role for CDK8 in BCR-ABL1 leukemia.

Nat Commun 2019 10 18;10(1):4741. Epub 2019 Oct 18.

Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.

Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.
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http://dx.doi.org/10.1038/s41467-019-12656-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802219PMC
October 2019

Immunotherapy-Based Targeting and Elimination of Leukemic Stem Cells in AML and CML.

Int J Mol Sci 2019 Aug 29;20(17). Epub 2019 Aug 29.

Department of Internal Medicine V (Hematology & Oncology), Medical University of Innsbruck, 1090 Innsbruck, Austria.

The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must have the potential to eliminate or completely suppress LSC, as only these cells can restore and propagate the malignancy for unlimited time periods. Since LSC represent a minor cell fraction in the leukemic clone, little is known about their properties and target expression profiles. Over the past few years, several cell-specific immunotherapy concepts have been developed, including new generations of cell-targeting antibodies, antibody-toxin conjugates, bispecific antibodies, and CAR-T cell-based strategies. Whereas such concepts have been translated and may improve outcomes of therapy in certain lymphoid neoplasms and a few other malignancies, only little is known about immunological targets that are clinically relevant and can be employed to establish such therapies in myeloid neoplasms. In the current article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field.
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http://dx.doi.org/10.3390/ijms20174233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747233PMC
August 2019

Redistribution, homing and organ-invasion of neoplastic stem cells in myeloid neoplasms.

Semin Cancer Biol 2020 02 10;60:191-201. Epub 2019 Aug 10.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a drug-resistant terminal phase. Organ-invasion may occur in any stage, but is usually associated with advanced disease and a poor prognosis. Sometimes, extra-medullary organ invasion shows a metastasis-like or even sarcoma-like destructive growth of neoplastic cells in local tissue sites. Examples are myeloid sarcoma, mast cell sarcoma and localized blast phase of chronic myeloid leukemia. So far, little is known about mechanisms underlying re-distribution and extramedullary dissemination of LSC in myeloid neoplasms. In this article, we discuss mechanisms through which LSC can mobilize out of the bone marrow niche, can transmigrate from the blood stream into extramedullary organs, can invade local tissue sites and can potentially create or support the formation of local stem cell niches. In addition, we discuss strategies to interfere with LSC expansion and organ invasion by targeted drug therapies.
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http://dx.doi.org/10.1016/j.semcancer.2019.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115853PMC
February 2020

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells.

Vet Comp Oncol 2019 Dec 13;17(4):553-561. Epub 2019 Aug 13.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE-dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI-1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI-1 cells. In C2 cells, the combination "ibrutinib + midostaurin" produced synergistic growth-inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE-dependent histamine release in primary MCT cells, with IC values ranging from 0.05 to 0.1 μM in NI-1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti-proliferative effects in canine neoplastic MCs and counteracts IgE-dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials.
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http://dx.doi.org/10.1111/vco.12520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900099PMC
December 2019

Remote programming of cochlear implants in users of all ages.

Acta Otolaryngol 2019 Mar;139(3):251-257

e Julius-Maximilians-Universität, Clinic and Polyclinic for Ear, Nose, and Throat Diseases , Würzburg , Germany.

Background: Remote programming for adult cochlear implant (CI) users is feasible, safe, and effective. Limited evidence, however, exists on if remote CI programming can also be productively done with paediatric CI users.

Aims/objectives: To assess the safety and feasibility of remote CI programming in CI users for all ages.

Materials And Methods: Forty-six (25 children, 21 adults) experienced CI users were fit locally and remotely. The results of these two fitting sessions were compared in terms of safety, Impedance Field Telemetry (IFT), Maximum Comfortable Levels (MCL), Threshold Levels (THR), audiometry, fitting duration, and speech understanding.

Results: The subjects' safety was not compromised during any of the fitting procedures. No significant difference was found for IFT, MCL, THR, audiometry, or speech understanding for either remote or local fitting. Remote fittings took slightly longer than local fittings when only the fitting time itself was measured.

Conclusions And Significance: Remote follow-up fitting is as safe, feasible, and effective as local fitting for CI users of all ages. A more extensive adoption of remote fitting may allow many CI users greater access to clinics and therefore increased benefit from CI use.
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http://dx.doi.org/10.1080/00016489.2018.1554264DOI Listing
March 2019

Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms.

Vet Comp Oncol 2019 Mar 24;17(1):1-10. Epub 2018 Sep 24.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.

In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms.
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http://dx.doi.org/10.1111/vco.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378619PMC
March 2019

Hitting two oncogenic machineries in cancer cells: cooperative effects of the multi-kinase inhibitor ponatinib and the BET bromodomain blockers JQ1 or dBET1 on human carcinoma cells.

Oncotarget 2018 May 29;9(41):26491-26506. Epub 2018 May 29.

Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.

In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs. This is due, at least in part, to compensatory feedback-loops in the kinome and transcription network of these tumors, which are activated in response to drug exposure. Therefore, we hypothesized that the combination of the multi-kinase inhibitor ponatinib with transcription modulators such as JQ1 or dBET1 might overcome this therapeutic recalcitrance. Using H-thymidine uptake, cell cycle analysis, and caspase-3 or Annexin V labeling, we demonstrate that single drugs induce moderate dose-dependent growth-inhibition and/or apoptosis in colon (HCT116, HT29), breast (MCF-7, SKBR3) and ovarian (A2780, SKOV3) cancer cells. Ponatinib elicited primarily apoptosis, while JQ1 and dBET1 caused G0/G1 cell cycle arrest and very mild cell death. Phospho-FGFR and MYC, major targets of ponatinib and BET inhibitors, were downregulated after treatment with single drugs. Remarkably, ponatinib was found to sensitize cells to BET antagonists by enhancing apoptotic cell death, and this effect was associated with downregulation of MYC. In summary, our data shows that ponatinib sensitizes colon, breast, and ovarian cancer cells to BET bromodomain inhibitors. Further studies are warranted to determine the clinical value of this phenomenon.
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http://dx.doi.org/10.18632/oncotarget.25474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995173PMC
May 2018

The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma.

Vet Comp Oncol 2018 Mar 11;16(1):55-68. Epub 2017 Apr 11.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Background: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma.

Materials And Methods: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1.

Results: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells.

Conclusion: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma.
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http://dx.doi.org/10.1111/vco.12311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824979PMC
March 2018

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1.

Cell Rep 2017 02;18(9):2162-2174

Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.
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http://dx.doi.org/10.1016/j.celrep.2017.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340981PMC
February 2017

Experiences with insecticide-treated curtains: a qualitative study in Iquitos, Peru.

BMC Public Health 2016 07 16;16:582. Epub 2016 Jul 16.

Department of Entomology and Nematology, University of California Davis, Davis, CA, USA.

Background: Dengue is an arthropod-borne viral disease responsible for approximately 400 million infections annually; the only available method of prevention is vector control. It has been previously demonstrated that insecticide treated curtains (ITCs) can lower dengue vector infestations in and around houses. As part of a larger trial examining whether ITCs could reduce dengue transmission in Iquitos, Peru, the objective of this study was to characterize the participants' experience with the ITCs using qualitative methods.

Methods: Knowledge, attitudes, and practices (KAP) surveys (at baseline, and 9 and 27 months post-ITC distribution, with n = 593, 595 and 511, respectively), focus group discussions (at 6 and 12 months post-ITC distribution, with n = 18 and 33, respectively), and 11 one-on-one interviews (at 12 months post-distribution) were conducted with 605 participants who received ITCs as part of a cluster-randomized trial.

Results: Focus groups at 6 months post-ITC distribution revealed that individuals had observed their ITCs to function for approximately 3 months, after which they reported the ITCs were no longer working. Follow up revealed that the ITCs required re-treatment with insecticide at approximately 1 year post-distribution. Over half (55.3 %, n = 329) of participants at 9 months post-ITC distribution and over a third (34.8 %, n = 177) at 27 months post-ITC distribution reported perceiving a decrease in the number of mosquitoes in their home. The percentage of participants who would recommend ITCs to their family or friends in the future remained high throughout the study (94.3 %, n = 561 at 9 months and 94.6 %, n = 488 at 27 months post-distribution). When asked why, participants reported that ITCs were effective at reducing mosquitoes (81.6 and 37.8 %, at 9 and 27 months respectively), that they prevent dengue (5.7 and 51.2 %, at 9 and 27 months), that they are "beautiful" (5.9 and 3.1 %), as well as other reasons (6.9 and 2.5 %).

Conclusion: ITCs have substantial potential for long term dengue vector control because they are liked by users, both for their perceived effectiveness and for aesthetic reasons, and because they require little proactive behavioral effort on the part of the users. Our results highlight the importance of gathering process (as opposed to outcome) data during vector control studies, without which researchers would not have become aware that the ITCs had lost effectiveness early in the trial.
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http://dx.doi.org/10.1186/s12889-016-3191-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947330PMC
July 2016

To spray or not to spray? Understanding participation in an indoor residual spray campaign in Arequipa, Peru.

Glob Public Health 2018 Jan 17;13(1):65-82. Epub 2016 May 17.

g Department of Family and Community Health , University of Pennsylvania School of Nursing , Philadelphia , PA , USA.

Current low participation rates in vector control programmes in Arequipa, Peru complicate the control of Chagas disease. Using focus groups (n = 17 participants) and semi-structured interviews (n = 71) conducted in March and May 2013, respectively, we examined barriers to and motivators of household participation in an indoor residual spray (IRS) campaign that had taken place one year prior in Arequipa. The most common reported barriers to participation were inconvenient spray times due to work obligations, not considering the campaign to be necessary, concerns about secondary health impacts (e.g. allergic reactions to insecticides), and difficulties preparing the home for spraying (e.g. moving heavy furniture). There was also a low perception of risk for contracting Chagas disease that might affect participation. The main motivator to participate was to ensure personal health and well-being. Future IRS campaigns should incorporate more flexible hours, including weekends; provide appropriate educational messages to counter concerns about secondary health effects; incorporate peer educators to increase perceived risk to Chagas in community; obtain support from community members and leaders to build community trust and support for the campaign; and assist individuals in preparing their homes. Enhancing community trust in both the need for the campaign and its operations is key.
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http://dx.doi.org/10.1080/17441692.2016.1178317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491364PMC
January 2018

Factors Associated with Correct and Consistent Insecticide Treated Curtain Use in Iquitos, Peru.

PLoS Negl Trop Dis 2016 Mar 11;10(3):e0004409. Epub 2016 Mar 11.

Entomology Branch, Division of Parasitic Diseases and Malaria, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

Dengue is an arthropod-borne virus of great public health importance, and control of its mosquito vectors is currently the only available method for prevention. Previous research has suggested that insecticide treated curtains (ITCs) can lower dengue vector infestations in houses. This observational study investigated individual and household-level socio-demographic factors associated with correct and consistent use of ITCs in Iquitos, Peru. A baseline knowledge, attitudes, and practices (KAP) survey was administered to 1,333 study participants, and ITCs were then distributed to 593 households as part of a cluster-randomized trial. Follow up KAP surveys and ITC-monitoring checklists were conducted at 9, 18, and 27 months post-ITC distribution. At 9 months post-distribution, almost 70% of ITCs were hanging properly (e.g. hanging fully extended or tied up), particularly those hung on walls compared to other locations. Proper ITC hanging dropped at 18 months to 45.7%. The odds of hanging ITCs correctly and consistently were significantly greater among those participants who were housewives, knew three or more correct symptoms of dengue and at least one correct treatment for dengue, knew a relative or close friend who had had dengue, had children sleeping under a mosquito net, or perceived a change in the amount of mosquitoes in the home. Additionally, the odds of recommending ITCs in the future were significantly greater among those who perceived a change in the amount of mosquitoes in the home (e.g. perceived the ITCs to be effective). Despite various challenges associated with the sustained effectiveness of the selected ITCs, almost half of the ITCs were still hanging at 18 months, suggesting a feasible vector control strategy for sustained community use.
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http://dx.doi.org/10.1371/journal.pntd.0004409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788147PMC
March 2016

Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis.

Blood 2015 Dec 20;126(26):2832-41. Epub 2015 Oct 20.

Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;

The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 µg/mL) compared with CD30(-) HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM.
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http://dx.doi.org/10.1182/blood-2015-03-637728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692143PMC
December 2015

Evaluation of left-turn lane offset using the naturalistic driving study data.

J Safety Res 2015 Sep 21;54:5-15. Epub 2015 Jul 21.

Human Factors North, Inc., 174 Spadina Ave, Suite 202, Toronto, ON M5T 2C2, Canada. Electronic address:

Introduction: The Strategic Highway Research Program 2 (SHRP 2) Naturalistic Driving Study (NDS) data were used to evaluate gap acceptance behavior of drivers at left-turn lanes with negative, zero, or positive offsets ranging from -29 ft to +6 ft. The objectives of the study were to develop guidance for the design of offset left-turn lanes used as a safety countermeasure, and to provide insight regarding the use of the NDS data to future users.

Method: The study included 3350 gaps in opposing traffic evaluated by 145 NDS volunteer drivers and 275 non-NDS drivers at 14 two-way stop-controlled intersections and 44 signalized opposing left-turn pairs. Logistic regression was used to model the critical gap length for drivers as a function of offset, under conditions when their view was either blocked or not by an opposing left-turning driver.

Results: The analysis found that the critical gap was longer at left-turn lanes with negative offsets than at those with zero or positive offsets, and was also longer when sight distance was blocked by an opposing left-turning vehicle. Sight distance was much more likely to be restricted by an opposing left-turning vehicle at negative-offset and drivers at those intersections were less likely to accept a gap when an opposing left-turn driver was present.

Conclusions: Longer gap lengths could potentially result in decreased operational efficiency of an intersection. In addition, drivers making left-turns at negative-offset left-turn lanes are, on average, more likely to leave the shortest amount of time between their turn and the arrival of the next opposing through-vehicle, which may present a potential safety concern.

Practical Applications: The findings provide guidance for highway designers considering using offset left-turn lanes as a crash countermeasure. This research also highlights the benefits and limitations of using the SHRP 2 NDS data to answer similar research questions.
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http://dx.doi.org/10.1016/j.jsr.2015.06.016DOI Listing
September 2015

Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity.

Int J Clin Exp Pathol 2014 15;7(9):6125-32. Epub 2014 Aug 15.

Department of Internal Medicine I, University Hospital Regensburg Germany.

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203231PMC
July 2015

Presenilin 1/γ-secretase modulates P-cadherin processing and influences cell adhesion in oral squamous cell carcinoma cell lines.

Carcinogenesis 2013 Nov 5;34(11):2622-8. Epub 2013 Jun 5.

Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany and.

P-cadherin belongs to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity in the oral epithelium. P-cadherin is only expressed in the basal and suprabasal cell layers of the oral epithelium, but in advanced oral squamous cell carcinoma (OSCC), a reduced membranous and an enhanced cytoplasmic truncated P-cadherin level is observed. In this study, we investigated the impact of presenilin (PS) 1/γ-secretase on P-cadherin processing in OSCC. Western blot analyses showed an enhanced PS1 expression in OSCC cell lines and in primary oral keratinocytes (POK) isolated from primary OSCC tissue (OSCC POK) compared with POKs isolated from normal oral mucosa. Immunocytochemical stainings and co-immunoprecipitation experiments revealed a cytoplasmic colocalization and a direct interaction of P-cadherin and PS1 in OSCC POKs. Blocking of PS1/γ-secretase activity by the PS1/γ-secretase inhibitors and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, another specific γ-secretase inhibitor yielded a 100 kDa P-cadherin band on western blots of OSCC cell line extracts. Small interfering RNA knockdown of PS1 equally generated a 100 kDa P-cadherin form in OSCC POKs. Mass spectrometry analyses and experiments with the glycosylation inhibitor tunicamycin characterized the appearing 100 kDa P-cadherin band as the unglycosylated full-length form of P-cadherin. On the functional level, cell attachment assays demonstrated an enhanced cell adhesion after PS1/γ-secretase inhibition only in the transiently P-cadherin expressing OSCC cell line PCI52 but not in the PCI52 control cells. In summary, our results show that PS1/γ-secretase contributes to P-cadherin processing and to reduced cell adhesion in OSCC.
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http://dx.doi.org/10.1093/carcin/bgt211DOI Listing
November 2013

P-cadherin controls the differentiation of oral keratinocytes by regulating cytokeratin 1/10 expression via C/EBP-beta-mediated signaling.

Differentiation 2012 Dec 7;84(5):345-54. Epub 2012 Nov 7.

Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Germany.

P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecules. In the normal oral epithelium it shows a strong expression in the basal cell layer which gradually decreases in the suprabasal cell layers. The exact role of P-cadherin during the development and homeostasis of the oral epithelium has not been elucidated, yet. Here, we show for the first time that P-cadherin controls differentiation by regulating cytokeratin (CK) 1/10 expression in primary oral keratinocytes (POK) from normal, but interestingly not in POKs from oral squamous cell carcinoma (OSCC) tissue. SiRNA knockdown of P-cadherin in normal POKs revealed a strong upregulation of CK1/10 expression on mRNA and protein level. In contrast, E-cadherin knockdown in normal oral keratinocytes did not show any influence on CK1/10 expression. Moreover, in comparison with normal control keratinocytes normal oral keratinocytes with reduced P-cadherin expression displayed an enhanced expression and a stronger nuclear staining of C/EBP-beta, a well-known regulator of CK1/10 expression in keratinocytes. Furthermore, after P-cadherin knockdown in normal POKs the promoter activity of a C/EBP-responsive luciferase construct was significantly higher than in normal POKs with regular P-cadherin expression. Additionally, we noticed a proliferation advantage in normal oral keratinocytes in contrast to keratinocytes with diminished P-cadherin expression. However, the inverted effect was seen in tumor derived primary oral keratinocytes. In summary, we show that P-cadherin contributes to the keratinocyte differentiation in the oral epithelium by influencing the CK1 and CK10 expression via C/EBP-beta-mediated signaling in normal but not in tumor derived oral keratinocytes from OSCC patients.
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http://dx.doi.org/10.1016/j.diff.2012.09.002DOI Listing
December 2012

The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells.

Exp Cell Res 2012 Mar 10;318(5):489-99. Epub 2011 Nov 10.

Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

There is a growing evidence that the human homologue of the Drosophila headcase (HECA) plays an important role in human carcinogenesis. So far specific protein interaction partners and affected signaling pathways of HECA are still elusive. In a recent study we showed that HECA overexpression in oral squamous-cell carcinoma (OSCC) keratinocytes has tumor suppressive effects resulting in a recuperation of cell cycle control concerning the entry and progression of S-phase, G2- and M-phase. Currently, quantitative RT-PCR and immunohistochemical analysis of primary tumor tissue from OSCC patients demonstrate that HECA expression is markedly decreased compared to normal control patients with abundant HECA expression. Additionally, there is nearly no HECA expression in OSCC metastases. Here, we show that HECA expression is negatively controlled by the Wnt-pathway and TCF4, a Wnt related transcription factor, binds to the HECA promoter. Furthermore, immunocytochemistry reveals colocalization of HECA with the cyclin dependent kinase CDK9. Immunoprecipitation experiments and proximity ligation assays further reveal an interaction of HECA with CDK2, CDK9, Cyclin A and Cyclin K, a direct transcriptional target of the p53 tumor suppressor. Silencing HECA in OSCC cell lines leads to a significant increase of cell division and a markedly increased resistance against the chemotherapeutic cisplatin. On the contrary, HECA overexpressing OSCC cell lines show decreased resistance of OSCC cells against cisplatin. Therefore, HECA could be considered as future therapeutic agent against Wnt-dependent tumor progression.
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http://dx.doi.org/10.1016/j.yexcr.2011.11.004DOI Listing
March 2012

Slit-2 facilitates interaction of P-cadherin with Robo-3 and inhibits cell migration in an oral squamous cell carcinoma cell line.

Carcinogenesis 2011 Jun 31;32(6):935-43. Epub 2011 Mar 31.

Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053Regensburg, Germany.

Slits are a group of secreted glycoproteins that act as molecular guidance cues in cellular migration. Recently, several studies demonstrated that Slit-2 can operate as candidate tumour suppressor protein in various tissues. In this study, we show Slit-2 expression in basal cell layers of normal oral mucosa colocalized with P-cadherin expression. In contrast, there is a loss of Slit-2 and P-cadherin expression in mucosa of oral squamous cell carcinoma (OSCC). Our in vitro investigations reveal a correlation of P-cadherin and Slit-2 expression: OSCC cells with induced P-cadherin expression (PCI52_PC) display an increased Slit-2 expression. However, abrogating P-cadherin function with a function-blocking antibody decreases Slit-2 secretion confirming a direct link between P-cadherin and Slit-2. Moreover, experiments with OSCC cells show that Slit-2 interferes with a Wnt related signalling pathway, which in turn affects Slit-2 expression in a feedback loop. Functionally, transwell migration assays demonstrate a Slit-2 dose-dependent decrease of PCI52_PC cell migration. However, there is no influence on migration in mock control cells. Responsible for this migration block might be an interaction of P-cadherin with Roundabout (Robo)-3, a high affinity receptor of Slit-2. Indeed, proximity ligation assays exhibit P-cadherin/Robo-3 interactions on PCI52_PC cells. Additionally, we detect a modulation of this interaction by addition of recombinant Slit-2. Down-regulation of Robo-3 expression via small interfering RNA neutralizes Slit-2 induced migration block in PCI52_PC cells. In summary, our experiments show antitumorigenic effects of Slit-2 on P-cadherin expressing OSCC cells supposedly via modulation of Robo-3 interaction.
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http://dx.doi.org/10.1093/carcin/bgr059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314282PMC
June 2011

P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation.

Carcinogenesis 2009 Oct 14;30(10):1781-8. Epub 2009 Jul 14.

Department of Oral and Maxillofacial Surgery, University of Regensburg, Regensburg, Germany.

Cadherins belong to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity. They play a major role in the development and homeostasis of epithelial architecture. Recently, it has become more and more evident that P-cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical cadherins, P-cadherin, E-cadherin and N-cadherin. This cell line was transfected with full-length P-cadherin (PCI52_PC). After overexpression of P-cadherin, PCI52_PC gained an epithelial-like brickstone morphology in contrast to the mock-transfected cells with a spindle-shaped mesenchymal morphology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells compared with a significantly reduced nuclear staining and translocation to the cytoplasm in P-cadherin-overexpressing cells. Interestingly, the effects triggered by P-cadherin overexpression could be reversed by transfecting the cells with an antisense P-cadherin plasmid construct. Additional investigations showed a reexpression of E-cadherin in all P-cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-cadherin-overexpressing cell lines showed activated GSK-3beta that phosphorylated Snail leading to its cytoplasmic translocation. In summary, our results reveal P-cadherin as one major component in reconfiguring mesenchymal cells with epithelial features by triggering GSK-3beta-mediated inactivation and cytoplasmatic translocation of Snail in OSCC.
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http://dx.doi.org/10.1093/carcin/bgp175DOI Listing
October 2009

[Abnormalities of adrenal steroidogenesis in Chilean boys with micropenis].

Rev Med Chil 2003 Jan;131(1):46-54

Unidad de Endocrinología, Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile.

Background: Mutations in type II 3 beta hydroxysteroid Dehydrogenase (3 beta HSD) are found in male children with severe undervirilized genitalia. Mild undervirilization (isolated micropenis or with distal hypospadia) can be associated with a partial deficit in 3 beta HSD activity.

Aim: To assess the frequency of abnormal adrenal response to ACTH, suggesting a deficit in adrenal enzymatic activity, in children with mild undervirilization.

Patients And Methods: We studied 26 male children with micropenis, aged one to eight years. Children with evidences of puberal development or in treatment with drugs that affect steroidal metabolism were excluded from the study. Serum levels of androstenedione (A), dehydroepiandrosterone (DHEA), progesterone (P), 17 hydroxyprogesterone (17 P) and the ratios DHEA/A, P/17 P, 17 P/DHEA were measured after an adrenal stimulation with 0.25 mg/m2 intramuscular ACTH.

Results: Two children had DHEA y DHEA/A values suggesting a defective 3 beta HSD activity. Other two children had high levels of 17 P, suggesting a deficiency of cytochrome p450c21. A CYP 21 gene mutation was found in one of the later children.

Conclusions: A low proportion of children with micropenis have a deficient 3 beta HSD activity.
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January 2003

Investigation of the potential release of polychlorinated dioxins and furans from PCP-treated utility poles.

Sci Total Environ 2002 May;290(1-3):15-39

US Environmental Protection Agency, Washington DC 20460, USA.

The United States (US) Environmental Protection Agency (EPA) estimated that the use of technical grade pentachlorophenol (PCP) between 1970 and 1995 to treat wood was approximately 400,000 metric tons in the US, and that between 4800 and 36,000 g of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) were incorporated annually in treated wood. The EPA has been unable, however, to estimate the rate of release of polychlorinated dibenzo-p-dioxins and dibenzofurans (CDD/Fs) from treated utility poles into the environment. There is some evidence that CDD/Fs leach from treated poles into the surrounding soils, but these studies do not allow for the calculation of a rate of release from this mechanism. Another possible release mechanism is the volatilization of dioxins into the atmosphere, but there are no data to demonstrate, much less quantify, this release. While not directly measuring the release of dioxins from treated utility poles into the environment, this study was designed to examine the potential for such release. The general approach taken was to collect PCP-treated poles of varying ages, to remove and analyze multiple samples from each pole cross-section, and to compare the spatial distribution of CDD/F congeners among poles of different ages. Evidence of concentration-depth profile changes over time may provide insight into the potential for dioxins to migrate through and then out of PCP-treated utility poles. It was found that the CDD/F concentrations were consistently higher in the outer portions of the poles than the center. This trend tends to be most marked in older poles and for the lower chlorinated congeners. The trend for dioxins to concentrate in the outer portions of the pole over time suggest migration within the poles, and this migration may result in some environmental release. Other possible explanations were also offered.
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http://dx.doi.org/10.1016/s0048-9697(01)01051-8DOI Listing
May 2002