AB186 Inhibits Migration of Triple-Negative Breast Cancer Cells and Interacts with α-Tubulin.

Breast cancer is one of the leading causes of cancer-related death among females worldwide. A major challenge is to develop innovative therapy in order to treat breast cancer subtypes resistant to current treatment. In the present study, we examined the effects of two Troglitazone derivatives Δ2-TGZ and AB186. Previous studies showed that both compounds induce apoptosis, nevertheless AB186 was a more potent agent. The kinetic of cellular events was investigated by real-time cell analysis system (RTCA) in MCF-7 (hormone dependent) and MDA-MB-231 (triple negative) breast cancer (TNBC) cells, followed by cell morphology analysis by immuno-localization. Both compounds induced a rapid modification of both impedance-based signals and cellular morphology. This process was associated with an inhibition of cell migration measured by wound healing and transwell assays in TNBC MDA-MB-231 and Hs578T cells. In order to identify cytoplasmic targets of AB186, we performed surface plasmon resonance (SPR) and pull-down analyses. Subsequently, 6 cytoskeleton components were identified as potential targets. We further validated α-tubulin as one of the direct targets of AB186. In conclusion, our results suggested that AB186 could be promising to develop novel therapeutic strategies to treat aggressive forms of breast cancer such as TNBC.

Claudin 1 inhibits cell migration and increases intercellular adhesion in triple-negative breast cancer cell line.

Triple-negative "claudin 1 low" subtype represents around 15% of breast cancer and displays poor prognosis. The loss of claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes. However, studies showed a controversial role of claudin 1 in cell migration. In this study, we aimed to clarify the effect of claudin 1 on migration of mesenchymal triple-negative breast cancer cells (TNBC). We reported that transient over expression of claudin 1 in MDA-MB-231 and Hs578T "claudin 1 low" TNBC cells inhibited cell migration using wound healing and transwell migration assays. In order to investigate more specifically the involvement of claudin 1, we generated stable MDA-MB-231 clones overexpressing claudin 1. Interestingly, the level of claudin 1 was correlated to the inhibition of cell migration and to the increase of cell-cell aggregation associated with enhanced formation of ß-catenin adherens junction and occludin tight junction. Finally, we reported for the first time the key role of claudin 1 in the inhibition of cell migration process associated with the disappearance of stress fibers. These data suggest that re-expression of claudin 1 could be a promising strategy for regulating the migration of TNBC which no longer express claudin 1.

A Comparison of Environmental Concerns in Two Disparate Montana and Nevada Communities.

Asbestos refers to six fibrous minerals that occur naturally in the environment in the United States and throughout the world. Deposits may be found in soil, rocks, and deposits of other minerals such as vermiculite and talc. These naturally occurring asbestos (NOA) minerals belong to the serpentine and amphibole family of minerals. This chapter reports shared components of community-driven environmental concerns related to exposure to NOA in a rural Montana and a suburban Nevada community. The specific aim is to establish an understanding of the community and community member's primary concern(s) related to NOA in both communities. The knowledge that NOA is commonly found in areas across the United States supports the need for additional research into the health effects of environmental exposure and best-practices to reduce exposure risk while allowing communities to thrive economically.

Pro-apoptotic effect of Δ2-TGZ in "claudin-1-low" triple-negative breast cancer cells: involvement of claudin-1.

PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.

PPARγ-inactive Δ2-troglitazone independently triggers ER stress and apoptosis in breast cancer cells.

Our aim was to better understand peroxisome proliferator-activated receptor gamma (PPARγ)-independent pathways involved in anti-cancer effects of thiazolidinediones (TZDs). We focused on Δ2-troglitazone (Δ2-TGZ), a PPARγ inactive TZD that affects breast cancer cell viability. Appearance of TUNEL positive cells, changes in mitochondrial membrane potential, cleavage of poly(ADP-ribose) polymerase (PARP)-1 and caspase-7 revealed that apoptosis occurred in both hormone-dependent MCF7 and hormone-independent MDA-MB-231 breast cancer cells after 24 and 48 h of treatment. A microarray study identified endoplasmic reticulum (ER) stress as an essential cellular function since many genes involved in ER stress were upregulated in MCF7 cells following Δ2-TGZ treatment. Δ2-TGZ-induced ER stress was further confirmed in MCF7 cells by phosphorylation of pancreatic endoplasmic reticulum kinase-like endoplasmic reticulum kinase (PERK) and its target eIF2α after 1.5 h, rapid increase in activating transcription factor (ATF) 3 mRNA levels, splicing of X-box binding protein 1 (XBP1) after 3 h, accumulation of binding immunogloblulin protein (BiP) and CCAAT-enhancer-binding protein homologous protein (CHOP) after 6 h. Immunofluorescence microscopy indicated that CHOP was relocalized to the nucleus of treated cells. Similarly, in MDA-MB-231 cells, overexpression of ATF3, splicing of XBP1, and accumulation of BiP and CHOP were observed following Δ2-TGZ treatment. In MCF7 cells, knock-down of CHOP or the inhibition of c-Jun N-terminal kinase (JNK) did not impair cleavage of PARP-1 and caspase-7. Altogether, our results show that ER stress is an early response of major types of breast cancer cells to Δ2-TGZ, prior to, but not causative of apoptosis.

Initial evaluation of the Robert Wood Johnson Foundation Nurse Faculty Scholars program.

BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars (RWJF NFS) program was developed to enhance the career trajectory of young nursing faculty and to train the next generation of nurse scholars. Although there are publications that describe the RWJF NFS, no evaluative reports have been published. The purpose of this study was to evaluate the first three cohorts (n = 42 scholars) of the RWJF NFS program. METHODS: A descriptive research design was used. Data were derived from quarterly and annual reports, and a questionnaire (seven open-ended questions) was administered via Survey Monkey Inc. (Palo Alto, CA, USA). RESULTS: During their tenure, scholars had on average six to seven articles published, were teaching/mentoring at the graduate level (93%), and holding leadership positions at their academic institutions (100%). Eleven scholars (26%) achieved fellowship in the American Academy of Nursing, one of the highest nursing honors. The average ratings on a Likert scale of 1 (not at all supportive) to 10 (extremely supportive) of whether or not RWJF had helped scholars achieve their goals in teaching, service, research, and leadership were 7.7, 8.0, 9.4, and 9.5, respectively. The majority of scholars reported a positive, supportive relationship with their primary nursing and research mentors; although, several scholars noted challenges in connecting for meetings or telephone calls with their national nursing mentors. CONCLUSIONS: These initial results of the RWJF NFS program highlight the success of the program in meeting its overall goal-preparing the next generation of nursing academic scholars for leadership in the profession.

Tex 19 paralogs exhibit a gonad and placenta-specific expression in the mouse.

We have previously suggested that TEX19, a mammalian-specific protein of which two paralogs exist in rodents, could be implicated in stem cell self-renewal and pluripotency. We have established here the expression profiles of Tex19.1 and Tex19.2 during mouse development and adulthood. We show that both genes are coexpressed in the ectoderm and then in primordial germ cells (PGCs). They are also coexpressed in the testis from embryonic day 13.5 to adulthood, whereas only Tex19.1 transcripts are detected in the developing and adult ovary as well as in the placenta and its precursor tissue, the ectoplacental cone. The presence of both Tex19.1 and Tex19.2 in PGCs, gonocytes and spermatocytes opens the possibility that these two genes could play redundant functions in male germ cells. Furthermore, the placental expression of Tex19.1 can explain why Tex19.1 knockout mice show embryonic lethality, in addition to testis defects.

CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15-20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic. Little is known about CLDN1 role on the chemosensitivity of breast cancer. Our clinical data analysis reveals that CLDN1 low expression is correlated to a poor prognostic in TNBC patients. Next, the sensitivity of various TNBC "claudin-1-high" or "claudin-1-low" cells to three compounds belonging to the main class of chemotherapeutic agents commonly used for the treatment of TNBC patients: 5-fluorouracil (5-FU), paclitaxel (PTX) and doxorubicin (DOX). Using RNA interference and stable overexpressing models, we demonstrated that CLDN1 expression increased the sensitivity of TNBC cell lines to these chemotherapeutic agents. Taken together, our data established the important role of CLDN1 in TNBC cells chemosensitivity and supported the hypothesis that CLDN1 could be a chemotherapy response predictive marker for TNBC patients. This study could allow new treatment protocols creation aimed to induce CLDN1 expression in TNBCs to increase their sensitivity to chemotherapy.

Temporal and spatial SOX9 expression patterns in the course of gonad development of the caudate amphibian Pleurodeles waltl.

The SOX family of transcription factors is thought to regulate gene expression in a wide variety of developmental processes. Namely, SOX9 expression is conserved in vertebrate sex determination or differentiation. Nevertheless, information about caudate amphibians is lacking. In this study, we provide data on Pleurodeles waltl, a species that displays a ZZ/ZW genetic mode of sex determination and a temperature-dependent mechanism of female-to-male sex reversal. Phylogenetic analysis of SOX9 P. waltl ortholog reveals that the deduced protein segregates from the group of anuran and could be more closely related to amniote than to anamniote. However, SOX9 lacks the PQA-rich domain present in amniotes. In larvae, SOX9 is expressed in both sexes in gonad-mesonephros complexes as soon as stage 42, before gonad differentiation. At stage 54(60d) at which testis differentiation is already in progress, analyses of isolated gonads reveal a male-enriched expression of SOX9, which was quantified by real-time PCR. At the end of metamorphosis (stage 56), SOX9 shows a nuclear localization only in the testis. In adults, SOX9 is still expressed in testes and ovaries. In the ovary, SOX9 is found in oocytes from stage I to stage VI but it is never detected in the nucleus. Our results suggest that in P. waltl, like in non mammalian vertebrates, SOX9 could play a role during the late phase of gonad differentiation rather than in sex determination. Its role in germ cells of the adult ovary has still to be elucidated.

Applying indigenous community-based participatory research principles to partnership development in health disparities research.

This case study of community and university research partnerships utilizes previously developed principles for conducting research in the context of Native American communities to consider how partners understand and apply the principles in developing community-based participatory research partnerships to reduce health disparities. The 7 partnership projects are coordinated through a National Institutes of Health-funded center and involve a variety of tribal members, including both health care professionals and lay persons and native and nonnative university researchers. This article provides detailed examples of how these principles are applied to the projects and discusses the overarching and interrelated emergent themes of sharing power and building trust.

New troglitazone derivatives devoid of PPARγ agonist activity display an increased antiproliferative effect in both hormone-dependent and hormone-independent breast cancer cell lines.

Numerous recent studies indicate that most anticancer effects of PPARγ agonists like thiazolidinediones are the result of PPARγ-independent pathways. These conclusions were obtained by several approaches including the use of thiazolidinedione derivatives like Δ2-Troglitazone (Δ2-TGZ) that does not activate PPARγ. Since biotinylation has been proposed as a mechanism able to increase the specificity of drug delivery to cancer cells which could express a high level of vitamin receptor, a biotinylated derivative of Δ2-TGZ (bΔ2-TGZ) has been synthetized. In the present article, we have studied the in vitro effects of this molecule on both hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cells. In both cell lines, bΔ2-TGZ was more efficient than Δ2-TGZ to decrease cell viability. bΔ2-TGZ was also more potent than Δ2-TGZ to induce the proteasomal degradation of cyclin D1 in both cell lines and those of ERα in MCF-7 cells. However, in competition experiments, the presence of free biotin in the culture medium did not decrease the antiproliferative action of bΔ2-TGZ. Besides, other compounds that had no biotin but that were substituted at the same position of the phenolic group of the chromane moiety of Δ2-TGZ decreased cell viability similarly to bΔ2-TGZ. Hence, we concluded that the increased antiproliferative action of bΔ2-TGZ was not due to biotin itself but to the functionalization of the terminal hydroxyl group. This should be taken into account for the design of new thiazolidinedione derivatives able to affect not only hormone-dependent but also hormone-independent breast cancer cells in a PPARγ-independent pathway.

[An overview of pluripotent stem cell lines]. / Tour d'horizon des lignées de cellules souches pluripotentes.

More than 20 years ago, the finding of a population of cells with the ability of self-renewal and differentiation inside teratocarcinomas (embryonic carcinoma cells) would allow their direct derivation from preimplantation embryos (embryonic stem cells, ESC). The phenomenal pluripotency properties of those cells and the therapeutical potential of their human counterparts triggered a massive interest from the scientific community. The research on the field of pluripotent stem cells improved a lot and many ES-like pluripotent stem cells of several embryonic and adult sources were described. Next step has been the reprogramming of terminally differentiated cells into embryonic cells, with the aim to produce patient-specific stem cells. The recent breakthrough has been the in vitro reprogramming of adult cells into ES cell-like cells named induced pluripotent stem cells (iPSC), using four transcription factors (Oct4, Sox2, Klf4, c-Myc). Even though some challenges remain, we are now one step closer to the eventuality to use these cells for clinical purposes. In this review we propose to analyse the several pluripotent stem cells existing today.

Barriers and facilitators to the incorporation of environmental health into public health nursing practice.

OBJECTIVES: To describe the environmental health (EH) demands placed on public health nurses (PHNs) as well as the barriers and facilitators to incorporating EH into PHN practice. DESIGN AND SAMPLE: A cross-sectional multimode (Web and pencil/paper) survey was used to collect data from PHNs in 1 rural western state. Research participants included 141 PHNs from a total of 228 survey invitations (61% response). MEASURES: A 39-item questionnaire was developed to measure the frequency of EH demands experienced by PHNs as well as the barriers and facilitators to the incorporation of EH into PHN practice and standard demographics. RESULTS: Significant numbers of PHNs reported less than baccalaureate preparation (29%), suggesting that EH competencies cannot be assumed. PHNs are often asked for basic EH information and cite lack of time and lack of interest on the part of the populations being cared for as barriers to incorporating EH into their practice. Facilitators included free or inexpensive continuing education programs offered via the Internet and additional Internet resources or staff resource people. CONCLUSION: PHNs represent a significant portion of the public health workforce and have implied and explicit mandates to address EH issues in their practice. Resources should be directed toward helping PHNs become better prepared to address the current and future EH needs of populations.

Developing a nursing personnel policy to address body art using an evidence-based model.

BACKGROUND: An increase in the prevalence of body art as a form of self-expression has motivated health care organizations to develop policies addressing nursing personnel's body art. METHODS: A systematic review of literature on body art was completed and a telephone survey of 15 hospitals was conducted to query existing policy statements addressing nursing personnel's body art. RESULTS: The literature established no prevalence of body art among nurses or effect of nurses' body art. Of the 13 hospitals (86%) that shared their policy on body art, none provided a rationale or references to support their existing policies. CONCLUSION: A lack of published evidence identifying the effect of body art among nurses shifts the burden of determining care outcomes to the leadership of individual hospitals. Further research on patients' perception of nursing personnel with visible body art, using an evidence-based model, is recommended.

Tex19, a mammalian-specific protein with a restricted expression in pluripotent stem cells and germ line.

Although the properties of embryonic stem (ES) cells make these cells very attractive in the field of replacement therapy, the molecular mechanisms involved in the maintenance of their pluripotency are not fully characterized. Starting from the observation that most pluripotent markers are also expressed by spermatogonia stem cells, we identified Tex19 as a new potential pluripotency marker. We show that Tex19 is a mammalian-specific protein duplicated in mouse and rat, renamed Tex19.1 and Tex19.2, whereas only one form is found in human. In mouse, both forms are localized on chromosome 11 and transcribed in opposite directions. Tex19 proteins are well conserved, showing two highly conserved domains that do not present any similarity with any other known domains. We show that Tex19.2 is specifically detected in the male somatic gonad lineage, whereas Tex19.1 expression is very similar to that of Oct4. Transcripts are maternally inherited, and expression starts as soon as the early embryo and later is limited to the germ line. Tex19.1 transcripts were also detected in mouse pluripotent stem cells, and expression of Tex19.1, like that of Oct4, decreases after murine embryonic stem and germ cell differentiation. Human TEX19 was more closely related to murine Tex19.1 and was also detected in adult testis and in undifferentiated ES cells. By immunofluorescence, we found that Tex19.1 protein localizes to the nucleus of mouse ES and inner cell mass cells. All these results suggest that Tex19.1, as well as human TEX19, could be a new factor involved in the maintenance of self-renewal or pluripotency of stem cells.

Methylmercury risk and awareness among American Indian women of childbearing age living on an inland northwest reservation.

American Indian women and children may be the most overrepresented among the list of disparate populations exposed to methylmercury. American Indian people fish on home reservations where a state or tribal fishing license (a source of advisory messaging) is not required. The purpose of this study was to examine fish consumption, advisory awareness, and risk communication preferences among American Indian women of childbearing age living on an inland Northwest reservation. For this cross-sectional descriptive study, participants (N=65) attending a Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinic were surveyed between March and June 2006. An electronic questionnaire adapted from Anderson et al. (2004) was evaluated for cultural acceptability and appropriateness by tribal consultants. Regarding fish consumption, approximately half of the women surveyed (49%) indicated eating locally caught fish with the majority signifying they consumed medium- and large-size fish (75%) that could result in exposure to methylmercury. In addition, a serendipitous discovery indicated that an unanticipated route of exposure may be fish provided from a local food bank resulting from sportsman's donations. The majority of women (80%) were unaware of tribal or state fish advisory messages; the most favorable risk communication preference was information coming from doctors or healthcare providers (78%). Since the population consumes fish and has access to locally caught potentially contaminated fish, a biomonitoring study to determine actual exposure is warranted.

Rural public health policy models to address an evolving environmental asbestos disaster.

The health-related dangers of asbestos exposure were recognized early in the 20th century when occupational exposure was found to be associated with excess pneumoconiosis among asbestos industry workers. Today, the epicenter for examining the public health effects and the human toll that this toxin has had on a population is located in the rural community of Libby, MT. Rurality and multideterminants of health frame both the history of asbestos-related disease and the service/policy challenges within a community dealing with chronic illness and designation as a Superfund clean-up site. Despite efforts by public health advocates to address the lingering aftermath of an environmental disaster in this community, policy gaps exist that continue to impact the population's health. The purpose of this paper is to describe the history and outcomes of asbestos exposure in a rural community and discuss 3 models that provide public health policy insights related to rural health and health care for a community affected by both a sentinel and ongoing environmental event.

Negotiating three worlds: academia, nursing science, and tribal communities.

PURPOSE: The purpose of this article is to use a cross-cultural model to guide the exploration of common issues and the dynamic interrelationships surrounding entrée to tribal communities as experienced by four nursing research teams. METHOD: Members of four research teams discuss the primary lessons learned about successful strategies and challenges encountered during their projects' early stages. RESULTS: Understanding the cultural values of relationship and reciprocity is critical to the success of research projects conducted in Native American communities. DISCUSSION: Conducting cross-cultural research involves complex negotiations among members of three entities: academia, nursing science, and tribal communities. The lessons learned in these four research projects may be instructive to investigators who have the opportunity to conduct research with tribal communities.

Association of Community Health Nursing Educators: disaster preparedness white paper for community/public health nursing educators.

The Association of Community Health Nursing Educators (ACHNE) has developed a number of documents designed to delineate the scope and function of community/public health nursing educators, researchers, and practitioners. In response to societal issues, increased emphasis on disaster preparedness in nursing and public health, and requests from partner organizations to contribute to curriculum development endeavors regarding disaster preparedness, the ACHNE Disaster Preparedness Task Force was appointed in spring 2007 for the purpose of developing this document. Task Force members developed a draft of the document in summer and fall 2007, input was solicited and received from ACHNE members in fall 2007, and the document was approved and published in January 2008. The members of ACHNE extend their appreciation to the members of the Emergency Preparedness Task Force for their efforts: Pam Frable, N.D., R.N.; Sandra Kuntz, Ph.D., C.N.S.-B.C. (Chair); Kristine Qureshi, D.N.Sc., C.E.N., R.N.; Linda Strong, Ed.D., R.N. This white paper is aimed at meeting the needs of community/public health nursing educators and clarifying issues for the nursing and public health communities. ACHNE is committed to promotion of the public's health through ensuring leadership and excellence in community and public health nursing education, research, and practice.