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The mammary gland is a secretory organ, which develops as a network of growing epithelial ducts composed of luminal and basal cells that invade the surrounding adipose tissue through a series of developmental cycles. Mammary stem cells (MaSCs) maintain an accurate tissue homeostasis, and their proliferation and cell fate determination are regulated by multiple hormones and local factors. The WNT pathway plays a critical role in controlling the enormous tissue expansion and remodeling during mammary gland development through the maintenance and differentiation of MaSCs, and its deregulation has been implicated in breast cancer (BC) initiation and progression. The R-spondins (RSPOs) are four secreted proteins that strongly enhance target cell sensitivity to WNT ligands. Moreover, leucine-rich repeat-containing G-protein-coupled receptors (LGRs) 4–6 are considered obligate high-affinity receptors for RSPOs and have been described as stem cell markers. Importantly, elevated RSPO expression has been recently identified in several tumor types from patients, including BC, and it has been reported that they play a significant role in mammary tumor progression in experimental models. In this review, exploring our present knowledge, we summarize the role of the RSPOLGR axis as a WNT-enhancing signaling cascade in the MaSC compartment and during the normal and neoplastic mammary gland development. In addition, we include an updated expression profile of the RSPOs and their action mediators at the cell membrane, the LGRs, and the ubiquitin-ligases ZNRF3/ RNF43, in different BC subtypes. Finally and based on these data, we discuss the significance of tumor-associated alterations of these proteins and their potential use as molecular targets for detection and treatment of BC. Fil: Tocci, Johanna Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Felcher, Carla María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Garcia Sola, Martin Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Kordon, Edith Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Introduction: Serum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis. Aim: We assessed the prognostic role of SUA in patients with and without MS. Methods: We used data from the multicentre Uric Acid Right for Heart Health study and considered cardiovascular mortality (CVM) as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. Results: A total of 9589 subjects (median age 58.5 years, 45% males) were included in the analysis, and 5100 (53%) patients had a final diagnosis of MS. After a median follow-up of 142 months, we observed 558 events. Using a previously validated cardiovascular SUA cut-off to predict CVM (> 5.1 mg/dL in women and 5.6 mg/dL in men), elevated SUA levels were significantly associated to a worse outcome in patients with and without MS (all p < 0.0001) and provided a significant net reclassification improvement of 7.1% over the diagnosis of MS for CVM (p = 0.004). Cox regression analyses identified an independent association between SUA and CVM (Hazard Ratio: 1.79 [95% CI, 1.15–2.79]; p < 0.0001) after the adjustment for MS, its single components and renal function. Three specific combinations of the MS components were associated with higher CVM when increasing SUA levels were reported, and systemic hypertension was the only individual component ever-present (all p < 0.0001). Conclusion: Increasing SUA levels are associated with a higher CVM risk irrespective of the presence of MS: a cardiovascular SUA threshold may improve risk stratification. Graphic abstract: [Figure not available: see fulltext.] © 2021, The Author(s).

Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 [95% CI, 1.21-1.93]) or CVM (hazard ratio, 2.08 [95% CI, 1.146-2.97]; P

Tristetraprolin (TTP), an mRNA-binding protein that negatively controls levels of inflammatory factors, is highly expressed in the lactating mouse mammary gland. To determine the biological relevance of this expression profile, we developed bi-transgenic mice in which this protein is specifically down-regulated in the secretory mammary epithelium in the secretory mammary epithelium during lactation. Our data show that TTP conditional KO mice produced underweight litters, possibly due to massive mammary cell death induced during lactation without the requirement of additional stimuli. This effect was linked to overexpression of inflammatory cytokines, activation of STAT3 and down-regulation of AKT phosphorylation. Importantly, blocking TNFa activity in the lactating conditional TTP KO mice inhibited cell death and similar effects were observed when this treatment was applied to wild-type animals during 48 h after weaning. Therefore, our results demonstrate that during lactation TTP wards off early involution by preventing the increase of local inflammatory factors. In addition, our data reveal the relevance of locally secreted TNFa for triggering programmed cell death after weaning. Fil: Goddio, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Gattelli, Albana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Tocci, Johanna Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Perez Cuervo, Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Stedile, Micaela Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Stumpo, Deborah. National Institute Of Environmental Health Science; Estados Unidos Fil: Hynes, Nancy. Friedrich Miescher Institute For Biomedical Research; Suiza Fil: Blackshear, Perry. National Institute Of Environmental Health Science; Estados Unidos Fil: Meiss, Roberto P.. Academia Nacional de Medicina de Buenos Aires; Argentina Fil: Kordon, Edith Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina

// Nadia Cambados 1 , Thomas Walther 2, 4, 5 , Karen Nahmod 6 , Johanna M. Tocci 1 , Natalia Rubinstein 1, 7 , Ilka Bohme 2, 3 , Marina Simian 8 , Rocio Sampayo 8 , Melisa Del Valle Suberbordes 1 , Edith C. Kordon 1, 9 and Carolina Schere-Levy 1 1 Instituto de Fisiologia, Biologia Molecular y Neurociencias, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina 2 Department of Obstetrics, University of Leipzig, Leipzig, Germany 3 Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany 4 Department Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork, Ireland 5 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany 6 Department of Pediatrics, Immunology, Allergy and Rheumatology, Center for Human Immunobiology, Texas Children’s Hospital, Houston, Texas, USA 7 Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina 8 Instituto de Nanosistemas, Universidad Nacional de San Martin, Buenos Aires, Argentina 9 Departmento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina Correspondence to: Carolina Schere-Levy, email: carolinaschere@gmail.com Keywords: AKT, angiotensin II, angiotensin-(1-7), breast cancer cells, epithelial–mesenchymal transition Received: November 04, 2016 Accepted: June 02, 2017 Published: July 17, 2017 ABSTRACT Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, has been implicated in multiple aspects of cancer progression such as proliferation, migration, invasion, angiogenesis and metastasis. Ang-(1-7), is a biologically active heptapeptide, generated predominantly from AngII by the enzymatic activity of angiotensin converting enzyme 2. Previous studies have shown that Ang-(1-7) counterbalances AngII actions in different pathophysiological settings. In this study, we have analysed the impact of Ang-(1-7) on AngII-induced pro-tumorigenic features on normal murine mammary epithelial cells NMuMG and breast cancer cells MDA-MB-231. AngII stimulated the activation of the survival factor AKT in NMuMG cells mainly through the AT1 receptor. This PI3K/AKT pathway activation also promoted epithelial–mesenchymal transition (EMT). Concomitant treatment of NMuMG cells with AngII and Ang-(1-7) completely abolished EMT features induced by AngII. Furthermore, Ang-(1-7) abrogated AngII induced migration and invasion of the MDA-MB-231 cells as well as pro-angiogenic events such as the stimulation of MMP-9 activity and VEGF expression. Together, these results demonstrate for the first time that Ang-(1-7) counteracts tumor aggressive signals stimulated by AngII in breast cancer cells emerging the peptide as a potential therapy to prevent breast cancer progression.

We developed Behaviorally Anchored Rating Scales (BARS) for measuring teaching practice, and compared them to the well-established Framework for Teaching (FfT; Danielson, 2013). BARS provide behavioral anchors delineating levels of performance via a set of behaviors. Our BARS focused on two dimensions of teaching, leading a classroom discussion and making content and practices explicit. We examined how a) rater agreement for BARS compares to rater agreement using the FfT, and b) how BARS and the FfT compare regarding perceived ease of use, perceived accuracy, and perceived advantages and disadvantages. Nineteen raters, who are users of the FfT and were trained to use BARS, independently evaluated video-taped teacher lessons using both methods. Rater agreement was higher for the FfT, which may, in part, be a factor of the raters' greater experience with that rating system. Nonetheless, raters reported that there are many aspects of BARS that are desirable.

We have recently identified R-spondin3 (RSPO3) as a novel key modulator of breast cancer development that may become a potential target for treatment of the basal subtype, which lacks efficient therapeutic options to date. RSPO3 is expressed in the basal stem cell-enriched compartment of mouse mammary glands whereas it is absent in the mature luminal cells. RSPO3 knockdown in mouse mammary tumor cells reduces canonical Wnt signaling pathway, epithelial-to-mesenchymal transition (EMT)-like features, migration capacity, and tumor formation in vivo. To evaluate the relevance of RSPO3 in human breast cancer, we analyzed samples from 75 patients with ductal infiltrating breast carcinomas, where we found a high prevalence of positive immunoreactivity for RSPO3 (70%). Expression data of The Cancer Genome Atlas Network from 1985 human breast carcinoma samples showed that RSPO3 is primarily expressed in Claudin-low breast cancer subtype, which is characterized for having stem cells features. In culture assays revealed that knockdown of RSPO3 expression reduced SOX2 expression and impaired mammary tumor cell ability to form mammospheres. Previous reports suggested the potential involvement of RUNX1-CBFβ on RSPO3 transcription in mammary tumor cells. Therefore, we evaluated if pharmacologic inhibition of RUNX1 activity would reduce RSPO3 expression and activity in the cancer stem cell compartment. Treatment of breast cancer cells with AI-10-104, a small molecule that inhibits CBFβ-RUNX interaction, reduced RSPO3 mRNA and protein levels, and reduced the migration ability of MDA-MB231 breast cancer cells, ability that was recovered upon treatment with recombinant RSPO3. In addition, AI-10-104 inhibited the expression of canonical Wnt pathway targets, EMT and stem-cell markers. Therefore, our results demonstrate that inhibition of RUNX-CBFβ transcriptional activity leads to a down-regulation of RSPO3 expression, constituting a new molecular target for therapeutic modulation in breast cancer treatment. Citation Format: Carla M. Felcher, Johanna M. Tocci, Martin E. Garcia Sola, John H. Bushweller, Lucio H. Castilla, Edith C. Kordon. Inhibition of RUNX-CBFβ binding reduces RSPO3 expression and EMT features in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5041.

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes, including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among patients with breast cancer. Thus, we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers., Facultad de Ciencias Médicas, Centro de Investigaciones Inmunológicas Básicas y Aplicadas

Despite the improvements in the management of hypertension during the last three decades, it continues to be one of the leading causes of cardiovascular morbidity and mortality worldwide. Effective and sustained reductions in blood pressure (BP) reduce the incidence of myocardial infarction, stroke, congestive heart failure and cardiovascular death. However, the proportion of patients who achieve the recommended BP goal (

Using information and communication technologies, it is applied the conceptual framework of Teaching to understand an e-learning chemistry course , at the Faculty of Engineering, La Plata National University. It was designed a didactic sequence centered on understanding. It was taken the topic of "alternative energies" as thread , considering the concept of chemical reaction as a central generative topic. The teaching sequence starts from a schematic image showing the process of obtaining energy through alternative sources and was accompanied by questions, they are answered by students in individual blogs. The research process with guided tutorial is done in the discussion forums on-line, up to the synthesis stage, where the final answers in the blogs reflects the level of understanding achieved. The aim to improve the performance of understanding was reached by almost all the students.

We performed comprehensive structure-activity relationship (SAR) studies on the peptide portion of antiproliferative factor (APF), a sialylated frizzled-8 related glycopeptide that inhibits normal bladder epithelial and urothelial carcinoma cell proliferation. Glycopeptide derivatives were synthesized by solid-phase methods using standard Fmoc chemistry and purified by RP-HPLC; all intermediate and final products were verified by HPLC-MS and NMR analyses. Antiproliferative activity of each derivative was determined by inhibition of (3)H-thymidine incorporation in primary normal human bladder epithelial cells. Structural components of the peptide segment of APF that proved to be important for biological activity included the presence of at least eight of the nine N-terminal amino acids, a negative charge in the C-terminal amino acid, a free amino group at the N-terminus, maintenance of a specific amino acid sequence in the C-terminal tail, and trans conformation for the peptide bonds. These data provide critical guidelines for optimization of structure in design of APF analogues as potential therapeutic agents.

Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability. Fil: Recouvreux, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Grasso, Esteban Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Echeverria, Pablo Christian. Universidad de Ginebra; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rocha Viegas, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Castilla, Lucio Hernán. University Of Massachussets. Medical School; Estados Unidos Fil: Schere Levy, Carolina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Tocci, Johanna Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Kordon, Edith Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Rubinstein, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina

Antiproliferative factor (APF) is a low molecular weight sialoglycopeptide that is secreted by bladder cells from interstitial cystitis patients and is a potent inhibitor of both normal bladder epithelial and bladder carcinoma cell proliferation. We hypothesized that APF may produce its antiproliferative effects by binding to a transmembrane receptor. This study demonstrates that cytoskeleton-associated protein 4/p63 (CKAP4/p63), a type II transmembrane receptor, binds with high affinity to APF. The antiproliferative activity of APF is effectively inhibited by preincubation with anti-CKAP4/p63-specific antibodies, as well as by short interfering RNA knockdown of CKAP4/p63. Immunofluorescent confocal microscopy showed co-localization of anti-CKAP4/p63 and rhodamine-labeled synthetic APF binding in both cell membrane and perinuclear areas. APF also inhibits the proliferation of HeLa cervical carcinoma cells that are known to express CKAP4/p63. These data indicate that CKAP4/p63 is an important epithelial cell receptor for APF.

This review article focuses primarily on the work carried in our laboratories over the last few years using luminescent and colorimetric sensors, where the anion recognition occurs through hydrogen bonding in organic or aqueous solvents. This review begins with the story of the discovery of fluorescent photoinduced electron transfer (PET) sensors for anions using charged neutral urea or thiourea receptors where both fluorescent and NMR spectroscopic methods monitored anion recognition. This work led to the development of dual luminescent and colorimetric anion sensors based on the use of the ICT based naphthalimide chromophore, where ions such as fluoride gave rise to changes in both the fluorescence and the absorption spectra of the sensors, but at different concentrations. Here, the former changes were due to hydrogen bonding interactions, whereas the latter was due to the deprotonation of acidic protons, giving rise to the formation of the bifluoride anion (HF2−). Modification of the 4-amino-l,8-naphthalimide moiety has facilitated the formation of colorimetric anion sensors that work both in organic or aqueous solutions. Such charge neutral receptor motifs have also been incorporated into organic scaffolds with norbomyl and calixarene backbones, which have enabled us to produce anion directed self-assembled structures.

The cancer stem cell theory suggests the existence of cells within breast cancers that possess the ability to self-renew and differentiate, albeit in a deregulated manner, which sustains tumor progression. Therefore, latent breast tumors and/or their metastasis may eventually resume growth thorough signals impacting on cancer stem cells and their niche. Since it has been determined that the Wingless Related Protein (Wnt) signaling is a likely niche factor and regulator of Mammary Stem Cells dynamics, it is conceivable that this pathway play a significant role in the “awakening” of dormant tumors. We have previously shown that in virgin females, MMTV-induced pregnancy-dependent (ER+PR+) tumor transplants were able to remain dormant for up to 300 days, but were able to resume growth after hormone stimulation. In a subsequent transplant generation, all these tumors became ER−PR− and grew in virgin females, indicating that cancer dormancy facilitated progression to hormone-independence. Our data also showed that mutations altering expression of genes involved in the Wnt pathway were prone to be selected during progression. To gain more insight into the mechanisms underlying these observations, we compared the gene expression profile of tumors that either underwent or not dormancy before progressing to hormone-independency. Confirming our previously reported data, we found that the most significant up-regulated gene in hormone-independent tumors that progressed after dormancy was Wnt1. In addition, in this group we have determined a systematic down-modulation of previously described mediators of normal pubertal mammary gland development. Using a hierarchical clustering analysis to classify breast cancer patients, we have also identified a specific group of breast carcinomas with significant modulation of genes also deregulated in the MMTV-induced tumors that resumed growth after dormancy. Interestingly, that group of human samples was mainly composed by patients with basal-like breast carcinomas, which also showed down-regulation of genes associated to pubertal mammary development. Therefore, we believe that the cluster of co-regulated genes in basal human breast cancer and mouse mammary tumors resuming growth after dormancy might be mechanistically associated to the activation of Wnt pathway, which might induce proliferation from mammary progenitor basal cells.

The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells.

The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells.

Tristetraprolin (TTP) is a RNA-binding protein that inhibits the expression of pro-inflammatory cytokines and invasiveness-associated genes. TTP levels are decreased in many different cancer types and it has been proposed that this protein could be used as a prognostic factor in breast cancer. Here, using publicly available DNA microarray datasets, “serial analysis of gene expression” libraries and qRT-PCR analysis, we determined that TTP mRNA is present in normal breast cells and its levels are significantly decreased in all breast cancer subtypes. In addition, by immunostaining, we found that TTP expression is higher in normal breast tissue and benign lesions than in infiltrating carcinomas. Among these, lower grade tumors showed increased TTP expression compared to higher grade cancers. Therefore, these data indicate that TTP protein levels would provide a better negative correlation with breast cancer invasiveness than TTP transcript levels. In mice, we found that TTP mRNA and protein expression is also diminished in mammary tumors. Interestingly, a strong positive association of TTP expression and mammary differentiation was identified in normal and tumor cells. In fact, TTP expression is highly increased during lactation, showing good correlation with various mammary differentiation factors. TTP expression was also induced in mammary HC11 cells treated with lactogenic hormones, mainly by prolactin, through Stat5A activation. The effect of this hormone was highly dependent on mammary differentiation status, as prolactin was unable to elicit a similar response in proliferating or neoplastic mammary cells. In summary, these studies show that TTP expression is strongly linked to the mammary differentiation program in human and mice, suggesting that this protein might play specific and relevant roles in the normal physiology of the gland., Facultad de Ciencias Médicas, Centro de Investigaciones Inmunológicas Básicas y Aplicadas

This statement, made by a sixth grade student at the conclusion of her working on a performance-based mathematics activity, captures an important feature of such an activity—that it is a realistic problem which holds meaning within the student's under standing of the world. Rather than math ematics problems being presented as small-size, isolated ("why this?") type of exercises, high quality performance activi ties require the students to use their ma thematic skills and knowledge in a larger, applied real-life context. The activity completed by this sixth grader is part of the PACKETSTM Program for Middle School Mathematics, a research based performance assessment program cur rently under developmentby the Educational Testing Service (ETS). The PACKETS Pro gram is a set of classroom-based materials for teachers to use as part of their instruc tional program. The activities are designed in such a way that student learning is pro moted at the same time that the teacher is

Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR- and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation. Fil: Beguelin, Wendy. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Cayrol, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Rivas, Martin Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Rosemblit, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Tocci, Johanna Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Charreau, Eduardo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina

Antiproliferative factor (APF), a sialylated glycopeptide secreted by explanted bladder epithelial cells from interstitial cystitis/painful bladder syndrome (IC/PBS) patients, and its unsialylated analogue (as-APF) significantly decrease proliferation of bladder epithelial cells and/or certain carcinoma cell lines in vitro. We recently reported a structure-activity relationship profile for the peptide portion of as-APF and revealed that truncation of the C-terminal alanine did not significantly affect antiproliferative activity. To better understand the structural basis for the maintenance of activity of this truncated eight amino acid as-APF (as-APF8), we synthesized several amino acid-substituted derivatives and studied their ability to inhibit bladder epithelial cell proliferation in vitro as well as their solution conformations by CD and NMR spectroscopy. While single amino acid changes to as-APF8 often strongly reduced activity, full potency was retained when the trivaline tail was replaced with three alanines. The Ala(6-8) derivative 9 is the simplest, fully potent APF analogue synthesized to date.

The purpose of this study was to investigate the relationships of attitudes toward mathematics with mathematics achievement, parental support, and gender. A secondary analysis was conducted using nationally representative samples of 13-year-old students in the United States (n = 3,846) and Thailand (n = 3,528), which were collected as a part of the Second International Mathematics Study (Garden, 1987). A multivariate general linear model was used to analyze the data within each country. Four attitude scales (Mathematics and Myself, Mathematics and Society, Mathematics as a Male Domain, and Mathematics Anxiety) were used as the criterion variables. Mathematics achievement, parental support, and gender were used as the predictor variables. In both countries, achievement, parental support, and gender were significant predictors of attitudes toward mathematics. The data suggest that there are gender differences in attitudes toward mathematics for 13-year-olds in the United States and Thailand. The lar...

SR58611A is a selective beta(3)-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect. SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 microM) but not chronic (10 mg/kg, p.o.) administration. These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s.

This study addresses three questions in a cross-nationl context: Are there age, gender, and country differences in adolescents' perceptions of social studies classroom climate? Are there correlations between students' political attitudes and perceived classroom climate? Does the use of a value analysis strategy in the discussion of controversial issues relate to students' political attitudes? The literature relevant to these three themes was examined, and questionnaires were administered to 1,459 students in social studies classes in the United States, the United Kingdom, West Germany, Denmark, and the Netherlands. Half of the students' classes participated in a semester-long treatment in which a value analysis treatment was used.

The reduction mechanism of the bronze Li(1.2)V3O8 in nonaqueous Li cells has been elucidated. Upon Li(+) insertion, a solid solution is formed with an upper composition of Li(approximately 3)V3O8. Within this composition range, Li(+) progressively fills the tetrahedral sites available in the unit cell. Four such sites are supposed to be filled at the upper composition limit. Beyond this, a new phase is nucleated to accommodate excess Li(+), this resulting in a constant cell's OCV. Li(+) insertions not greater than 3.0 eq/mol are reversible, as shown by the cycling behavior and the X-ray paterns. Owing to the outstanding structure stability and to the high speed of Li(+) diffusion in Li(1.2)V3O8, extended cycling at high rates is achievable with cells based on this bronze. 445 cycles at discharge rates variable in the range of 2-10 mA/sq cm have been obtained. 13 references.

With the aim of optimizing the performance of Li/Li1+xV3O8 cells, several aspects of cathode preparation have been examined. The influence of synthesis technique, nature and amount of conductive additives, compacting pressure, cathode loading, and particle size, has been investigated. Furthermore, the role played by the solutions on cathode efficiency has been outlined. The formulations which perform best are based on small-sized particles blended with about 20% acetylene black and compacted at very high pressures to improve the contact between particles. Such cathodes can provide high capacities at high rates and good cycling efficiencies. The kinetic loss of capacity, observed during the first few cycles, may be alleviated by choosing solutions with high fluidity and conductivity.

The enthalpies of Li + insertion into two V oxides of interest as cathodes for secondary Li batteries, i.e. V 6 O 13 and Li 1+ x V 3 O 8 have been directly measured by solution calorimetry. By comparing the integral molar enthalpies Δ H 0 / x with the corresponding Δ G 0 / x values, Δ S 0 / x higher than expected have been found for Li 1+ x V 3 O 8 . This has been correlated to a reorganization of its distorted structure induced by the initial Li + insertion. Two other cathode materials, having the same variation of the potential with Li + content, i.e. MoO 3 and (Mo 0.3 V 0.7 ) 2 O 5 , show even higher Δ S 0 / x values. The entropic values stemming from structural reorganizations add to the configurational entropies of inserted ions in determining the initial profile of E as a function of Li + .

A calorimetric study of the ionization process of 2,5-dihydroxybenzoic acid, in water—DMSO mixtures, ranging from pure water up to 0.8 mole fraction is presented. This compound shows a very different behaviour with respect to the 2,3-dihydroxy derivative because of the two hydroxyl groups which, in the relative para position, stabilize and delocalize the charge on the anion. For this reason, 2,5-(OH) 2 PhCOOH is, with the exception of 2,6-(OH) 2 PhCOOH, the strongest acid in an acidity scale of dihydroxy derivatives.

The recent commercial introduction of a method for detecting albumin in meconium makes screening for cystic fibrosis feasible for many hospitals. If the tests is adopted, confirmatory tests should be available. Quantitative analyses of sweat for sodium by flame photometry and for chloride by silver titration and ion-sleective electrodes are now used as confirmatory tests. We compare results of these confirmatory methods applied to presons with cystic fibrosis, respiratory disorders, or digestive disorders, and to control subjects.

A calorimetric study of six α-amino acids is presented. These form three couples which belong to three different classes of α-amino acids. Different values of the ionization enthalpy can be related to the structure variation of the R substituent group. A sharp difference was found between hydrophobic and hydrophilic R groups.

Nonylbenzo-hexaquinone, an insoluble polymer of high theoretical specific capacity (0.489 A h/g), has been used as the cathode material in organic electrolytes instead of benzoquinone and its derivatives. The reduction mechanism is rather complex and involves two main steps, the first of which, as shown by cyclic voltammetry, is, in turn, a multi-process step. It corresponds to the uptake of 6 Li+/molecule or 0.234 A h/g. The second step tends to merge with electrolyte reduction, thus preventing a correct estimate of the total number of Li+ involved. The first reduction step is partly reversible (2.0–2.5 e− out of 6), whereas the second is irreversible. 150 cycles were obtained when cycling was performed between 2.0 and 3.5 V at 0.5 mA/cm2. A typical energy density during cycling was 127 W h/kg (electrodes only, additives included).

γ-Aminobutyric acid was found in the kidney and in some other tissues in six children. The material obtained was characterized by chromatography on cation exchange columns and on thin layer chromatography, by electrophoresis, and by the synthesis of the trimethylamino derivative, the chromatographic and electrophoretic behavior, melting point, and crystal structure of the AuCl3 salt of which were identical with those of the derivative synthesized from authentic γ-aminobutyric acid. It is concluded that in man, unlike the animals reported, γ-aminobutyric acid is not a unique constituent of the central nervous system.

Oral phenylalanine loads were given to 15 mothers of children with cleft lip and palate defects and 19 control women. Four of the 15 mothers exhibited unusual tolerance curves, i.e., the phenylalanine levels did not rise appreciably during four hours nor did the tyrosine levels increase normally. Two of the women studied also showed a deviation from normal in the appearance of tyrosine in the blood after a tyrosine load. Attempts to stress the mothers who exhibited a normal response to the single phenylalanine load by giving them a double load were not successful. The possible implications of these findings are discussed.

The daily para-hydroxyphenylacetic acid (p-HPAA) excretion was examined in four adults under varying dietary intake. The diet varied considerably in the content of precursor amino acid, tyrosine and other phenolic acids. When the subjects were on a complete fast but for water, the total volume of urine almost doubled, the creatinine excretion doubled but the p-HPAA excretion remained approximately the same for each individual. These experiments indicate that the daily excretion of p-HPAA may be independent of dietary intake and rather constant from one day to the next in individuals. Differences occur between individuals in the daily excretion of p-HPAA while receiving the same diet, but they are within a relatively narrow range. The 24-h excretion of p-HPAA was examined in 53 people of all ages. The p-HPAA excretion begins to increase around the age of puberty. However, there were several children and adults in the study who excreted no detectable amount of p-HPAA. Tyrosine loads were given to 2 people and the urinary p-HPAA was determined over several hours. While only a small percentage of the fed tyrosine was converted to p-HPAA it is apparently a large contributor to this pool.

Following a preliminary investigation, Li/Li1+xV3O8 cells have been examined. Using samples of low x content, up to 3 eq Li+ could be accepted both chemically and electrochemically by one mole of active material. Li+ is accomodated in the tetrahedral sites existing between the (V3O8)(1+x)- layers. Li+ jumping from site to site is fast and permits high rate capabilities: at 10 mA/cm2, 1.1 eq Li+ per mole could still be inserted. The structure does not show irreversible alterations upon extended lithiation, allowing long cycle lives to be achieved. Kinetic constraints limit the recovery of the full capacity of the first discharge at medium-high rates, but the second-discharge capacity declines slowly with cycle number.

The recent commercial introduction of a method for detecting albumin in meconium makes screening for cystic fibrosis feasible for many hospitals. If the tests is adopted, confirmatory tests should be available. Quantitative analyses of sweat for sodium by flame photometry and for chloride by silver titration and ion-sleective electrodes are now used as confirmatory tests. We compare results of these confirmatory methods applied to presons with cystic fibrosis, respiratory disorders, or digestive disorders, and to control subjects.