Miracle-dz/UniFAR-FTUs huggingface dataset:
Letrozol comparado con tamoxifeno, como terapia neoadyuvante para cáncer de mama hormonodependiente localmente avanzado, en pacientes posmenopáusicas

Objective: To present display the complete clinical answering frequency and the complete pathological answer with the use of induction hormonoteraphy. Methods: Meta-analysis in 40 patients with breast cancer, to chanalicular infiltrate, eligible were treated in a prospective study, to double blind person, using: letrozol, 2.5 mg, or tamoxifen, 20 mg, known widely like selective modulator of estrogen receivers; oral route, during 36 consecutive months. Reports at the beginning were taken, subsequent to 3, 6 and 12 months to evaluate the frequency of complete respond. The patients, who did not show answer neoadjuvant therapy, were put under treatment with radiotherapy. The patients, who showed good partial pathological respond, or clinical partial respond, went candidates to radical mastectomy. According to the protocol of the study, the patients subsequent to surgery who showed partial pathological respond or complete pathological respond, continued adjuvant handling adyuvant therapy by two years consecutive or until the presence of progression of the disease. It was used like statistical method Ji square, with p of Table cloth to evaluate the differences.
New product development: customers' and suppliers' assessment of the same project

Traditionally, the performance of new product development (NPD) projects has been assessed by R&D or project managers. Rarely have researchers sought customers' points of view. This study collected performance assessments from both the customer and the supplier of a new product or process and compared their perceptions of the importance of several critical success factors (CSFs). The results show that, even though customers and suppliers may agree on the overall performance of a project, their perceptions of the CSFs pertaining to that performance differ significantly.
GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity

Thrombocytopenia inhibits tumor growth and especially metastasis in mice, whereas additional depletion of NK cells reverts this antimetastatic phenotype. It has therefore been speculated that platelets may protect hematogenously disseminating tumor cells from NK-dependent antitumor immunity. Tumor cells do not travel through the blood alone, but are rapidly coated by platelets, and this phenomenon has been proposed to shield disseminating tumor cells from NK-mediated lysis. However, the underlying mechanisms remain largely unclear. In this study, we show that megakaryocytes acquire expression of the TNF family member glucocorticoid-induced TNF-related ligand (GITRL) during differentiation, resulting in GITRL expression by platelets. Upon platelet activation, GITRL is upregulated on the platelet surface in parallel with the α-granular activation marker P-selectin. GITRL is also rapidly mobilized to the platelet surface following interaction with tumor cells, which results in platelet coating. Whereas GITRL, in the fashion of several other TNF family members, is capable of transducing reverse signals, no influence on platelet activation and function was observed upon GITRL triggering. However, platelet coating of tumor cells inhibited NK cell cytotoxicity and IFN-γ production that could partially be restored by blocking GITR on NK cells, thus indicating that platelet-derived GITRL mediates NK-inhibitory forward signaling via GITR. These data identify conferment of GITRL pseudoexpression to tumor cells by platelets as a mechanism by which platelets may alter tumor cell immunogenicity. Our data thus provide further evidence for the involvement of platelets in facilitating evasion of tumor cells from NK cell immune surveillance.
Knowledge production of firms: research networks and the "scientification" of business R&D

Research and Development (R&D) expenditure grew during the 1980s and 1990s. The USA ranks first, Japan second and the EU third. Business R&D displays a cyclical pattern, university research, on the contrary, expanded more gradually. Interestingly, basic research grew faster than applied research. The consequences of this are paralleling efforts for different R&D activities, a re-conceptualisation of applied and university-related research and an increased demand, but also more opportunities, for direct university/business linkages. We will focus in this article on firms, identifying which options they have to meet these challenges. We propose the concept of the "academic firm". Through a limited "scientification" of business R&D and participation in research networks, firms can enhance their knowledge production.
Strategic business leadership through innovation and globalisation: a case study of Ranbaxy Limited

Ranbaxy Laboratories Ltd. (RLL) is the largest pharmaceutical company incorporated in India. It is also amongst the top league globally and is ranked 9th largest generic company worldwide. Ranbaxy is also credited with the tag of true Indian multinational. The company traces its roots to a chemist shop in Delhi. It is one of the first Indian pharmaceutical company to start a joint venture abroad. Rapid growth of Ranbaxy is attributed mainly to its focused research and joint ventures in India and abroad. It is also innovation and market driven, with a strong distribution network. The company was able to grow successfully in highly competitive markets. In the current business scenario, Ranbaxy is focusing on innovation, alliances, mergers and globalisation to achieve its long-term vision of becoming a global pharmaceutical giant with a turnover of $1 billion by 2004. The fruits of such efforts are evident in the latest financial result, as a large chunk of its income comes from new products and exports of generics. The growth of Ranbaxy can be attributed to its ability to identify good windows of opportunity and its ability to grow by leveraging innovation, regulatory knowledge and alliances.
Selective Blockade of Herpesvirus Entry Mediator–B and T Lymphocyte Attenuator Pathway Ameliorates Acute Graft-versus-Host Reaction

The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F1 transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases.
Identification of human UGT isoforms responsible for glucuronidation of efavirenz and its three hydroxy metabolites

Uridine 5′-diphosphate-glucuronosyltransferases (UGTs) involved in the glucuronide formation of efavirenz (EFV) and its three hydroxy metabolites, 8-hydroxyefavirenz (8-OH EFV), 7-hydroxyefavirenz (7-OH EFV), and 8,14-dihydroxyefavirenz (8,14-diOH EFV), were assessed. Among 12 recombinant UGT isoforms tested, only UGT2B7 showed catalytic activity in the formation of EFV-N-glucuronide (EFV-G) as previously reported. On the other hand, almost all UGT isoforms were involved in the glucuronidation of the three hydroxy metabolites, although their relative contribution is unclear. The catalytic activities in the formation of EFV-G by 17 different human liver microsomes exhibit a more than 40-fold inter-individual variability, whereas those of glucuronidation of the three hydroxy metabolites showed almost identical activity. The formation of EFV-G showed a significant correlation (r = 0.920; p < 0.0001) with UGT2B7-catalysed azidothymidine glucuronidation in 17 different human liver microsomes. Furthermore, fluconazole, a known UGT2B7 inhibitor, potently inhibited the formation of EFV-G up to 80%. This suggests that EFV might be a specific UGT2B7 substrate in vitro. This is the first study identifying specific UGT isozymes that glucuronidate EFV and its three hydroxy metabolites. Continued identification and characterisation of these pathways may help reduce adverse effects such as CNS toxicity in EFV therapy.
Comment on “The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility”

Boross et al. ([1][1]) recently described a C57BL/6 FcγRIIB-deficient mouse, usefully confirming FcγRIIB's contribution to autoimmunity initially ascribed to it by observations in deficient mice made on the more problematic B6/129 background ([2][2]) and in transgenic mice ([3][3]). In introducing
Influência da dor anterior nos resultados das reconstruções do ligamento cruzado anterior

OBJETIVO: Analisar o impacto que a dor residual traz aos resultados funcionais apos dois anos da reconstrucao artroscopica do LCA e comparando o tipo de enxerto utilizado durante o procedimento (patelar x flexores). METODO: Realizou-se estudo epidemiologico, retrospectivo, incluindo as 129 reconstrucoes do LCA, com acompanhamento medio de 28 meses. Foi procurada a presenca, a intensidade e a localizacao da dor anterior. Foram realizados testes provocadores de dor, estudo da sensibilidade e aplicados escores funcionais (IKDC, femoropatelar e SF-36), comparando os resultados com o tipo de enxerto utilizado. RESULTADOS: A dor anterior esteve presente em 28% dos pacientes com uma intensidade media de 2,9 em 10. A dor quando presente fez os escores funcionais baixarem de forma significativa. Alteracoes de sensibilidade e na marcha sobre os joelhos foram frequentes com uso do tendao patelar; assim, porem, nao houve diferenca estatistica quanto a presenca da dor. CONCLUSAO: A presenca de dor anterior, mesmo que minima nas reconstrucoes ligamentares do LCA, tem um efeito deleterio no resultado final em medio prazo. Devido a influencia da coleta do enxerto na presenca de alteracoes da sensibilidade e marcha sobre os joelhos, a escolha do mesmo deve levar em conta a atividade profissional e esportiva do paciente.
Ex Vivo Enzymatic Treatment of Aged CD4 T Cells Restores Cognate T Cell Helper Function and Enhances Antibody Production in Mice

Previous in vitro studies showed that CD4 T cells from old mice have defects in TCR signaling, immune synapse formation, activation, and proliferation. We reported that removing a specific set of surface glycoproteins by ex vivo treatment with O-sialoglycoprotein endopeptidase (OSGE) can reverse many aspects of the age-related decline in CD4 T cell function. However, the specific mechanism by which this process occurs remains unclear, and it is unknown whether this enzymatic treatment can also restore important aspects of adaptive immunity in vivo. By using an in vivo model of the immune response based on adoptive transfer of CD4 T cells from pigeon cytochrome C–specific transgenic H-2(k/k) TCR-Vα11Vβ3 CD4+ mice to syngeneic hosts, we demonstrate that aging diminishes CD28 costimulatory signals in CD4 T cells. These age-associated defects include changes in phosphorylation of AKT and expression of glucose transporter type I, inducible T cell costimulatory molecule, and CD40L, suggesting that the lack of CD28 costimulation contributes to age-dependent loss of CD4 function. All of these deficits can be reversed by ex vivo OSGE treatment. Blocking B7–CD28 interactions on T cells prevents OSGE-mediated restoration of T cell function, suggesting that changes in surface glycosylation, including CD28, may be responsible for the age-related costimulation decline. Finally, we show that the age-related decline in CD4 cognate helper function for IgG production and long-term humoral immunity can also be restored by OSGE treatment of CD4 T cells prior to adoptive transfer.
Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention.

BACKGROUND Self-management interventions improve various outcomes for many chronic diseases. The definite place of self-management in the care of chronic obstructive pulmonary disease (COPD) has not been established. We evaluated the effect of a continuum of self-management, specific to COPD, on the use of hospital services and health status among patients with moderate to severe disease. METHODS A multicenter, randomized clinical trial was carried out in 7 hospitals from February 1998 to July 1999. All patients had advanced COPD with at least 1 hospitalization for exacerbation in the previous year. Patients were assigned to a self-management program or to usual care. The intervention consisted of a comprehensive patient education program administered through weekly visits by trained health professionals over a 2-month period with monthly telephone follow-up. Over 12 months, data were collected regarding the primary outcome and number of hospitalizations; secondary outcomes included emergency visits and patient health status. RESULTS Hospital admissions for exacerbation of COPD were reduced by 39.8% in the intervention group compared with the usual care group (P =.01), and admissions for other health problems were reduced by 57.1% (P =.01). Emergency department visits were reduced by 41.0% (P =.02) and unscheduled physician visits by 58.9% (P =.003). Greater improvements in the impact subscale and total quality-of-life scores were observed in the intervention group at 4 months, although some of the benefits were maintained only for the impact score at 12 months. CONCLUSIONS A continuum of self-management for COPD patients provided by a trained health professional can significantly reduce the utilization of health care services and improve health status. This approach of care can be implemented within normal practice.
In vitro models of xenobiotic metabolism in trout for use in environmental bioaccumulation studies

1. In vitro screens are sought as informative, alternatives to the use of animals in vivo and to improve upon the current use of fish liver 9000 g supernatants (S9) in environmental risk assessment. 2. The rates of ethoxyresorufin-O-deethylation (relative to S9 protein) measured under different conditions of culture of rainbow trout hepatocytes were significantly higher than those detected in S9, in the order of freshly isolated hepatocytes > 10-day spheroid cultures > primary hepatocytes in culture > S9. The percentage of conjugated metabolites was also similar between freshly isolated and spheroid cultured hepatocytes (9.9 and 13.5%). 3. The rate of oxidation was enhanced (1.7 fold) when S9 was supplemented with cofactors for phase II conjugation but this was only approximately one tenth of the rate in freshly isolated hepatocytes (7.1 pmol/min/mg S9 protein equivalent). 4. Hepatocytes also hydroxylated ibuprofen, producing two metabolites, in contrast to only one (identified as the 1-hydroxy derivative) using hepatic S9 fractions. 5. Since the bioaccumulation potential of chemicals is often based on un-supplemented S9 in incubations ≥1 h when activity declines, it is recommended that predictability would be greatly improved through the use of hepatocyte spheroids, due to their maintenance of activity and longevity.
Yersinia enterocolitica YadA Mediates Complement Evasion by Recruitment and Inactivation of C3 Products

Yersinia adhesin A (YadA) is a major virulence factor of Yersinia enterocolitica. YadA mediates host cell binding and autoaggregation and protects the pathogen from killing by the complement system. Previous studies demonstrated that YadA is the most important single factor mediating serum resistance of Y. enterocolitica, presumably by binding C4b binding protein (C4BP) and factor H, which are both complement inhibitors. Factor H acts as a cofactor for factor I-mediated cleavage of C3b into the inactive form iC3b and thus prevents formation of inflammatory effector compounds and the terminal complement complex. In this study, we challenged the current direct binding model of factor H to YadA and show that Y. enterocolitica YadA recruits C3b and iC3b directly, without the need of an active complement cascade or additional serum factors. Enhanced binding of C3b does not decrease survival of YadA-expressing Yersiniae because C3b becomes readily inactivated by factor H and factor I. Binding of factor H to YadA is greatly reduced in the absence of C3. Experiments using Yersinia lacking YadA or expressing YadA with reduced trimeric stability clearly demonstrate that both the presence and full trimeric stability of YadA are essential for complement resistance. A novel mechanism of factor H binding is presented in which YadA exploits recruitment of C3b or iC3b to attract large amounts of factor H. As a consequence, formation of the terminal complement complex is limited and bacterial survival is enhanced. These findings add a new aspect of how Y. enterocolitica effectively evades the host complement system.
Role of Mincle in Alveolar Macrophage-Dependent Innate Immunity against Mycobacterial Infections in Mice

The role of macrophage-inducible C-type lectin Mincle in lung innate immunity against mycobacterial infection is incompletely defined. In this study, we show that wild-type (WT) mice responded with a delayed Mincle induction on resident alveolar macrophages and newly immigrating exudate macrophages to infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), peaking by days 14–21 posttreatment. As compared with WT mice, Mincle knockout (KO) mice exhibited decreased proinflammatory mediator responses and leukocyte recruitment upon M. bovis BCG challenge, and they demonstrated increased mycobacterial loads in pulmonary and extrapulmonary organ systems. Secondary mycobacterial infection on day 14 after primary BCG challenge led to increased cytokine gene expression in sorted alveolar macrophages of WT mice, but not Mincle KO mice, resulting in substantially reduced alveolar neutrophil recruitment and increased mycobacterial loads in the lungs of Mincle KO mice. Collectively, these data show that WT mice respond with a relatively late Mincle expression on lung sentinel cells to M. bovis BCG infection. Moreover, M. bovis BCG-induced upregulation of C-type lectin Mincle on professional phagocytes critically shapes antimycobacterial responses in both pulmonary and extrapulmonary organ systems of mice, which may be important for elucidating the role of Mincle in the control of mycobacterial dissemination in mice.
Myeloid-Derived Suppressor Cells Suppress Antitumor Immune Responses through IDO Expression and Correlate with Lymph Node Metastasis in Patients with Breast Cancer

Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45+CD13+CD33+CD14−CD15− significantly increased in primary cancer tissues and patients’ peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3+ regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33+ progenitors isolated from healthy donors’ umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs’ immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.
Drug interactions of diclofenac and its oxidative metabolite with human liver microsomal cytochrome P450 1A2-dependent drug oxidation

Abstract 1. The purpose of this study was to investigate the inhibitory effects of diclofenac on human cytochrome P450 1A2-, 2C19- and 3A4-mediated drug oxidations and to evaluate the drug interaction potential of diclofenac and 4′-hydroxydiclofenac. 2. Diclofenac was converted to 4′-hydroxydiclofenac by recombinantly expressed human P450 1A2 with Km and Vmax values of 33 µM and 0.20 min−1, respectively. Diclofenac and 4′-hydroxydiclofenac suppressed flurbiprofen 4′-hydroxylation by P450 2C9 strongly and moderately, respectively; however, they did not affect P450 2C19-dependent S-mephenytoin hydroxylation or P450 3A4-dependent midazolam hydroxylation. 3. Although the caffeine 3-N-demethylation activity of liver microsomal P450 1A2 was inhibited by simultaneous incubation with diclofenac, the riluzole N-hydroxylation activities of recombinant P450 1A2 and human liver microsomes were inhibited after preincubation with diclofenac or 4′-hydroxydiclofenac for 20 min in the presence of NADPH. Using the inhibition constant (37 µM) of diclofenac on caffeine 3-N-demethylation and the reported 95th percentiles of maximum plasma concentration (10.5 µM) after an oral dose of diclofenac, the in vivo estimated increase in area under the plasma concentration–time curve was 29%. 4. These results suggest that diclofenac could inhibit drug clearance to a clinically important degree that depends on P450 1A2. Clinically relevant drug interactions in vivo with diclofenac are likely to be invoked via human P450 1A2 function in addition to those caused by the effect of diclofenac on P450 2C9.
Assembly of the TLR2/6 Transmembrane Domains Is Essential for Activation and Is a Target for Prevention of Sepsis

TLR2, together with TLR1 and TLR6, is essential for detecting lipopeptides and bacterial cell wall components such as lipoteichoic acid from Gram-positive bacteria. In this study, we report that transmembrane domain (TMD)–derived peptides from TLR2 and TLR6 specifically inhibit TLR2 activation. Secretion of the cytokines TNF-α and IL-6 by cultured macrophages (RAW264.7 cell line) was inhibited by these peptides in response to TLR2 activation by lipoteichoic acid (TLR2/6 activator) or palmitoyl (3)-Cys-Ser-Lys(4)-OH (TLR2/1 activator) but not by LPS (TLR4 activator). Extensive biophysical and biochemical assays, combined with GALLEX experiments, show that these peptides heterodimerize with their complementary TMDs on their reciprocal protein. These results suggest that TLR2/6/1 TMD assembly is essential for activating this complex. Importantly, when administered to mice inflicted by TLR2, but not TLR4-driven lethal inflammation, a selected peptide rescued 60% of these septic mice, showing potent in vivo inhibition of TNF-α and IL-6 secretion. Furthermore, this peptide also showed high protection in a whole bacteria model. Owing to the importance of TLR2 regulation under a variety of pathological conditions, compounds that can fine-tune this activity are of great importance.