Lewis X antigen mediates adhesion of human breast carcinoma cells to activated endothelium. Possible involvement of the endothelial scavenger receptor C-Type lectin

Lewis x (Lex, CD15), also known as SSEA-1 (stage specific embryonic antigen-1), is a trisaccharide with the structure Galβ(1–4)Fucα(1–3)GlcNAc, which is expressed on glycoconjugates in human polymorphonuclear granulocytes and various tumors such as colon and breast carcinoma. We have investigated the role of Lex in the adhesion of MCF-7 human breast cancer cells and PMN to human umbilical endothelial cells (HUVEC) and the effects of two different anti-Lex mAbs (FC-2.15 and MCS-1) on this adhesion. We also analyzed the cytolysis of Lex+-cells induced by anti-Lex mAbs and complement when cells were adhered to the endothelium, and the effect of these antibodies on HUVEC. The results indicate that MCF-7 cells can bind to HUVEC, and that MCS-1 but not FC-2.15 mAb inhibit this interaction. Both mAbs can efficiently lyse MCF-7 cells bound to HUVEC in the presence of complement without damaging endothelial cells. We also found a Lex-dependent PMN interaction with HUVEC. Although both anti-Lex mAbs lysed PMN in suspension and adhered to HUVEC, PMN aggregation was only induced by mAb FC-2.15. Blotting studies revealed that the endothelial scavenger receptor C-type lectin (SRCL), which binds Lex-trisaccharide, interacts with specific glycoproteins of Mr␣∼␣28 kD and 10 kD from MCF-7 cells. The interaction between Lex+-cancer cells and vascular endothelium is a potential target for cancer treatment.Fil: Elola, Maria Teresa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Capurro, Mariana Isabel. University of Toronto; CanadáFil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación, Docencia y Prevención del Cáncer; ArgentinaFil: Coombs, Peter J.. Imperial College London; Reino UnidoFil: Taylor, Maureen E.. Imperial College London; Reino UnidoFil: Drickamer, Kurt. Imperial College London; Reino UnidoFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación, Docencia y Prevención del Cáncer; Argentin

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P = 0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P = 0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P = 0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P = 0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P = 0.047) and worse PFS (HR: 0.45, P = 0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P = 0.0005) and PFS (HR: 0.51, P = 0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. British Journal of Cancer (2009) 101, 715-721. doi: 10.1038/sj.bjc.6605177 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research U

Endocrine therapy for breast cancer: a model of hormonal manipulation

Oestrogen receptor (ER) is the driving transcription factor in 70% of breast cancer. Endocrine therapies targeting the ER represent one of the most successful anticancer strategies to date. In the clinic, novel targeted agents are now being exploited in combination with established endocrine therapies to maximise efficacy. However, clinicians must balance this gain against the risk to patients of increased side effects with combination therapies. This article provides a succinct outline of the principles of hormonal manipulation in breast cancer, alongside the key evidence that underpins current clinical practice. As the role of endocrine therapy in breast cancer continues to expand, the challenge is to interpret the data and select the optimal strategy for a given clinical scenario

Sexual behavior and drug consumption among young adults in a shantytown in Lima, Peru

<p>Abstract</p> <p>Background</p> <p>Risky sexual behaviors of young adults have received increasing attention during the last decades. However, few studies have focused on the sexual behavior of young adults in shantytowns of Latin America. Specifically, studies on the association between sexual behaviors and other risk factors for sexually transmitted infections (STI) and HIV/AIDS transmission, such as the consumption of illicit drugs or alcohol are scarce in this specific context.</p> <p>Methods</p> <p>The study participants were 393 men and 400 women between 18 and 30 years of age, from a shantytown in Lima, Peru. Data were obtained via survey: one section applied by a trained research assistant, and a self-reporting section. Logistic regression was used to estimate associations between use of any illicit drug, high-risk sexual behaviors and reported STI symptoms, adjusting for alcohol consumption level and various socio-demographic characteristics.</p> <p>Results</p> <p>Among men, age of sexual debut was lower, number of lifetime sexual partners was higher, and there were higher risk types of sexual partners, compared to women. Though consistent condom use with casual partners was low in both groups, reported condom use at last intercourse was higher among men than women. Also, a lifetime history of illicit drug consumption decreased the probability of condom use at last sexual intercourse by half. Among men, the use of illicit drugs doubled the probability of intercourse with a casual partner during the last year and tripled the probability of reported STI symptoms.</p> <p>Conclusion</p> <p>Drug consumption is associated with high-risk sexual behaviors and reported STI symptoms in a Lima shantytown after controlling for alcohol consumption level. Development of prevention programs for risky sexual behaviors, considering gender differences, is discussed.</p

Sleep study, respiratory mechanics, chemosensitive response and quality of life in morbidly obese patients undergoing bariatric surgery: a prospective, randomized, controlled trial

<p>Abstract</p> <p>Background</p> <p>Obesity is a major public health problem in both developed and developing countries alike and leads to a series of changes in respiratory physiology. There is a strong correlation between obesity and cardiopulmonary sleep disorders. Weight loss among such patients leads to a reduction in these alterations in respiratory physiology, but clinical treatment is not effective for a long period of time. Thus, bariatric surgery is a viable option.</p> <p>Methods/Design</p> <p>The present study involves patients with morbid obesity (BMI of 40 kg/m²or 35 kg/m²to 39.9 kg/m²with comorbidities), candidates for bariatric surgery, screened at the Santa Casa de Misericórdia Hospital in the city of Sao Paulo (Brazil). The inclusion criteria are grade III morbid obesity, an indication for bariatric surgery, agreement to participate in the study and a signed term of informed consent. The exclusion criteria are BMI above 55 kg/m², clinically significant or unstable mental health concerns, an unrealistic postoperative target weight and/or unrealistic expectations of surgical treatment. Bariatric surgery candidates who meet the inclusion criteria will be referred to Santa Casa de Misericórdia Hospital and will be reviewed again 30, 90 and 360 days following surgery. Data collection will involve patient records, personal data collection, objective assessment of HR, BP, neck circumference, chest and abdomen, collection and analysis of clinical preoperative findings, polysomnography, pulmonary function test and a questionnaire on sleepiness.</p> <p>Discussion</p> <p>This paper describes a randomised controlled trial of morbidly obese patients. Polysomnography, respiratory mechanics, chemosensitive response and quality of life will be assessed in patients undergoing or not undergoing bariatric surgery.</p> <p>Trial Registration</p> <p>The protocol for this study is registered with the Brazilian Registry of Clinical Trials - ReBEC (RBR-9k9hhv).</p

In Vitro Evaluation of a Soluble Leishmania Promastigote Surface Antigen as a Potential Vaccine Candidate against Human Leishmaniasis

International audiencePSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in severalLeishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice.We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced in aL. tarentolae expression system. This was done in individuals cured of cutaneous leishmaniasis due to L. major (CCLm) or L.braziliensis (CCLb) or visceral leishmaniasis due to L. donovani (CVLd) and in healthy individuals. Healthy individuals weresubdivided into immune (HHR-Lm and HHR-Li: Healthy High Responders living in an endemic area for L. major or L. infantuminfection) or non immune/naive individuals (HLR: Healthy Low Responders), depending on whether they produce high orlow levels of IFN-c in response to Leishmania soluble antigen. Low levels of total IgG antibodies to LaPSA-38S were detectedin sera from the studied groups. Interestingly, LaPSA-38S induced specific and significant levels of IFN-c, granzyme B and IL-10 in CCLm, HHR-Lm and HHR-Li groups, with HHR-Li group producing TNF-a in more. No significant cytokine response wasobserved in individuals immune to L. braziliensis or L. donovani infection. Phenotypic analysis showed a significant increasein CD4+ T cells producing IFN-c after LaPSA-38S stimulation, in CCLm. A high positive correlation was observed between thepercentage of IFN-c-producing CD4+ T cells and the released IFN-c. We showed that the LaPSA-38S protein was able toinduce a mixed Th1 and Th2/Treg cytokine response in individuals with immunity to L. major or L. infantum infectionindicating that it may be exploited as a vaccine candidate. We also showed, to our knowledge for the first time, the capacityof Leishmania PSA protein to induce granzyme B production in humans with immunity to L. major and L. infantum infectio

Scientific Discovery Through Fictionally Modelling Reality

How do scientific models represent in a way that enables us to discover new truths about reality and draw inferences about it? Contemporary accounts of scientific discovery answer this question by focusing on the cognitive mechanisms involved in the generation of new ideas and concepts in terms of a special sort of reasoning—or model-based reasoning—involving imagery. Alternatively, I argue that answering this question requires that we recognise the crucial role of the propositional imagination in the construction and development of models for the purpose of generating hypotheses that are plausible can- didates for truth. I propose simple fictionalism as a new account of models as Waltonian games of make-believe and suggest that models can lead to genuine scientific discovery when they are used as representations that denote real world phenomena and generate two main kinds of theoretical hypotheses, model-world comparisons and direct attributions

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events