Risk prediction models with incomplete data with application to prediction of estrogen receptor-positive breast cancer: prospective data from the Nurses' Health Study

Introduction A number of breast cancer risk prediction models have been developed to provide insight into a woman\u27s individual breast cancer risk. Although circulating levels of estradiol in postmenopausal women predict subsequent breast cancer risk, whether the addition of estradiol levels adds significantly to a model\u27s predictive power has not previously been evaluated. Methods Using linear regression, the authors developed an imputed estradiol score using measured estradiol levels (the outcome) and both case status and risk factor data (for example, body mass index) from a nested case-control study conducted within a large prospective cohort study and used multiple imputation methods to develop an overall risk model including both risk factor data from the main cohort and estradiol levels from the nested case-control study. Results The authors evaluated the addition of imputed estradiol level to the previously published Rosner and Colditz log-incidence model for breast cancer risk prediction within the larger Nurses\u27 Health Study cohort. The follow-up was from 1980 to 2000; during this time, 1,559 invasive estrogen receptor-positive breast cancer cases were confirmed. The addition of imputed estradiol levels significantly improved risk prediction; the age-specific concordance statistic increased from 0.635 ± 0.007 to 0.645 ± 0.007 (P \u3c 0.001) after the addition of imputed estradiol. Conclusion Circulating estradiol levels in postmenopausal women appear to add to other lifestyle factors in predicting a woman\u27s individual risk of breast cancer

Fairy Tales: Attraction and Stereotypes in Same-Gender Relationships

We examine the process of romantic attraction in same-gender relationships using open and closed-ended questionnaire data from a sample of 120 men and women in Northern California. Agreeableness (e.g., kind, supportive) and Extraversion (e.g., fun, sense of humor) are the two most prominent bases of attraction, followed by Physical Attractiveness (e.g., appearance, sexy). The least important attractors represent traits associated with material success (e.g., financially secure, nice house). We also find evidence of seemingly contradictory attraction processes documented previously in heterosexual romantic relationships, in which individuals become disillusioned with the qualities in a partner that were initially appealing. Our findings challenge common stereotypes of same-gender relationships. The results document broad similarities between same-gender and cross-gender couples in attraction

hnRNP I Inhibits Notch Signaling and Regulates Intestinal Epithelial Homeostasis in the Zebrafish

Regulated intestinal stem cell proliferation and differentiation are required for normal intestinal homeostasis and repair after injury. The Notch signaling pathway plays fundamental roles in the intestinal epithelium. Despite the fact that Notch signaling maintains intestinal stem cells in a proliferative state and promotes absorptive cell differentiation in most species, it remains largely unclear how Notch signaling itself is precisely controlled during intestinal homeostasis. We characterized the intestinal phenotypes of brom bones, a zebrafish mutant carrying a nonsense mutation in hnRNP I. We found that the brom bones mutant displays a number of intestinal defects, including compromised secretory goblet cell differentiation, hyperproliferation, and enhanced apoptosis. These phenotypes are accompanied by a markedly elevated Notch signaling activity in the intestinal epithelium. When overexpressed, hnRNP I destabilizes the Notch intracellular domain (NICD) and inhibits Notch signaling. This activity of hnRNP I is conserved from zebrafish to human. In addition, our biochemistry experiments demonstrate that the effect of hnRNP I on NICD turnover requires the C-terminal portion of the RAM domain of NICD. Our results demonstrate that hnRNP I is an evolutionarily conserved Notch inhibitor and plays an essential role in intestinal homeostasis

Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β1 was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β1, talin and FAK pathways that regulate NF-kB nuclear activity

Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization

Renal cell carcinoma (RCC) are frequently chemo- and radiation resistant. Thus, there is a need for identifying biological features of these cells that could serve as alternative therapeutic targets. We performed suppression subtractive hybridization (SSH) on patient-matched normal renal and RCC tissue to identify variably regulated genes. 11 genes were strongly up-regulated or selectively expressed in more than one RCC tissue or cell line. Screening of filters containing cancer-related cDNAs confirmed overexpression of 3 of these genes and 3 additional genes were identified. These 14 differentially expressed genes, only 6 of which have previously been associated with RCC, are related to tumour growth/survival (EGFR, cyclin D1, insulin-like growth factor-binding protein-1 and a MLRQ sub-unit homologue of the NADH:ubiquinone oxidoreductase complex), angiogenesis (vascular endothelial growth factor, endothelial PAS domain protein-1, ceruloplasmin, angiopoietin-related protein 2) and cell adhesion/motility (protocadherin 2, cadherin 6, autotaxin, vimentin, lysyl oxidase and semaphorin G). Since some of these genes were overexpressed in 80–90% of RCC tissues, it is important to evaluate their suitability as therapeutic targets. © 2001 Cancer Research Campaig

Consciência da doença na demência: resultados preliminares em pacientes com doença de Alzheimer leve e moderada Awareness of disease in dementia: preliminary results in patients with mild and moderate Alzheimer's disease

OBJETIVO: Avaliar a presença e o grau de consciência da doença na doença de Alzheimer (DA) em estágio leve e moderado. MÉTODO: Pacientes com DA leve/moderada (n=42) avaliados em corte transversal através da Escala de Avaliação do Impacto Psicossocial do Diagnóstico de Demência (APSID), Mini-Exame do Estado Mental (MEEM) e Estadiamento Clínico das Demências (CDR). RESULTADOS: No estágio leve (n=18), 66,7% dos pacientes perceberam os sintomas cognitivos e os prejuízos causados na vida cotidiana. No estágio moderado (n=24), 20,8% tinham consciência da doença preservada; em 45,8% observou-se somente a noção sobre a presença de sintomas cognitivos; ausência total de consciência da doença foi encontrada em 33,3%. CONCLUSÃO: Os dados encontrados indicam a associação entre consciência e evolução clínica da doença. Pacientes com CDR 1 reconhecem melhor os sintomas cognitivos e dificuldades de atividade de vida diária. A maioria dos pacientes com CDR 2 reconhece seus sintomas, mas não percebe a gravidade e as conseqüências nas atividades de vida diária.<br>OBJECTIVE: To evaluate the presence and the level of awareness of disease in mild and moderate Alzheimer's disease (AD). METHOD: Cross-sectional evaluation of patients with mild/moderate AD (n=42) assessed by Assessment of Psychosocial Impact of the Dementia Diagnosis (APSID), Mini-mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR). RESULTS: Awareness of disease and its consequences were present in 66.7% patients with mild AD (n=18). In moderate AD (n=24), 20.8% presented total awareness, 45.8% presented only awareness of cognitive symptoms. Unawareness of disease was observed in 33.3%. CONCLUSIONS: The present data show association between awareness and level of severity of disease. CDR 1 patients show a better recognition of cognitive and daily life activity symptoms, whereas CDR 2 patients recognized their cognitive symptoms but failed to appraise their severity and consequences in daily life activities