Similarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS.

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection

Level of suicidal intent predicts overall mortality and suicide after attempted suicide: a 12-year follow-up study

BACKGROUND: The aim of this study was to comprehensively examine clinical risk factors, including suicide intent and hopelessness, for suicide and risk of death from all causes after attempted suicide over a 12-year follow-up period. METHODS: A systematic sample of 224 patients from consecutive cases of attempted suicide referred to health care in four Finnish cities between 1 January and 31 July 1990 was interviewed. RESULTS: After 12 years of follow-up 22% of these patients had died, 8% by committing suicide. The only statistically significant risk factor for eventual suicide was high scores on Beck's Suicidal Intention Scale. Male gender, older age, physical illness or disability and high scores on Beck's Suicidal Intention Scale predicted death overall. CONCLUSIONS: Following attempted suicide, high intention to kill oneself is a significant risk factor for both death from all causes and suicide

GOBO: Gene Expression-Based Outcome for Breast Cancer Online

Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo), allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1) rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2) identification of co-expressed genes for creation of potential metagenes, 3) association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881-sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform

Repetition and severity of suicide attempts across the life cycle: a comparison by age group between suicide victims and controls with severe depression

<p>Abstract</p> <p>Background</p> <p>Suicide attempts have been shown to be less common in older age groups, with repeated attempts generally being more common in younger age groups and severe attempts in older age groups. Consistently, most studies have shown an increased suicide risk after attempts in older age. However, little is known about the predictive value of age on repeated and severe suicide attempts for accomplished suicide. The aim of the present study was to investigate the reduced incidence for initial, repeated, or severe suicide attempts with age in suicide victims and controls by gender.</p> <p>Methods</p> <p>The records of 100 suicide victims and matched controls with severe depression admitted to the Department of Psychiatry, Lund University Hospital, Sweden between 1956 and 1969, were evaluated and the subjects were monitored up to 2006. The occurrence of suicide attempts (first, repeated, or severe, by age group) was analysed for suicide victims and controls, with gender taken into consideration.</p> <p>Results</p> <p>There was a reduced risk for an initial suicide attempt by older age in females (suicide victims and controls) and male controls (but not suicide victims). The risk for repeated suicide attempts appeared to be reduced in the older age groups in female controls as compared to female suicide victims. The risk for severe suicide attempts seemed reduced in the older age groups in female suicide victims. This risk was also reduced in male controls and in male controls compared to male suicide victims.</p> <p>Conclusion</p> <p>In the older age groups repeated attempts appeared to be predictive for suicide in women and severe attempts predictive in men.</p

Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort

A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Proliferation markers have been shown to recognize patients at high risk for recurrence. Ki67 has recently been included in the St Gallen guidelines. We investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size < 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Tumor tissue was immunostained for cyclin B1. Two investigators evaluated the staining independently by counting approximately 100, 200, 500, and 1000 cells. Cyclin B1 was statistically significantly associated to breast cancer death, in both uni- and multivariate analyses (adjusted for tumor size, age, and endocrine therapy), with odds ratios 2-3 for both investigators. The agreement between the two investigators was good to very good, regardless of the number of counted cells (kappa values between 0.74 and 0.82).Cyclin B1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort which can identify high-risk patients with a good to very good reproducibility. (c) 2009 UICC

Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer

Molecular serum portraits in patients with primary breast cancer predict the development of distant metastases

The risk of distant recurrence in breast cancer patients is difficult to assess with current clinical and histopathological parameters, and no validated serum biomarkers currently exist. Using a recently developed recombinant antibody microarray platform containing 135 antibodies against 65 mainly immunoregulatory proteins, we screened 240 sera from 64 patients with primary breast cancer. This unique longitudinal sample material was collected from each patient between 0 and 36 mo after the primary operation. The velocity for each serum protein was determined by comparing the samples collected at the primary operation and then 3–6 mo later. A 21-protein signature was identified, using leave-one-out cross-validation together with a backward elimination strategy in a training cohort. This signature was tested and evaluated subsequently in an independent test cohort (prevalidation). The risk of developing distant recurrence after primary operation could be assessed for each patient, using her molecular portraits. The results from this prevalidation study showed that patients could be classified into high- versus low-risk groups for developing metastatic breast cancer with a receiver operating characteristic area under the curve of 0.85. This risk assessment was not dependent on the type of adjuvant therapy received by the patients. Even more importantly, we demonstrated that this protein signature provided an added value compared with conventional clinical parameters. Consequently, we present here a candidate serum biomarker signature able to classify patients with primary breast cancer according to their risk of developing distant recurrence, with an accuracy outperforming current procedures

Evidence that p53-mediated cell-cycle-arrest inhibits chemotherapeutic treatment of ovarian carcinomas

© 2007 Moreno et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.DOI: 10.1371/journal.pone.0000441Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-treated with chemotherapy (neo-adjuvant) prior to surgery group into two distinct clusters. One group clusters with carcinomas from patients not pretreated with chemotherapy prior to surgery (C-L), while the other clusters with non-malignant adenomas (A-L). We show here that although the C-L cluster is preferentially associated with p53 loss-of-function (LOF) mutations, the C-L cluster cancer patients display a more favorable clinical response to chemotherapy as evidenced by enhanced long-term survivorships. Our results support a model whereby p53 mediated cell-cycle-arrest/DNA repair serves as a barrier to optimal chemotherapeutic treatment of ovarian and perhaps other carcinomas and suggest that inhibition of p53 during chemotherapy may enhance clinical outcome