Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists.

Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6.

Identification of MAGEC2/CT10 as a High Calcium-Inducible Gene in Triple-Negative Breast Cancer.

The expression of the melanoma/cancer-testis antigen MAGEC2/CT10 is restricted to germline cells, but like most cancer-testis antigens, it is frequently upregulated in advanced breast tumors and other malignant tumors. However, the physiological cues that trigger the expression of this gene during malignancy remain unknown. Given that malignant breast cancer is often associated with skeletal metastasis and co-morbidities such as cancer-induced hypercalcemia, we evaluated the effect of high Ca on the calcium-sensing receptor (CaSR) and potential mechanisms underlying the survival of triple-negative breast cancer (TNBC) cells at high Ca.

Reduced Expression of Annexin A6 Induces Metabolic Reprogramming That Favors Rapid Fatty Acid Oxidation in Triple-Negative Breast Cancer Cells.

The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6), in the metabolic adaptation of basal-like (AnxA6-low) versus mesenchymal-like (AnxA6-high), as well as in lapatinib-resistant TNBC cells. Using model basal-like and mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity.

Key event-informed risk models for benzene-induced acute myeloid leukaemia.

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndromes (MDS) and AML.

The rapid endocytic uptake of fetuin-A by adherent tumor cells is mediated by Toll-like receptor 4 (TLR4).

Fetuin-A is a serum glycoprotein synthesized and secreted into blood by the liver and whose main physiological function is the inhibition of ectopic calcification. However, a number of studies have demonstrated that it is a multifunctional protein. For example, endocytic uptake of fetuin-A by tumor cells resulting in rapid cellular adhesion and spreading has been reported.

Modes of action considerations in threshold expectations for health effects of benzene.

Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed.

Diverse Roles of Annexin A6 in Triple-Negative Breast Cancer Diagnosis, Prognosis and EGFR-Targeted Therapies.

The calcium (Ca)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities.

Derivation of an occupational exposure limit for benzene using epidemiological study quality assessment tools.

This paper derives an occupational exposure limit for benzene using quality assessed data. Seventy-seven genotoxicity and 36 haematotoxicity studies in workers were scored for study quality with an adapted tool based on that of Vlaanderen et al., 2008 (Environ Health.

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.

Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells.

Implication of calcium activated RasGRF2 in Annexin A6-mediated breast tumor cell growth and motility.

The role of AnxA6 in breast cancer and in particular, the mechanisms underlying its contribution to tumor cell growth and/or motility remain poorly understood. In this study, we established the tumor suppressor function of AnxA6 in triple negative breast cancer (TNBC) cells by showing that loss of AnxA6 is associated with early onset and rapid growth of xenograft TNBC tumors in mice. We also identified the Ca activated RasGRF2 as an effector of AnxA6 mediated TNBC cell growth and motility.

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.

Introduction: This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).

Patients And Methods: We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel.

Quantitative Infrared Absorption Spectra and Vibrational Assignments of Crotonaldehyde and Methyl Vinyl Ketone Using Gas-Phase Mid-Infrared, Far-Infrared, and Liquid Raman Spectra: s-cis vs s-trans Composition Confirmed via Temperature Studies and ab Initio Methods.

Methyl vinyl ketone (MVK) and crotonaldehyde are chemical isomers; both are also important species in tropospheric chemistry. We report quantitative vapor-phase infrared spectra of crotonaldehyde and MVK vapors over the 540-6500 cm range. Vibrational assignments of all fundamental modes are made for both molecules on the basis of far- and mid-infrared vapor-phase spectra, liquid Raman spectra, along with density functional theory and ab initio MP2 and high energy-accuracy compound theoretical models (W1BD).

Assignment of the Fundamental Modes of Hydroxyacetone Using Gas-Phase Infrared, Far-Infrared, Raman, and ab Initio Methods: Band Strengths for Atmospheric Measurements.

Hydroxyacetone (acetol) is a simple organic molecule of interest in both the astrophysical and atmospheric communities. It has recently been observed in biomass burning events and is a known degradation product of isoprene oxidation. However, its vibrational assignment has never been fully completed, and few quantitative data are available for its detection via infrared spectroscopy.

Quantitative IR spectrum and vibrational assignments for glycolaldehyde vapor: glycolaldehyde measurements in biomass burning plumes.

Glycolaldehyde (GA, 2-hydroxyethanal, C2H4O2) is a semivolatile molecule of atmospheric importance, recently proposed as a precursor in the formation of aqueous-phase secondary organic aerosol (SOA). There are few methods to measure GA vapor, but infrared spectroscopy has been used successfully. Using vetted protocols we have completed the first assignment of all fundamental vibrational modes and also derived quantitative IR absorption band strengths using both neat and pressure-broadened GA vapor.

Quantitative infrared intensity studies of vapor-phase glyoxal, methylglyoxal, and 2,3-butanedione (diacetyl) with vibrational assignments.

Glyoxal, methylglyoxal, and 2,3-butanedione (diacetyl) are all known biomass burning effluents and suspected aerosol precursors. Pressure-broadened quantitative infrared spectra of glyoxal, methylglyoxal, and diacetyl vapors covering the 520-6500 cm(-1) range are reported at 0.112 cm(-1) resolution, each with a composite spectrum derived from a minimum of 10 different sample pressures for the compound, representing some of the first quantitative intensity data for these analytes.

The infrared spectra of Bacillus bacteria part II: sporulated Bacillus--the effect of vegetative cells and contributions of calcium dipicolinate trihydrate, CaDP.3H2O.

Our previous paper showed that certain infrared (IR) peaks, e.g., the peak at 1739 cm(-1), are due to varying (trace) amounts of vegetative cells amongst the Bacillus spores and that these and other vegetative bands are associated with lipid-soluble compounds, likely an ester or phospholipid.

The infrared spectra of Bacillus bacteria part I: vegetative Bacillus versus sporulated cells and the contributions of phospholipids to vegetative infrared spectra.

This paper highlights the distinctions between the infrared (IR) absorption spectra of vegetative versus sporulated Bacillus bacteria. It is observed that there are unique signatures clearly associated with either the sporulated or vegetative state and that vegetative cells (or cell debris) can contribute to the spore spectra. A distinct feature at approximately 1739 cm(-1) appears to be unique to vegetative cell spectra and can also be used as an indicator of vegetative cells or cell debris in the spore spectra.

Chronic physical effects and health care utilization in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group study.

Purpose: This study compares late effects of treatment on physical well-being and utilization of health care resources between ovarian germ cell tumor (OGCT) survivors and age/race/education-matched controls.

Patients And Methods: Eligible patients had OGCT treated with surgery and chemotherapy and were disease-free for at least 2 years at time of enrollment. The matched control group was selected from acquaintances recommended by survivors.

Case-control comparison of quality of life in long-term ovarian germ cell tumor survivors: a gynecologic oncology group study.

Ovarian germ cell cancer is a rare tumor. Approximately 1000 to 2000 women in the United States will be diagnosed with ovarian germ cell cancer in 2007. When it occurs, it is usually diagnosed before age 20 and is highly responsive to therapy.

High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors.

Background: Metastatic testicular tumors that have not been successfully treated by means of initial chemotherapy are potentially curable with salvage chemotherapy.

Methods: We conducted a retrospective review of 184 consecutive patients with metastatic testicular cancer that had progressed after they received cisplatin-containing combination chemotherapy. We gave 173 patients two consecutive courses of high-dose chemotherapy consisting of 700 mg of carboplatin per square meter of body-surface area and 750 mg of etoposide per square meter, each for 3 consecutive days, and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells; the other 11 patients received a single course of this treatment.

Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group Study.

Purpose: To compare malignant ovarian germ cell tumor survivors with a matched control group of females on menstrual and reproductive outcomes, sexual functioning, and dyadic adjustment.

Patients And Methods: Eligible patients met the following criteria: (1) history of malignant ovarian germ cell tumor; (2) treatment with surgery plus platinum-based chemotherapy; (3) age at least 18 years and continuously disease-free with minimum follow-up of 2 years; (4) capability of completing questionnaire and telephone interview; and (5) completion of written informed consent. The control group was drawn from acquaintances recommended by survivors and matched for age, race, and education.

Quality control of human tissues--experience from the Indiana University Cancer Center-Lilly Research Labs human tissue bank.

The success of molecular research and its applications in both the clinical and basic research arenas is strongly dependent on the collection, handling, storage, and quality control of fresh human tissue samples. This tissue bank was set up to bank fresh surgically obtained human tissue using a Clinical Annotated Tissue Database (CATD) in order to capture the associated patient clinical data and demographics using a one way patient encryption scheme to protect patient identification. In this study, we determined that high quality of tissue samples is imperative for both genomic and proteomic molecular research.

Quality of life in long-term survivors of ovarian germ cell tumors: a Gynecologic Oncology Group study.

Purpose: This report describes the strength and significance of the association between antecedent and mediating variables across four categories of quality of life (QOL) outcomes in 132 disease free women with ovarian germ cell survivors.

Methods: Survivors (n=132) participated in a mailed questionnaire and computer-assisted telephone survey. Participants in four prospective GOG protocols were contacted their treating physician for verbal consent to be approached by investigators at the Indiana University Cancer Center about a quality of life study.

Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant.

Purpose: To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with tandem transplantation.

Patients And Methods: One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University (Indianapolis, IN) from February 1996 to December 2004. After further evidence of progressive disease, 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes, days 1, 8, and 15 every 4 weeks for a maximum of six courses.

Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors.

Purpose: Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy.

Patients And Methods: Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled.