Oxylipins as Biomarkers for Aromatase Inhibitor-Induced Arthralgia (AIA) in Breast Cancer Patients.

Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the inflammatory metabolomic changes in the development of AIA. This single-arm, prospective clinical trial enrolled 28 postmenopausal women with early-stage (0-3) ER+ breast cancer starting adjuvant anastrozole.

Feasibility Trial to Evaluate Tendon Stiffness Obtained from Shear Wave Elastography Imaging as a Biomarker of Aromatase Inhibitor-Induced Arthralgias.

Aromatase inhibitor-induced arthralgia (AIA) comprises significant, activity-limiting musculoskeletal symptoms, including joint pain, myalgia, and joint stiffness. We conducted a prospective feasibility study in postmenopausal women diagnosed with early-stage (0-3) hormone receptor positive (HR+) breast cancer who were candidates for treatment with adjuvant AI therapy ( = 16). Tendons of the hands and wrists and the median nerve were imaged using gray-scale and power Doppler ultrasound (US) and US SWE.

Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR).

TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer.

Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR.

Patients And Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison.

Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia.

Purpose: Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.

Methods: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks).

Unbiased Lipidomic Profiling of Triple-Negative Breast Cancer Tissues Reveals the Association of Sphingomyelin Levels with Patient Disease-Free Survival.

The reprogramming of lipid metabolism is a hallmark of many cancers that has been shown to promote breast cancer progression. While several lipid signatures associated with breast cancer aggressiveness have been identified, a comprehensive lipidomic analysis specifically targeting the triple-negative subtype of breast cancer (TNBC) may be required to identify novel biomarkers and therapeutic targets for this most aggressive subtype of breast cancer that still lacks effective therapies. In this current study, our global LC-MS-based lipidomics platform was able to measure 684 named lipids across 15 lipid classes in 70 TNBC tumors.

Obesity and Breast Cancer Prognosis: Evidence, Challenges, and Opportunities.

Purpose To summarize the evidence of an association between obesity and breast cancer prognosis. Methods We reviewed the literature regarding overweight and obesity and breast cancer survival outcomes, overall and with regard to breast cancer subtypes, breast cancer therapies, biologic mechanisms, and possible interventions. We summarize our findings and provide clinical management recommendations.

Metformin in breast cancer - an evolving mystery.

Metformin, a diabetes drug with well-established side effect and safety profiles, has been widely studied for its anti-tumor activities in a number of cancers, including breast cancer. But its mechanism of action in the clinical arena remains elusive. In a window of opportunity trial of metformin in non-diabetic breast cancer patients, Dowling and colleagues examined both the direct actions of the drug on cancer cells (as mediated by AMP kinase), as well as its indirect actions (as mediated by circulating insulin).

Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients.

Background: To determine the relationship between obesity, diabetes, and survival in a large cohort of breast cancer patients receiving modern chemotherapy and endocrine therapy.

Patients And Methods: We identified 6342 patients with stage I-III breast cancer treated between 1996 and 2005. Patients were evaluated according to body mass index (BMI) category and diabetes status.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1).

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population.

Background: Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved.

Methods: We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990-2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation.

Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3).

Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds.

Zellweger spectrum disorder (ZSD) is a heterogeneous group of diseases with high morbidity and mortality caused by failure to assemble normal peroxisomes. There is no therapy for ZSD, but management is supportive. Nevertheless, one-half of the patients have a phenotype milder than classic Zellweger syndrome and exhibit a progressive disease course.

Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme.

How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion.

Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.

Purpose: Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this.

The crystal structure and dimerization interface of GADD45gamma.

Gadd45 proteins are recognized as tumor and autoimmune suppressors whose expression can be induced by genotoxic stresses. These proteins are involved in cell cycle control, growth arrest, and apoptosis through interactions with a wide variety of binding partners. We report here the crystal structure of Gadd45gamma, which reveals a fold comprising an alphabetaalpha sandwich with a central five-stranded mixed beta-sheet with alpha-helices packed on either side.

Manganese superoxide dismutase induction by iron is impaired in Friedreich ataxia cells.

Iron-mediated oxidative stress has been implicated in the pathology of the neurodegenerative disease Friedreich ataxia (FRDA). Here, we show that normal upregulation of the stress defense protein manganese superoxide dismutase (MnSOD) fails to occur in FRDA fibroblasts exposed to iron. This impaired induction was observed at iron levels in which increased activation of the redox-sensitive factor NF-kappaB was absent.

Analysis of the enzymatic domains in the modular portion of the coronafacic acid polyketide synthase.

Coronafacic acid (CFA) is the polyketide component of coronatine (COR), a phytotoxin produced by the plant pathogen Pseudomonas syringae. The CFA polyketide synthase (PKS) consists of two open reading frames (ORFs) that encode type I multifunctional proteins and several ORFs that encode monofunctional proteins. Sequence comparisons of the modular portions of the CFA PKS with other prokaryotic, modular PKSs elucidated the boundaries of the domains that are involved in the individual stages of polyketide assembly.

Knock-out of the cyaY gene in Escherichia coli does not affect cellular iron content and sensitivity to oxidants.

Friedreich ataxia is a recessively inherited neurodegenerative disease caused by deficiency of a highly conserved mitochondrial protein, frataxin. Frataxin deficiency results in mitochondrial iron accumulation and oxidative stress. Frataxin shows homology with the CyaY proteins of gamma-purple bacteria, whose function is unknown.

Biosynthesis of the Pseudomonas polyketide coronafacic acid requires monofunctional and multifunctional polyketide synthase proteins.

Coronafacic acid (CFA) is the polyketide component of the phytotoxin coronatine, a virulence factor of the plant pathogen Pseudomonas syringae. Our current knowledge of polyketide biosynthesis largely is based on the analysis of polyketide synthases (PKSs) in actinomycetes and other Gram-positive bacteria. Consequently, the cloning and characterization of the CFA biosynthetic gene cluster will contribute significantly to our knowledge of polyketide synthesis in Pseudomonas.

Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients.

Somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions in the central nervous system.

Most patients with Friedreich's ataxia (FRDA) carry expanded GAA repeats in both homologues of the frataxin gene on chromosome 9. We determined the size of the GAA repeats in autopsied samples from the CNS of six FRDA patients. We observed heterogeneity of repeat sizes in different CNS regions, indicative of extensive mitotic instability.

Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin.

The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function.

Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo.

Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused either by an intronic GAA triplet repeat expansion that suppresses the expression of the frataxin gene on chromosome 9q13, or, rarely, by point mutations in the frataxin gene. We investigated the expression of the mouse frataxin homologue during embryonic development by Northern blot analysis and RNA in situ hybridization. Very faint expression could be detected from E10.