Progress Of Association Research Articles

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p<0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p=0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

Medication Overuse and Medication Overuse Headache: Risk Factors, Comorbidities, Associated Burdens and Nonpharmacologic and Pharmacologic Treatment Approaches.

With a worldwide high disease burden, medication overuse headache (MOH) is an endemic and disabling neurological disorder. Because of the limitations of previous study designs, there are still debates and questions regarding the disease's nature and treatment strategy. This review will discuss the following concepts; (1) recent progress in association between medication overuse (MO) and MOH; (2) the burden, risk factors and comorbidities of MOH; (3) evidence of treatment in patients with MOH. The causal relationship between MO and MOH has not been identified. Currently, the treatment policy is still mainly based on small clinical observations, some with highly specified patients. In addition to withdrawal and preventive treatment, some studies have provided evidence for nonpharmacological treatments. Well-designed studies for specific treatment strategies with enough statistical power are warranted to make more relevant, better clinical decisions.

Liver enzyme profile and progression in association with thyroid autoimmunity in Graves' disease.

ObjectiveTo investigate the associations of Graves' disease (GD) severity, autoimmunity and longitudinal liver enzyme changes with time in a cohort with well‐characterized GD.DesignRetrospective cohort study.PatientsPatients diagnosed with Graves' disease, treated at Royal Prince Alfred Hospital Sydney, Adult Thyroid Clinic from 2000 to 2012 inclusive.MeasurementsInclusion criteria were patients with a complete set of TSH, FT4, FT3, liver enzymes and TSH receptor antibody (TRAb) results prior to commencement of thionamide therapy.ResultsOf the 146 patients who had complete results, 69 (47%) had at least one abnormal liver enzyme. Gamma glutamyltransferase (GGT) was most frequently abnormal (74%), followed by alanine aminotransferase (ALT) (57%), alkaline phosphatase (ALP) (39%) and then aspartate aminotransferase (AST) (29%). Subsequent to thyroid function normalization, 78% of the liver enzymes were normalized, 10% were persistently abnormal and 12% were lost to follow‐up. Circulating TRAb, FT3 and FT4 results were categorized into mild, moderate and severe elevations. At univariate regression analyses, TRAb, FT3 and FT4 levels were each significantly associated with abnormal liver enzyme profile. Multivariate regression including TRAB, FT3 and FT4 as independent variables demonstrated FT3 and FT4 were more strongly associated with abnormal liver profile than TRAb. However, the initial FT3 and FT4 levels were not associated with abnormal liver profile in the subgroup with persistently abnormal liver profile.ConclusionGraves' disease is commonly associated with abnormal liver enzymes, and most commonly with abnormal levels of GGT, and that an abnormal liver enzyme profile is more directly linked to the degree of thyrotoxicosis than levels of TRAB.

PRP‑1 significantly decreases the ALDHhigh cancer stem cell population and regulates the aberrant Wnt/β‑catenin pathway in human chondrosarcoma JJ012cells.

Chondrosarcomas are malignant bone tumors refractory to chemotherapy and radiation treatment; thus, novel therapeutic strategies are required. Proline-rich polypeptide 1 (PRP-1) has previously demonstrated antitumor properties in chondrosarcoma. To further investigate the role of PRP-1 in chondrosarcoma cells, its effects on cancer stem cell (CSC) populations were determined by analyzing aldehyde dehydrogenase (ALDH) activity, an established marker of CSCs, in association with regulation of the Wnt/β-catenin signaling. A significant decrease in ALDHhigh CSCs was observed following treatment of chondrosarcoma JJ012 cells with PRP-1. For RT2 profiler PCR array analysis of Wnt/β-catenin signaling genes, cells were sorted into: i) Bulk JJ012 cells; ii) ALDHhigh cells sorted from untreated JJ012 cells (ALDHhigh-untreated); and iii) ALDHlow cells sorted from PRP-1-treated JJ012 cells (ALDHlow-PRP-1). The expression levels of Wnt/β-catenin signaling genes were determined to be downregulated in the ALDHhigh-untreated cells and upregulated in ALDHlow-PRP-1 cells when compared to the bulk JJ012 cells. Additionally, two important oncogenes involved in this pathway, MMP7 and CCND2, were found to be downregulated in the ALDHlow-PRP-1 cells. Immunocytochemistry demonstrated the localization of β-catenin in the nuclei of the PRP-1-treated cells. Western blotting indicated increased β-catenin expression in the ALDHlow-PRP-1 cells compared with the bulk JJ012 cells. Analysis of the cytoplasmic and nuclear fractions of cells treated with increasing concentrations of PRP-1 and β-catenin nuclear translocation inhibitor CGP57380, suggested the nuclear translocation of β-catenin following PRP-1 treatment. In addition, treatment of JJ012 cells with a specific ALDH inhibitor, diethylaminobenzaldehyde, and PRP-1 resulted in a significant decrease in cytoplasmic β-catenin protein expression. This indicated that ALDH inactivation may be associated with the nuclear translocation of β-catenin. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway has been previously documented. The findings of the present study support the notion that Wnt/β-catenin activation may serve a differential role in sarcomas, limiting tumor progression in association with decreased CSC activity.

MicroRNA-16-5p-containing exosomes derived from bone marrow-derived mesenchymal stem cells inhibit proliferation, migration, and invasion, while promoting apoptosis of colorectal cancer cells by downregulating ITGA2.

Colorectal cancer (CRC) is a form of cancer developing from either the colon or rectum. Nowadays, research supports the functionality of exosome expressing microRNAs (miRNAs) as potential biomarker for various cancers including CRC. This study was performed with the intent of investigating the roles of both bone marrow-derived mesenchymal stem cells (BMSCs) and exosomal miR-16-5p in CRC by regulating integrin α2 (ITGA2). A microarray-based analysis was conducted to screen the CRC-associated differentially expressed genes (DEGs) as well as potential regulatory miRNAs. Next, the role of miR-16-5p in terms of its progression in association with CRC was determined. Subsequently, CRC cells were exposed to exosomes secreted by BMSCs transfected with miR-16-5p, isolated and cocultured with CRC cells in an attempt to identify the role of exosomes. Effects of BMSCs-derived exosomes overexpressing miR-16-5p on biological functions of CRC cells and tumorigenicity were all subsequently detected. Effects of miR-16-5p treated with CRC cells in regard to CRC in vivo were also measured. ITGA2 was overexpressed, while miR-16-5p was poorly expressed in CRC cells and miR-16-5p targeted ITGA2. The in vitro experiments revealed that the BMSCs-derived exosomes overexpressing miR-16-5p inhibited proliferation, migration, and invasion, while simultaneously stimulating the apoptosis of the CRC cells via downregulation of ITGA2. Furthermore, the results of in vivo experiments confirmed that the BMSCs-derived exosomes overexpressing miR-16-5p repressed the tumor growth of CRC. Collectively, BMSCs-derived exosomes overexpressing miR-16-5p restricted the progression of CRC by downregulating ITGA2.

Research progress in association between indoor air environment and elderly cardiovascular diseases

The relationship between indoor air environment and elderly with cardiovascular diseases (CVD) was reviewed through literature research in this paper. In heat and humidity environment, studies have shown that changes in heat environment such as high temperature, cold and step-changes were highly associated with cardiovascular diseases in the elderly. The influence of air humidity on cardiovascular diseases was uncertain. In indoor air quality, PM10, PM2.5, CO, SO2, NO2 and ozone had correlation with cardiovascular diseases in the elderly, with the higher incidence and mortality resulting from higher concentrations of pollutants. It is significant to establish the relationship between indoor air environment and elderly cardiovascular diseases in different climatic zones. The multi-parameter joint action of indoor air environment and comprehensive characterization and evaluation method will be the future research orientation. In addition, the combined field of medicine and engineering may provide more research ideas for environmental and health issues in the future.

Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center-Follicular Helper T Cells.

CD4 germinal center (GC)-follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis. Wild-type and Adora2a-deficient mouse KRN T cell receptor-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-Ag7 were transferred into immunodeficient Tcra-/- I-Ag7 -expressing mice to induce arthritis. Recipients were then treated with either the selective A2aR agonist CGS-21680 (CGS) or phosphate buffered saline alone. Severity of disease, autoantibody titers, KRN T cell numbers and phenotype, and GPI-specific isotype class-switched plasmablasts were tracked. CGS treatment inhibited the development of arthritis and differentiation of KRN GC-Tfh cells, blocked the appearance of high-affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in serum titers of anti-GPI IgG1. In addition, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reductions in the number of KRN GC-Tfh cells and anti-GPI IgG1 serum titers. Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh cell lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. These data in a mouse model of autoimmune arthritis suggest that A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC-Tfh cell differentiation.

Gene Expression Analysis of the Activating Factor 3/Nuclear Protein 1 Axis in a Non-alcoholic Steatohepatitis Mouse Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a chronic liver disease related to metabolic syndrome that can progress to liver cirrhosis. The involvement of the endoplasmic reticulum (ER) stress response in NAFLD progression and the roles played by activating factor 3 (ATF3) and the downstream nuclear protein 1 (NUPR1) are poorly understood. The aim of this study was to determine the gene expression profiles around the ATF3/NUPR1 axis in relation to the development of NAFLD using novel mouse models. Fatty liver Shionogi (FLS) mice (n = 12) as a NAFLD model and FLS-ob/ob mice (n = 28) as a NASH model were fed a standard diet. The FLS mice were sacrificed at 24 weeks of age as a control, whereas the FLS-ob/ob mice were sacrificed at 24, 36, and 48 weeks of age. Hepatic steatosis, inflammation, and fibrosis were evaluated by biochemical, histological, and gene expression analyses. The expression levels of the ER-stress related genes Jun proto-oncogene (C-jun), Atf3, Nupr1, and C/EBP homologous protein (Chop) were measured in liver tissue. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Control mice demonstrated hepatic steatosis alone without apparent fibrosis. On the other hand, FLS-ob/ob mice showed severe steatohepatitis at both 24 and 36 weeks of age and severe fibrosis at both 36 and 48 weeks of age. The expression levels of Atf3, Nupr-1, and C-jun significantly increased from 24 to 48 weeks of age in FLS-ob/ob mice compared with control mice. The expression level of Chop was already high in FLS mice and maintained similar levels in FLS-ob/ob mice; the expression level was consistent with the percentage of TUNEL-positive cells. The ATF3/NUPR1 axis plays a pivotal role in NASH progression in association with C-jun and Chop and appears to induce apoptosis from early steatosis in the NASH model mice.

Histopathological and biochemical changes in the development of nonalcoholic fatty liver disease induced by high-sucrose diet at different times.

The high intake of sweetened drinks is associated with obesity and insulin resistance. These pathologies are directly related to the development of nonalcoholic fatty liver disease (NAFLD), considered a condition of metabolic syndrome (MS). Due to their increasing worldwide prevalence, experimental animal models have been developed to gain a better understanding of its physiopathology; notwithstanding, few studies have evaluated its progression in association with MS and ingestion of sweetened drinks. Therefore, the aim of this study was to understand the pathophysiologic characteristics of NAFLD related to sucrose concentration and time of ingestion in rats. Wistar rats were divided into 2 groups with free access to either tap water or 30% sucrose, and euthanized at 12, 16, or 20 weeks; and 2 additional groups were given free access to either 40% or 50% sucrose and were euthanized at 20 weeks. Biochemical parameters and levels of serum cytokines were measured, and histology was performed. Ingestion of 30% sucrose induced liver steatosis until 16 weeks (grade 2) and 20 weeks (grade 3). Meanwhile, during 20 weeks, 40% sucrose induced grade 5 of nonalcoholic steatohepatitis (NASH) and 50% sucrose induced grade 6 of NASH and fibrosis. This study demonstrated that increasing time of induction and concentration of sucrose ingestion resulted in a higher grade of NAFLD.

Schwann Cell Responses and Plasticity in Different Dental Pulp Scenarios.

Mammalian teeth have evolved as dentin units that enclose a complex system of sensory innervation to protect and preserve their structure and function. In human dental pulp (DP), mechanosensory and nociceptive fibers form a dense meshwork of nerve endings at the coronal dentin-pulp interface, which arise from myelinated and non-myelinated axons of the Raschkow plexus (RP). Schwann cells (SCs) play a crucial role in the support, maintenance and regeneration after injury of these fibers. We have recently characterized two SC phenotypes hierarchically organized within the coronal and radicular DP in human teeth. Myelinating and non-myelinating SCs (nmSCs) display a high degree of plasticity associated with nociceptive C-fiber sprouting and axonal degeneration in response to DP injuries from dentin caries or physiological root resorption (PRR). By comparative immunolabeling, confocal and electron microscopy, we have characterized short-term adaptive responses of SC phenotypes to nerve injuries, and long-term changes related to aging. An increase of SCs characterizes the early responses to caries progression in association with axonal sprouting in affected DP domains. Moreover, during PRR, the formation of bands of Büngner is observed as part of SC repair tracks functions. On the other hand, myelinated axon density is significantly reduced with tooth age, as part of a gradual decrease in DP defense and repair capacities. The remarkable plasticity and capacity of SCs to preserve DP innervation in different dental scenarios constitutes a fundamental aspect to improve clinical treatments. This review article discusses the central role of myelinating and non-mSCs in long-term tooth preservation and homeostasis.

Rapid HIV disease progression following superinfection in an HLA-B*27:05/B*57:01-positive transmission recipient

Background The factors determining differential HIV disease outcome among individuals expressing protective HLA alleles such as HLA-B*27:05 and HLA-B*57:01 remain unknown. We here analyse two HIV-infected subjects expressing both HLA-B*27:05 and HLA-B*57:01. One subject maintained low-to-undetectable viral loads for more than a decade of follow up. The other progressed to AIDS in < 3 years.Results The rapid progressor was the recipient within a known transmission pair, enabling virus sequences to be tracked from transmission. Progression was associated with a 12% Gag sequence change and 26% Nef sequence change at the amino acid level within 2 years. Although next generation sequencing from early timepoints indicated that multiple CD8+ cytotoxic T lymphocyte (CTL) escape mutants were being selected prior to superinfection, < 4% of the amino acid changes arising from superinfection could be ascribed to CTL escape. Analysis of an HLA-B*27:05/B*57:01 non-progressor, in contrast, demonstrated minimal virus sequence diversification (1.1% Gag amino acid sequence change over 10 years), and dominant HIV-specific CTL responses previously shown to be effective in control of viraemia were maintained. Clonal sequencing demonstrated that escape variants were generated within the non-progressor, but in many cases were not selected. In the rapid progressor, progression occurred despite substantial reductions in viral replicative capacity (VRC), and non-progression in the elite controller despite relatively high VRC.ConclusionsThese data are consistent with previous studies demonstrating rapid progression in association with superinfection and that rapid disease progression can occur despite the relatively the low VRC that is typically observed in the setting of multiple CTL escape mutants.

Research progress in association between PM(2.5) and pediatric asthma

Research progress in association between PM(2.5) and pediatric asthma

The Second Phase of Realism in American Fiction: The Rise and Fall of the Social Self

Contributing to the current effort to rethink American realism, this essay concentrates on the work of second-generation realist novelists both well known (Dreiser, Wharton) and forgotten (Robert Grant, Robert Herrick, and Booth Tarkington). I argue that, during the first two decades of the twentieth century, American novelists did for fiction what their contemporaries, the pragmatists, did for philosophy: they reconceive the modern subject for a new modernity. Like the philosophical tradition of the previous two centuries, earlier realist fiction understood the liberal individual as the exemplary modern subject. However, in an age characterized by “the regress of self-sufficiency and the progress of association,” as one contemporary economist had it, liberal individualism’s stock dropped among a number of thinkers—artists and academics alike. As the essay demonstrates the way in which novelists participate in this culturewide effort to transform realism and redefine modern subjectivity in the US, it also challenges the received relationship between women and consumption. To overturn the standard view that consumption was largely a solipsistic activity in women, I show the ways in which this body of fiction, together with pragmatist writings, exposes the thoroughgoing sociality of consumer culture.

New Strategies in Multiple Myeloma: Immunotherapy as a Novel Approach to Treat Patients with Multiple Myeloma.

Multiple myeloma is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Although new therapeutic options introduced in recent years have resulted in improved survival outcomes, multiple myeloma remains incurable for a large number of patients, and new treatment options are urgently needed. Over the last 5 years, there has been a renewed interest in the clinical potential of immunotherapy for the treatment of multiple myeloma. Clinical progression of myeloma is known to be associated with progressive immune dysregulation and loss of immune surveillance that contribute to disease progression in association with progressive genetic complexity, rendering signaling-based treatments less effective. A variety of strategies to reverse the multiple myeloma-induced immunosuppression has been developed either in the form of immunomodulatory drugs, checkpoint inhibitors, mAbs, engineered T cells, and vaccines. They have shown encouraging results in patients with relapsed refractory multiple myeloma and hold great promise in further improving patient outcomes in multiple myeloma. This review will summarize the major approaches in multiple myeloma immunotherapies and discuss the mechanisms of action and clinical activity of these strategies. Clin Cancer Res; 22(24); 5959-65. ©2016 AACR.

Research progress in association between interleukin-23 and liver diseases

Research progress in association between interleukin-23 and liver diseases

Research progress in association between interleukin 28B gene polymorphism and hepatitis B

Research progress in association between interleukin 28B gene polymorphism and hepatitis B

O10.06 * A PHASE II STUDY OF AINO (ITALIAN ASSOCIATION OF NEURO-ONCOLOGY) ON BEVACIZUMAB AND FOTEMUSTINE FOR RECURRENT GLIOBLASTOMA: OUTCOME, PATTERNS OF RELAPSE AND SALVAGE TREATMENTS

BACKGROUND: Information on outcome after the combination of bevacizumab and nitrosoureas in recurrent glioblastomas are lacking. PATIENTS AND METHODS: We have performed a phase 2 trial of combined bevacizumab (BEV) and fotemustine (FTM)(a higly lipophilic nitrosourea) for patients with GBM at first relapse after radiotherapy and concomitant and adjuvant temozolomide. Treatment consisted of BEV at 10 mg/kg on day 1, 15 and FTM at 75 mg/m2/die on day 1, 8 and, after 3 weeks interval, followed by BEV at 10 mg/kg and FTM at 75mg/m2 every 3 weeks as a maintenance treatment, until tumor progression or unacceptable toxicity. MRI was performed at baseline, after 6 weeks from the start of therapy, and thereafter every 2 months. Response on MRI was evaluated according to RANO. RESULTS: Between May 2007 and December 2010, 54 patients were enrolled. The median age was 57 years. Forty-six patients had unifocal tumors, while 8 multifocal tumors. At study entry 41/54 of patients were on steroids, with a median dosage of 4mg. Twenty patients had MGMT unmethylated tumors while 18 had MGMT methylated tumors (in 16 patients data were not available). Median PFS was 5.2 months, and PFS-6 rate was 42.6%. Median OS was 9.1 months and OS-6 and OS-12 were 75.9% and 29.7% respectively. The overall RR was 52% (4% CR, 48% PR) with 37% of SD and 11% of PD. The median time to maximum response was 4 weeks (range 4-12 weeks). Among the 41 patients who were on steroids at study initiation, 32 were able to taper, including 17 who completely stopped. MGMT methylation was not associated with response, PFS or OS. Patterns of tumor failure on MRI after study treatment were available in 50/54 patients. All 8 tumors, that were multifocal before treatment, had a multifocal progression. Forty-two patients had unifocal tumors before treatment, and patterns of progression were as follows: local (enhancing) in 76%, distant (enhancing) in 7%, multifocal (local + distant enhancing) in 4.5%, diffuse (nonenhancing) in 9.5% and isolated leptomeningeal spread in 2%. The pattern of tumor failure was not associated with previous response to treatment. Overall survival after failure was not significantly different according to patterns of tumor progression. Following progression on BEV + FTM, 21/50 patients received salvage chemotherapy and in 1 of these patients BEV was maintained beyond progression in association with chemotherapy. Twenty-nine out of 50 patients received supportive care alone. Patients who received salvage chemotherapy had a median survival of 4.53 months, while patients who received supportive care alone had a median survival of 2.2 months. CONCLUSIONS: This study failed to demonstrate a superiority of the combination of BEV and FTM over either BEV or FTM alone as historical controls. Patterns of tumor progression after treatment did not influence the outcome while the prognosis was poor regardless of salvage chemotherapy or palliative care.

Abstract 305: Myeloid Cell-Specific VEGF-A Deletion Inhibits Experimental Abdominal Aortic Aneurysms

Mural macrophage infiltration and angiogenesis are histopathological hallmarks of abdominal aortic aneurysms (AAA). Macrophages produce angiogenic cytokine VEGF-A in many pathologic settings. It is not known whether VEGF-A produced by macrophages plays a role in aneurysm disease. In this study, we generated myeloid cell-specific VEGF-A conditional knockout (CKO) mice using the Cre/LoxP technology, and evaluated the influences of myeloid VEGF-A ablation on the formation and progression of aneurysm disease. AAAs were created in 10-12 week old male CKO and wild type (WT) mice via intra-aortic porcine pancreatic elastase (PPE) infusion and assessed by serial ultrasound measurements of aortic diameters followed by histology at sacrifice. Following PPE infusion, aneurysmal degeneration was significantly blunted in CKO mice. Histologically, medial elastin fragmentation, macrophage density, and mural angiogenesis were significantly diminished in the aortae of CKO mice compared to those in WT mice. Additionally, myeloid VEGF-A deletion caused marked reduction in peritoneal CD115-positive or F4/80-positive macrophages following thioglycollate injection. In conclusion, targeted deletion of VEGF-A in myeloid cells suppresses aneurysm initiation and progression in association with reduced mural macrophage accumulation and angiogenesis.

Nucleostemin expression in invasive breast cancer

BackgroundRecently, the cancer stem cell hypothesis has become widely accepted. Cancer stem cells are thought to possess the ability to undergo self-renewal and differentiation, similar to normal stem cells. Nucleostemin (NS), initially cloned from rat neural stem cells, binds to various proteins, including p53, in the nucleus and is thought to be a key molecule for stemness. NS is expressed in various types of cancers; therefore, its role in cancer pathogenesis is thought to be important. This study was conducted to clarify the clinicopathological and prognostic impact of NS in invasive breast cancers.MethodThe correlation between NS immunoreactivity and clinicopathological parameters was examined in 220 consecutive surgically resected invasive breast cancer tissue samples by using tissue microarrays. The presence of nuclear NS and p53 immunoreactivity in 10% or more of cancer cells was considered as a positive result.ResultsAmong the 220 patients, 154 were hormone-receptor (HR)-positive, 22 HER2-positive/HR-negative, and 44 HR-negative/HER2-negative. One hundred and forty-two tumors (64.5%) showed NS positivity, and this positivity was significantly correlated with estrogen receptor (ER) (P = 0.050), human epidermal growth factor receptor 2 (HER2) (P = 0.021), and p53 (P = 0.031) positivity. The patients with NS-positive tumors showed significantly shorter disease-free survival than those with NS-negative tumors. Furthermore, the patient group with NS- and p53-positive tumors showed significantly poorer prognosis than other patient groups. Multivariate analysis showed that NS status was an independent prognostic indicator.ConclusionsNS may play a significant role in the determination of breast cancer progression in association with p53 alterations. The NS status of patients with luminal and HER2 type breast cancers may be a useful prognostic marker.

The Antidepressant Desipramine and α2-Adrenergic Receptor Activation Promote Breast Tumor Progression in Association with Altered Collagen Structure

Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adrenergic receptor in vivo altered 4T1 tumor progression in vivo. Chronic treatment with the antidepressant desipramine (DMI) to inhibit norepinephrine reuptake increased 4T1 tumor growth but not metastasis. Treatment with a highly selective α2-adrenergic receptor agonist, dexmedetomidine (DEX), increased tumor growth and metastasis. Neither isoproterenol (ISO), a β-AR agonist, nor phenylephrine, an α1-AR agonist, altered tumor growth or metastasis. Neither DMI- nor DEX-induced tumor growth was associated with increased angiogenesis. In DMI-treated mice, tumor VEGF, IL-6, and the prometastatic chemokines RANTES, M-CSF, and MIP-2 were reduced. Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice, tumor SHG was significantly altered without changing fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote tumor progression in the absence of direct sympathetic input to breast tumor cells. The results also suggest that SNS activation may regulate tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of breast tumor pathogenesis, and suggest that the therapeutic use of adrenergic receptor blockers, tricyclic antidepressants, and adrenergic receptor agonists must be approached cautiously in patients with breast cancer.