Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.     

Non-clastogenicity in mouse bone marrow of fructose/lysine and other sugar/amino acid browning products with in vitro genotoxicity

Heated sugar/amino acid reaction mixtures, known to contain products that are clastogenic and/or mutagenic to cells in vitro, were evaluated for clastogenic activity in mouse bone marrow using the erythrocyte micronucleus assay. Heated (i.e. browned) fructose/lysine reaction mixtures were also evaluated in the Salmonella his-reversion assay and the Chinese hamster ovary (CHO) cell chromosomal aberration assay to confirm and extend previous in vitro observations. Significant mutagenicity of fructose/lysine mixtures was observed in Salmonella typhimurium strains TA100, TA2637, TA98 and TA102, with greater activity in mixtures heated at pH 10 than at pH 7. S-9 decreased the activity in strains TA100, TA2637 and TA98, but increased the activity in strain TA102. Both pH 7 and pH 10 reaction mixtures of the fructose/lysine browning reaction were highly clastogenic in CHO cells. Heated mixtures of fructose and lysine, and of glucose or ribose with lysine, histidine, tryptophan or cysteine, did not increase the frequency of micronucleated erythrocytes in mice when administered by the oral route. This indicates the absence of chromosomal aberrations in erythrocyte precursor cells, and indicates that the genotoxic components of the browned mixtures are not absorbed and distributed to bone marrow cells in amounts sufficient to induce micronuclei when given orally. Because sugar/amino acid browning reactions occur commonly in heated foods, it is important to evaluate further the in vivo genotoxicity of browning products in cell populations other than bone marrow.     

The development of neurons in the cat perigeniculate nucleus and reticular nucleus of the thalamus

The postnatal development of soma size and cytochrome oxidase activity was examined in the perigeniculate nucleus (PGN) and reticular nucleus of the thalamus (RNT). Neurons in the PGN and RNT exhibited a rapid increase in soma size between 2 and 4 weeks of age. During this period of cell growth there is an increase in the intensity of cytochrome oxidase staining within the cell body. Cells in both the PGN and RNT decrease in size after 4 weeks of age, and become very fusiform in shape. During this postnatal period, there is also a shift in cytochrome oxidase staining from the cell body to the dendrites.     

An analysis of the paradoxical effect of morphine on runway speed and food consumption

A previously reported paradigm in which rats run down a runway for food reward followed by morphine injection was analyzed to assess the utility of the paradigm in studies of opiate reinforcement. One experiment replicated the original report that post-trial morphine caused both an increase in runway speed and a decrease in food consumption (taste aversion) over successive trials, and showed in addition that the increase in runway speed did not occur as a result of food deprivation alone, but required the animals to have consumed food in the goal box. A second study using the quaternary opiate antagonist methyl naltrexone to block the peripheral effects of morphine suggested that the increase in runway speed has a peripheral locus while the taste aversion has a central one. A third experiment in which morphine was microinjected into either the lateral ventricle or the ventral tegmental area supported these observations, in that intracranial morphine failed to result in an increased runway speed, but did produce taste aversion after microinjection into either site. These findings also suggest that the increase in runway speed caused by post-trial morphine in this experiment has a peripheral locus of effect, which is probably distinct from the central effect that supports morphine self-administration and conditioned place preference. Offprint requests to: W.A.CorrigallThe views expressed in this publication are those of the authors and do not necessarily reflect those of the Addiction Research Foundation     

Northern Ireland: Political violence and self- reported physical symptoms in a community sample

In order to investigate the possible relationship between physical health and political violence in Northern Ireland a random sample of residents of four electoral areas (two with relatively high violence and two with relatively low violence) was interviewed at home. Each person was asked to rate their health in terms of common physical symptoms, to indicate their use of family doctor and hospital services, and to rate the level of political violence in their neighbourhood. Analysis of covariance (with a measure of psychological well-being, a measure of trait neuroticism plus age and socioeconomic status as covariates) revealed that women reported more physical symptoms than did men, people in the ‘high’ violence areas reported more symptoms than did those in the ‘low’ violence areas, while those who rated their own neighbourhood most highly in terms of perceived violence also reported the greatest number of physical symptoms. However, a series of χ² tests revealed no association between political violence or perceived political violence and uptake of services.     

Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

Contribution of Gender to Pathophysiology and Clinical Presentation of IBS: Should Management Be Different in Women?

The irritable bowel syndrome (IBS) is found more commonly in women than men. It is more prevalent in patients with chronic fatigue syndrome, fibromyalgia, and chronic pelvic pain, all syndromes characterized by pain and found predominantly in women. This article reviews evidence for a role of biological sex factors and gender on the pathways mediating visceral pain. The effect of gonadal hormones on gastrointestinal motility and the sensory afferent pathway and central processing of visceral stimuli and the contribution of gender role to the clinical presentation are discussed. Although differences in responses to treatment modalities between genders exist, the approach to IBS patients in both genders is quite similar. Nevertheless, a special attention to gender role and stress-related factors should be addressed. New developments in research, outlined in the paper, might bring more gender-specific treatments in the future.     

Single-antibiotic use for penetrating abdominal trauma

A prospective randomized study compared the use of moxalactam disodium vs clindamycin phosphate and tobramycin sulfate for treatment of 190 patients with penetrating abdominal trauma. Twenty-seven patients were disqualified because of early death or failure to follow the protocol. The patients in each group were comparable regarding the cause and severity of injury. No significant difference was seen in the incidence of intra-abdominal infection between the moxalactam-treated group (13%) and the clindamycin- and tobramycin-treated group (9%). The intra-abdominal infection rate in patients with colon injuries (21%) was significantly increased when compared with the patients without colon injuries (6%), but the antibiotic regimen did not significantly change the infection rate. No evidence of bleeding problems from moxalactam were noted. Changes in prothrombin and partial thromboplastin times appeared to be related to shock rather than the use of moxalactam. The most severe coagulopathies occurred prior to moxalactam therapy and were seen only in those patients who had shock requiring 10 or more units of blood. Moxalactam is as effective as combination (clindamycin and tobramycin) antimicrobial therapy in patients with penetrating abdominal trauma.