Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome

Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages??proliferating macrophages (promacs)??with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P?=?0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions.     

Morphological and biochemical investigation into the possible neuroprotective effects of kolaviron (Garcinia kola bioflavonoid) on the brains of rats exposed to vanadium

In this study, the morphological and biochemical susceptibility of the rat brain to vanadium, in the form of sodium metavanadate, and the comparative ameliorative effect of Garcinia kola and kolaviron (G. kola extract), was examined. Brain regions examined were the cerebrum, cerebellum, hippocampus and the olfactory bulb. We showed that vanadium administration caused cellular vacuolation, congestion, and Purkinje cell degeneration and a marked reduction in myelin tracts. Biochemical tests revealed increased lipid peroxidation induced by vanadium, which was ameliorated with the administration of G. kola and kolaviron. Vanadium administration caused an increase in thiobarbituric acid-reactive substances (TBARS) in the cerebrum and hippocampus, whereas the administration of kolaviron resulted in a reduction of the TBARS level by 65.7 and 80%, respectively, in the regions aforementioned. Also, the administration of kolaviron resulted in an increased activity of superoxide dismutase (61.24%) in all brain regions assessed, when compared with the group administered vanadium alone. Results obtained from this study led to the conclusion that kolaviron reduces vanadium-induced oxidative stress in the brain.     

High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients

Inherited mutations in the BRCA1 and BRCA2 genes are the strongest genetic predictors of breast cancer and are the primary causes of familial breast/ovarian cancer syndrome. The frequency, spectrum and penetrance of mutant BRCA1/BRCA2 alleles have been determined for several populations, but little information is available for populations of African ancestry, who suffer a disproportionate burden of early onset breast cancer. We have performed complete sequence analysis of all BRCA1 and BRCA2 exons and intron-exon boundaries for 434 Nigerian breast cancer patients from the University College Hospital in Ibadan, Nigeria. In contrast to previous suggestions that BRCA1/BRCA2 mutation frequencies are low or undetectable in African American populations, we find that Nigerian breast cancer patients have an exceptionally high frequency of BRCA1 and BRCA2 mutations (7.1 and 3.9%, respectively). Sixteen different BRCA1 mutations were detected, seven of which have never been reported previously, while thirteen different BRCA2 mutations were seen, six of which were previously unreported. Thus, our data support enrichment for genetic risk factors in this relatively young cohort. To improve breast cancer outcomes, we suggest that family-based models of risk assessment and genetic counseling coupled with interventions to reduce breast cancer risk should be broadly disseminated in Nigeria and other underserved and understudied populations.     

Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657

PURPOSE Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers. PATIENTS AND METHODS Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets. Results In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets. CONCLUSION In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.     

Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer

Breast cancer is the most prevalent cancer worldwide. Many published articles have evaluated the association between the transforming growth factor beta 1 (TGFB1) T29C polymorphism and breast cancer risk. However, the results remain inconclusive. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 12 studies including 10,417 breast cancer cases and 11,455 controls were identified. Overall, no significant associations between the TGFB1 T29C polymorphism and breast cancer risk were found for CC versus TT (OR = 1.00, 95% CI = 0.92–1.09), TC versus TT (OR = 0.98, 95% CI = 0.93–1.05), CC/TC versus TT (OR = 0.99, 95% CI = 0.93–1.05), and CC versus TC/TT (OR = 1.00, 95% CI = 0.93–1.08). In the subgroup analysis by ethnicity, source of controls, and menopausal status, there was still no significant association detected in all genetic models. In conclusion, the present meta-analysis suggests that the TGFB1 T29C polymorphism is not a low-penetrant risk factor for developing breast cancer.     

Correlation of acetylcholinesterase activity in the brain and blood of wistar rats acutely infected with Trypanosoma congolense

ObjectiveTo investigate the neurotransmitter enzyme Acetylcholinesterase (AChE) activity in the brain and blood of rats infected with Trypanosoma congolense (T. congo).MethodsPresence and degree of parasitemia was determined daily for each rat by the rapid matching method. AChE activity was determined by preparing a reaction mixture of brain homogenate and whole blood with 5, 5-dithiobisnitrobenzioc acid (DTNB or Ellman's reagent) and Acetylthiocholine (ATC). The increase in absorbance was recorded at 436 nm over 10 min at 2 min intervals. Trypanosome species identification (before inoculation and on day 10 post infection) was done by Polymerase chain reaction using specific primers.ResultsThe AChE activity in the brain and blood decreased significantly as compared with the uninfected control. The AChE activity dropped to 0.32 from 2.20 μmol ACTC min^?1mg protein^?1 in the brain and 4.57 to 0.76 μmol ACTC min-1mg protein^?1 in the blood. The animals treated with Diminaveto at 3.5 mg/kg/d were observed to have recovered significantly from parasitemia and were able to regain AChE activity in the blood but not in the brain as compared to the control groups. We also observed, that progressive parasitemia resulted to alterations in PCV, Hb, RBC, WBC, neurophils, total protein, lymphocytes, monocytes and eosinophil in acute infections of T. congo. Polymerase chain reaction (PCR) of infected blood before inoculation and on day 10 post infection revealed 600 bp on agarose gel electrophoresis.ConclusionsThis finding suggest that decrease in AChE activity increases acetylcholine concentration in the synaptic cleft resulting to neurological failures in impulse transfer in T. congo infection rats.     

RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers

The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in approximately 50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10-2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06-2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04-3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.     

Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization.

PURPOSE: To better define cytogenetic mechanisms of CDKN2 loss at 9p21 and of DBCCR1 loss at 9q33 in bladder cancer, and to determine correlation with p53 and pRb. EXPERIMENTAL DESIGN: Two-color fluorescence in situ hybridization (FISH) using a chromosome 9 centromeric probe and locus-specific probes was performed. p53 and pRb were assessed by immunohistochemistry. RESULTS: Thirty-seven of fifty-five (67%) samples exhibited 9p21 loss, and 32 of 44 (73%) exhibited 9q33 loss. Twelve of 43 informative samples exhibited only 9p21 loss (5 cases) or only 9q33 loss (7 cases). Homozygous deletions were noted at 9p21 and 9q33 in 31 and 14% of cases, respectively, but 9q33 homozygous deletions were generally observed in only a minor clone. There was no correlation of any chromosome 9 loss with stage, but stage did correlate with chromosome 9 ploidy status; aneusomy 9 was observed in 33% of T(a) lesions and 71% of more advanced cases (P = 0.01). Aneusomy 9 was loosely correlated with p53 abnormalities (P = 0.07), but no correlation between any chromosome 9 and pRb abnormalities was discerned. CONCLUSIONS: This study strengthens the proposition that chromosome 9 losses occur early in bladder oncogenesis and before p53 alterations or development of aneusomy. The correlation of aneusomy 9 with p53 abnormalities is consistent with the presumed role of p53 in maintaining cytogenetic stability. Although the observed homozygous deletions strengthen the hypotheses that CDKN2 and DBCCR1 are important tumor suppressor genes, there is no evidence that either is a more critical or an earlier target for oncogenesis.     

Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers

Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan–Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.