Breast tumor-derived factors stimulate reduction of estrone to estradiol in nonmalignant breast tissue

Summary This study examines the paracrine influence by human breast carcinoma cells (UISO-BCA-1) on nonmalignant breast tissuein vitro. The 17-OH-SDH-mediated reductive pathway (estroneestradiol) was significantly increased in nonmalignant breast tissue coincubated with human breast carcinoma cells, compared to control tissues incubated in the media alone. No influence on the enzyme activity was noticed in coincubated breast cancer cells. Preincubation of breast cancer cells with estradiol (10^–8 M) significantly decreased the enzyme activity in coincubated nonmalignant breast tissue, which was restored to control levels by addition of R5020 (10^–8 M), tamoxifen (10^–6 M), or a combination of both. In nonmalignant tissues incubated in the presence of growth factor TGF, enzyme activity was reduced to between 46% and 76%. No other growth factors (IGF I, IGF II, PDGF) influenced enzyme activity. In nonmalignant tissues incubated with malignant tumor cytosol, enzyme activity was increased in 16% cases, inhibited in 21%, and not significantly changed in 63%.The data from the present study suggest that factors produced by breast carcinoma cells may influence interconversion of estradiol in nonmalignant tissue. In patients, factors produced by malignant tumor mass may have paracrine influence on surrounding nonmalignant breast tissue and, thereby, may influence the estrogen availability to tumor mass.     

Bergmann's rule near the equator: latitudinal clines in body size of an Andean passerine bird

Critical correlative support for Bergmann's ecogeographic rule is provided by symmetrical patterns of size variation in Diglossa carbonaria, a tropical passerine bird whose geographic range in the Andes Mountains of South America straddles the equator. Body size is positively correlated with latitude both north and south of the equator. Moreover, parapatric taxa that exhibit either partial (north-western Bolivia) or complete (northern Peru) reproductive isolation converge in body size. Relative uniformity in the length of the highly modified flower-piercing bill among populations of D. carbonaria that differ significantly in body size suggests that character displacement or interspecific competition is not responsible for these patterns. These findings support the hypothesis that climate, particularly temperature seasonality, is an important environmental determinant of geographic size variation in homeotherms. In addition they demonstrate that clinal variation correlated with subtle climatic gradients can occur in tropical environments.     

Multigenic control of skin tumor susceptibility in SENCARA/Pt mice

Skin tumors induced in mice by initiation-promotion (2 microg DMBA-2 microg TPA) protocols were found to be under multigenic control. Eighty- one N2 mice from the cross (BALB/cAnPt x SENCARA/Pt)F1 x SENCARA/Pt that were either solidly resistant (no papillomas) or highly susceptible (> or = 7 papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite markers to check for associations with susceptible and resistant phenotypes. A locus on Chr 5 (Skts4) was found to control the susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to papilloma formation. In addition, higher than expected linkage scores were seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is required to establish whether genes determining papilloma formation are located in these regions of the genome. In general, no evidence was seen for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in 17 microdissected papillomas from (BALB/c x SENCARA)F1 hybrid mice.      

Development of a new metastatic human breast carcinoma xenograft line.

Xenografts originated from human tumours offer the most appropriate research material for in vivo experimental research. However, primary human breast carcinomas are difficult to grow when transplanted in athymic mice: tumour take is less than 15%. Recently, we have achieved 60% tumour take by injecting tumour cell suspensions mixed with Matrigel. Human breast xenografts originated from primary breast carcinoma also frequently show the potential to metastasize spontaneously. In the present study, we generated a human breast carcinoma xenograft line (UISO-BCA-NMT-18) that shows 100% tumorigenicity and 80-100% lung metastasis when transplanted s.c. in athymic mice. We have studied in detail the characteristics of the xenograft and the patient''s tumour from which the xenograft line originated. Both the xenograft and the patient''s tumour showed intense staining for mutant p53 nuclear protein, and high expression of U-PA, PAI and u-PAR. In vivo growth of the xenograft is stimulated by exogenous supplementation of oestrogen. This xenograft is continuously growing in mice and has shown 80-100% metastasis for the last three successive in vivo passages. This well-characterized, oestrogen-responsive, metastatic breast carcinoma xenograft line will provide excellent research material for metastasis-related research.     

Malignancy‐induced autoimmunity to MUC1: initial antibody characterization

Abstract: Numerous reports document the existence of autoantibodies to MUC1 in the circulation of individuals with breast and other solid malignancies, with the majority of researchers utilizing MUC1 peptides in their detection. This report documents the purification, using peptide and whole molecule, and characterization of such autoantibodies from an individual with an unusual, highly MUC1‐positive, myosarcoma. Purification of autoantibodies from serum was performed using affinity chromatography against either MUC1 peptide or whole molecule MUC1 [derived both from the patient (Pt‐MUC1) and from a pool of sera from patients with advanced breast cancer (ABC‐MUC1)]. Enzyme‐linked immunosorbent assays (ELISAs) were used to compare specificity of purified autoantibodies. Peptide epitopes were determined by Ptifcan system against 7‐mer peptides covering the 20 amino acid repeat of the MUC1 extracellular domain. Substantially higher amounts of autoantibodies were isolated when purifying against Pt‐MUC1 rather than either ABC‐MUC1 or peptide. Whole molecule purified autoantibodies demonstrated an increased specificity for tumour‐derived MUC1. Pt‐MUC1 autoantibodies were of both the immunoglobulin (Ig)G and IgM class, whilst autoantibodies purified against ABC‐MUC1 and MUC1 peptide were IgG only. A greater range of peptide epitopes was defined by those autoantibodies purified against whole molecule. This report presents data indicating the presence of autoantibodies to MUC1 in an individual diagnosed with a MUC1 over‐expressing myosarcoma. Confirmation of these autoantibodies as being specific for tumour‐associated MUC1 is given. Further, it suggests that, although autoantibodies are present that recognize core protein determinants, the initial, and dominant, immunizing epitope is not purely pretentious in nature.     

Major limb amputation and mortality in patients with neuro‐ischaemic lower extremity wounds managed in a tertiary hospital: Focus on the differences among patients with diabetes,peripheral arterial disease and both

A majority of lower extremities neuro‐ischaemic wounds (NIU) are related to: (a) only diabetes (DM); (b) only peripheral artery disease (PAD); (c) co‐existing diabetes and peripheral artery disease (DM‐PAD). This study aims to characterise the major clinical outcomes of forementioned three groups of lower extremity wound patients in Singapore. Patients hospitalised for lower extremity NIU between January 2014 and October 2017 in a tertiary hospital in Singapore were analysed. Patients'' major limb amputation and mortality were assessed using Cox regression models. Cumulative survival and amputation‐free survival among the three classified groups were calculated using Kaplan‐Meier analysis. Compared with patients with only DM, those in the PAD group and the DM‐PAD group had higher risk of major limb amputation (adjusted hazard ratio: 2.47, 95% CI: 1.65‐3.70; adjusted hazard ratio: 2.01, 95% CI: 1.53‐2.65 respectively) and mortality (adjusted hazard ratio: 2.36, 95% CI: 1.57‐3.55; adjusted hazard ratio: 2.46, 95% CI: 1.86‐3.26 respectively). The 3‐year survival and amputation‐free survival were lowest in the DM‐PAD group (52.1% and 41.5% respectively), followed by the PAD group (53.3% and 44.6% respectively) and the DM group (74.2% and 68.5% respectively). Lower extremity NIU patients with PAD or DM‐PAD were found to have poorer clinical prognosis than those with DM only.     

Randomised controlled trial of intermittent vs continuous energy restriction during chemotherapy for early breast cancer

Background Excess adiposity at diagnosis and weight gain during chemotherapy is associated with tumour recurrence and chemotherapy toxicity. We assessed the efficacy of intermittent energy restriction (IER) vs continuous energy restriction (CER) for weight control and toxicity reduction during chemotherapy.Methods One hundred and seventy-two women were randomised to follow IER or CER throughout adjuvant/neoadjuvant chemotherapy. Primary endpoints were weight and body fat change. Secondary endpoints included chemotherapy toxicity, cardiovascular risk markers, and correlative markers of metabolism, inflammation and oxidative stress.Results Primary analyses showed non-significant reductions in weight (−1.1 (−2.4 to +0.2) kg, p = 0.11) and body fat (−1.0 (−2.1 to +0.1) kg, p = 0.086) in IER compared with CER. Predefined secondary analyses adjusted for body water showed significantly greater reductions in weight (−1.4 (−2.5 to −0.2) kg, p = 0.024) and body fat (−1.1 (−2.1 to −0.2) kg, p = 0.046) in IER compared with CER. Incidence of grade 3/4 toxicities were comparable overall (IER 31.0 vs CER 36.5%, p = 0.45) with a trend to fewer grade 3/4 toxicities with IER (18%) vs CER (31%) during cycles 4–6 of primarily taxane therapy (p = 0.063).Conclusions IER is feasible during chemotherapy. The potential efficacy for weight control and reducing toxicity needs to be tested in future larger trials.Clinical trial registration ISRCTN04156504.Subject terms: Randomized controlled trials, Breast cancer, Nutrition, Weight management, Breast cancer