Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4

Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER+) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4. Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin ݱ, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Surgical management of mesh-related complications after prior pelvic floor reconstructive surgery with mesh

Contains fulltext : 96379.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: The objective of this study is to evaluate the complications and anatomical and functional outcomes of the surgical treatment of mesh-related complications. METHODS: A retrospective cohort study of patients who underwent complete or partial mesh excision to treat complications after prior mesh-augmented pelvic floor reconstructive surgery was conducted. RESULTS: Seventy-three patients underwent 30 complete and 51 partial mesh excisions. Intraoperative complications occurred in 4 cases, postoperative complications in 13. Symptom relief was achieved in 92% of patients. Recurrence of pelvic organ prolapse (POP) occurred in 29% of complete and 5% of partial excisions of mesh used in POP surgery. De novo stress urinary incontinence (SUI) occurred in 36% of patients who underwent excision of a suburethral sling. CONCLUSIONS: Mesh excision relieves mesh-related complications effectively, although with a substantial risk of serious complications and recurrence of POP or SUI. More complex excisions should be performed in skilled centers

Experimental ovine toxoplasmosis: influence of the gestational stage on the clinical course, lesion development and parasite distribution

P. 1-14The relation between gestational age and foetal death risk in ovine toxoplasmosis is already known, but the mechanisms involved are not yet clear. In order to study how the stage of gestation influences these mechanisms, pregnant sheep of the same age and genetic background were orally dosed with 50 oocysts of Toxoplasma gondii (M4 isolate) at days 40 (G1), 90 (G2) and 120 (G3) of gestation. In each group, four animals were culled on the second, third and fourth week post infection (pi) in order to evaluate parasite load and distribution, and lesions in target organs. Ewes from G1 showed a longer period of hyperthermia than the other groups. Abortions occurred in all groups. While in G2 they were more frequent during the acute phase of the disease, in G3 they mainly occurred after day 20 pi. After challenge, parasite and lesions in the placentas and foetuses were detected from day 19 pi in G3 while in G2 or G1 they were only detected at day 26 pi. However, after initial detection at day 19 pi, parasite burden, measured through RT-PCR, in placenta or foetus of G3 did not increase significantly and, at in the third week pi it was lower than that measured in foetal liver or placenta from G1 to G3 respectively. These results show that the period of gestation clearly influences the parasite multiplication and development of lesions in the placenta and foetus and, as a consequence, the clinical course in ovine toxoplasmosis.S

Competition for Cooperation: variability, benefits and heritability of relational wealth in hunter-gatherers

Many defining human characteristics including theory of mind, culture and language relate to our sociality, and facilitate the formation and maintenance of cooperative relationships. Therefore, deciphering the context in which our sociality evolved is invaluable in understanding what makes us unique as a species. Much work has emphasised group-level competition, such as warfare, in moulding human cooperation and sociality. However, competition and cooperation also occur within groups; and inter-individual differences in sociality have reported fitness implications in numerous non-human taxa. Here we investigate whether differential access to cooperation (relational wealth) is likely to lead to variation in fitness at the individual level among BaYaka hunter-gatherers. Using economic gift games we find that relational wealth: a) displays individual-level variation; b) provides advantages in buffering food risk, and is positively associated with body mass index (BMI) and female fertility; c) is partially heritable. These results highlight that individual-level processes may have been fundamental in the extension of human cooperation beyond small units of related individuals, and in shaping our sociality. Additionally, the findings offer insight in to trends related to human sociality found from research in other fields such as psychology and epidemiology

Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer

Phylogeography of Supralittoral Rocky Intertidal Ligia Isopods in the Pacific Region from Central California to Central Mexico

Ligia isopods are widely distributed in the Pacific rocky intertidal shores from central California to central Mexico, including the Gulf of California. Yet, their biological characteristics restrict them to complete their life cycles in a very narrow range of the rocky intertidal supralittoral. Herein, we examine phylogeographic patterns of Ligia isopods from 122 localities between central California and central Mexico. We expect to find high levels of allopatric diversity. In addition, we expect the phylogeographic patterns to show signatures of past vicariant events that occurred in this geologically dynamic region.We sequenced two mitochondrial genes (Cytochrome Oxidase I and 16S ribosomal DNA). We conducted Maximum Likelihood and Bayesian phylogenetic analyses. We found many divergent clades that, in general, group according to geography. Some of the most striking features of the Ligia phylogeographic pattern include: (1) deep mid-peninsular phylogeographic breaks on the Pacific and Gulf sides of Baja peninsula; (2) within the Gulf lineages, the northern peninsula is most closely related to the northern mainland, while the southern peninsula is most closely related to the central-southern mainland; and, (3) the southernmost portion of the peninsula (Cape Region) is most closely related to the southernmost portion of mainland.Our results shed light on the phylogenetic relationships of Ligia populations in the study area. This study probably represents the finest-scale phylogeographic examination for any organism to date in this region. Presence of highly divergent lineages suggests multiple Ligia species exist in this region. The phylogeographic patterns of Ligia in the Gulf of California and Baja peninsula are incongruent with a widely accepted vicariant scenario among phylogeographers, but consistent with aspects of alternative geological hypotheses and phylo- and biogeographic patterns of several other taxa. Our findings contribute to the ongoing debate regarding the geological origin of this important biogeographic region

Gut Microbiota Dysbiosis Is Associated with Inflammation and Bacterial Translocation in Mice with CCl4-Induced Fibrosis

BACKGROUND: Gut is the major source of endogenous bacteria causing infections in advanced cirrhosis. Intestinal barrier dysfunction has been described in cirrhosis and account for an increased bacterial translocation rate. HYPOTHESIS AND AIMS: We hypothesize that microbiota composition may be affected and change along with the induction of experimental cirrhosis, affecting the inflammatory response. ANIMALS AND METHODS: Progressive liver damage was induced in Balb/c mice by weight-controlled oral administration of carbon tetrachloride. Laparotomies were performed at weeks 6, 10, 13 and 16 in a subgroup of treated mice (n = 6/week) and control animals (n = 4/week). Liver tissue specimens, mesenteric lymph nodes, intestinal content and blood were collected at laparotomies. Fibrosis grade, pro-fibrogenic genes expression, gut bacterial composition, bacterial translocation, host's specific butyrate-receptor GPR-43 and serum cytokine levels were measured. RESULTS: Expression of pro-fibrogenic markers was significantly increased compared with control animals and correlated with the accumulated dose of carbon tetrachloride. Bacterial translocation episodes were less frequent in control mice than in treated animals. Gram-positive anaerobic Clostridia spp count was decreased in treated mice compared with control animals and with other gut common bacterial species, altering the aerobic/anaerobic ratio. This fact was associated with a decreased gene expression of GPR43 in neutrophils of treated mice and inversely correlated with TNF-alpha and IL-6 up-regulation in serum of treated mice along the study protocol. This pro-inflammatory scenario favoured blood bacterial translocation in treated animals, showing the highest bacterial translocation rate and aerobic/anaerobic ratio at the same weeks. CONCLUSIONS: Gut microbiota alterations are associated with the development of an inflammatory environment, fibrosis progression and bacterial translocation in carbon tetrachloride-treated mice

Uncovering Suitable Reference Proteins for Expression Studies in Human Adipose Tissue with Relevance to Obesity

Protein expression studies based on the two major intra-abdominal human fat depots, the subcutaneous and the omental fat, can shed light into the mechanisms involved in obesity and its co-morbidities. Here we address, for the first time, the identification and validation of reference proteins for data standardization, which are essential for accurate comparison of protein levels in expression studies based on fat from obese and non-obese individuals.To uncover adipose tissue proteins equally expressed either in omental and subcutaneous fat depots (study 1) or in omental fat from non-obese and obese individuals (study 2), we have reanalyzed our previously published data based on two-dimensional fluorescence difference gel electrophoresis. Twenty-four proteins (12 in study 1 and 12 in study 2) with similar expression levels in all conditions tested were selected and identified by mass spectrometry. Immunoblotting analysis was used to confirm in adipose tissue the expression pattern of the potential reference proteins and three proteins were validated: PARK7, ENOA and FAA. Western Blot analysis was also used to test customary loading control proteins. ENOA, PARK7 and the customary loading control protein Beta-actin showed steady expression profiles in fat from non-obese and obese individuals, whilst FAA maintained steady expression levels across paired omental and subcutaneous fat samples.ENOA, PARK7 and Beta-actin are proper reference standards in obesity studies based on omental fat, whilst FAA is the best loading control for the comparative analysis of omental and subcutaneous adipose tissues either in obese and non-obese subjects. Neither customary loading control proteins GAPDH and TBB5 nor CALX are adequate standards in differential expression studies on adipose tissue. The use of the proposed reference proteins will facilitate the adequate analysis of proteins differentially expressed in the context of obesity, an aim difficult to achieve before this study