The transmodulation of HER2 and EGFR by Substance P in breast cancer cells requires c-Src and metalloproteinase activation.

BACKGROUND: Substance P (SP) is a pleiotropic cytokine/neuropeptide that enhances breast cancer (BC) aggressiveness by transactivating tyrosine kinase receptors like EGFR and HER2. We previously showed that SP and its cognate receptor NK-1 (SP/NK1-R) signaling modulates the basal phosphorylation of HER2 and EGFR in BC, increasing aggressiveness and drug resistance. In order to elucidate the mechanisms responsible for NK-1R-mediated HER2 and EGFR transactivation, we investigated the involvement of c-Src (a ligand-independent mediator) and of metalloproteinases (ligand-dependent mediators) in HER2/EGFR activation. RESULTS AND DISCUSSION: Overexpression of NK-1R in MDA-MB-231 and its chemical inhibition in SK-BR-3, BT-474 and MDA-MB-468 BC cells significantly modulated c-Src activation, suggesting that this protein is a mediator of NK-1R signaling. In addition, the c-Src inhibitor 4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2. On the other hand, SP-dependent phosphorylation of HER2 and EGFR decreased substantially in the presence of the MMP inhibitor 1-10, phenanthroline monohydrate, and the dual inhibition of both c-Src and MMP almost abolished the activation of HER2 and EGFR. Moreover, the use of these inhibitors demonstrated that this Src and MMP-dependent signaling is important to the cell viability and migration capacity of HER2+ and EGFR+ cell lines. CONCLUSION: Our results indicate that the transactivation of HER2 and EGFR by the pro-inflammatory cytokine/neuropeptide SP in BC cells is a c-Src and MMP-dependent process

Dressing the sacrifice: Textiles, textile production and the sacrificial economy at Casas del Turuñuelo in fifth-century BC Iberia

AbstractERC Starting Gran

LA VILLA BAJOIMPERIAL Y TARDO ANTIGUA DE LOS MONDRAGONES (GRANADA)

The villa of Mondragones is an unpublished archaeological site located in the north of Granada, very closed to the ancient Municipium Florentinum Iliberritanum, and it is part of its ager. It is a very  vast settlement  where it’s easy to identify  the principal  elements  of a villa, as the domus, the pars fructuaria and pars rustica. The site has been occupied from the f irst century A.D.  to the  seventh  century  A.D.,  that  let  us analyze  the  changes  occurred  from  the  fourth century A.D. in the hinterland  of Eliberri.La villa de los Mondragones es un yacimiento arqueológico inédito que se localiza en la zona norte  de Granada,  muy  cerca  del  antiguo  Municipium Florentinum Iliberritanum,  formando parte de su  ager.  Se trata de un asentamiento  de gran extensión  en el que se identif ican los elementos fundamentales de una villa, como son la domus, la pars fructuaria y elementos de la pars rustica. Tiene  un periodo  de  ocupación  que va desde  su fundación  en el siglo I d.C. hasta el siglo VII d.C. lo cual permite analizar los cambios producidos a partir del siglo IV d.C. y las transformaciones  de la Antigüedad  Tardía en el  territorio  más próximo  a la ciudad de Eliberri

The effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: A systematic review

Objective: To systematically review the evidence about the effect of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) with pure urothelial carcinoma (pUC) in radical cystectomy (RC) candidates affected by variant histology (VH) bladder cancer. Methods: A review of the current literature was conducted through the Medline and National Center for Biotechnology Information (NCBI) PubMed, Scopus databases in May 2020. The updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed for this systematic review. Keywords used were ‘bladder cancer’, ‘bladder carcinoma’, ‘bladder tumour’ and ‘bladder cancer variants’ and ‘neoadjuvant chemotherapy’. Only original articles in English published after 2000 and reporting oncological outcomes a series of more than five patients with VH were included. We excluded series in which the oncological outcomes of patients with pUC and VH were undistinguishable. Results: The literature search identified 2231 articles. A total of 51 full-text articles were assessed for eligibility, with 17 eventually considered for systematic review, for a cohort of 450,367 patients, of which 5010 underwent NAC + RC. The median age at initial diagnosis ranged from 61 to 71 years. Most patients received cisplatin-gemcitabine, methotrexate-vinblastine-adriamycin-cisplatin, or carboplatin-based chemotherapy. Only one study reported results of neoadjuvant immunotherapy. The median follow-up ranged from 1 to 120 months. The results showed that squamous cell carcinoma (SCC) is less sensitive to NAC than pUC and that SCC predicts poorer prognosis. NAC was found to be a valid approach in treating small cell carcinoma and may have potential benefit in micropapillary carcinoma. Conclusions: NAC showed the best oncological outcomes in small cell variants and micropapillary carcinoma, while NAC survival benefit for SCC and adenocarcinoma variants needs further studies. Drawing definite considerations on the efficacy of NAC in VH is complicated due to the heterogeneity of present literature. Present results need to be confirmed in randomised controlled trial

Stability of biocontrol products carrying Candida sake CPA-1 in starch derivatives as a function of water activity

[EN] The preservation and shelf-life of formulations of the biocontrol agent Candida sake CPA-1 and starch derivatives as a function of water activity (aW) were studied in terms of the physical stability of the products and cell viability. Formulations of biocontrol products (BCPs), based on combinations of potato starch and pregelatinised potato starch (F1 and F2) or maltodextrines (MD) (F3) containing cell protectants, were obtained by fluidised-bed drying. The carriers and the formulated products were stored at 20°C under different aW conditions. The water sorption and water plasticization behaviour of the different products were analysed through the water sorption isotherms and glass transition temperatures (Tg). Likewise, the viability of C. sake over time was determined as a function of the aW. The solubility of the products was also assessed. Although formulations stored at 20°C and low aW (≤ 0.33) exhibited a better shelf-life, a significant decrease in cell survival ratio after 180 storage days was observed. Cold storage (5°C) was required to better maintain the cell viability, thus prolonging the shelf-life of BCPs. Formulations containing MD were the most effective at preserving cell viability and also exhibited the highest water solubility. All the formulations were physically stable at ambient temperature; therefore, the cell stability is the critical point at which to establish both the aW levels and temperature during storage. Packaging the product using high water vapour barrier material and under cold storage would be necessary to ensure a high number of viable cells and an effective and competitive BCPThe authors are grateful to the Spanish Government for the financial support from the national project RTA2012-00067-C02 (Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria, Spain and FEDER funds) and to the Conselleria d'Educacio of the Generalitat Valenciana, (Spain) for A. Marin's PhD grant.Marín-Gozalbo, A.; Atarés Huerta, LM.; Cháfer Nácher, MT.; Chiralt, A. (2017). Stability of biocontrol products carrying Candida sake CPA-1 in starch derivatives as a function of water activity. Biocontrol Science and Technology. 27(2):268-287. https://doi.org/10.1080/09583157.2017.1279587S26828727

SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations

Background Tumor cell subpopulations can either compete with each other for nutrients and physical space within the tumor niche, or co-operate for enhanced survival, or replicative or metastatic capacities. Recently, we have described co-operative interactions between two clonal subpopulations derived from the PC-3 prostate cancer cell line, in which the invasiveness of a cancer stem cell (CSC)-enriched subpopulation (PC-3M, or M) is enhanced by a non-CSC subpopulation (PC-3S, or S), resulting in their accelerated metastatic dissemination. Methods M and S secretomes were compared by SILAC (Stable Isotope Labeling by Aminoacids in Cell Culture). Invasive potential in vitro of M cells was analyzed by Transwell-Matrigel assays. M cells were co-injected with S cells in the dorsal prostate of immunodeficient mice and monitored by bioluminescence for tumor growth and metastatic dissemination. SPARC levels were determined by immunohistochemistry and real-time RT-PCR in tumors and by ELISA in plasma from patients with metastatic or non-metastatic prostate cancer. Results Comparative secretome analysis yielded 213 proteins differentially secreted between M and S cells. Of these, the protein most abundantly secreted in S relative to M cells was SPARC. Immunodepletion of SPARC inhibited the enhanced invasiveness of M induced by S conditioned medium. Knock down of SPARC in S cells abrogated the capacity of its conditioned medium to enhance the in vitro invasiveness of M cells and compromised their potential to boost the metastatic behavior of M cells in vivo. In most primary human prostate cancer samples, SPARC was expressed in the epithelial tumoral compartment of metastatic cases. Conclusions The matricellular protein SPARC, secreted by a prostate cancer clonal tumor cell subpopulation displaying non-CSC properties, is a critical mediator of paracrine effects exerted on a distinct tumor cell subpopulation enriched in CSC. This paracrine interaction results in an enhanced metastatic behavior of the CSC-enriched tumor subpopulation. SPARC is expressed in the neoplastic cells of primary prostate cancer samples from metastatic cases, and could thus constitute a tumor progression biomarker and a therapeutic target in advanced prostate cancer

Genome-Wide Analysis of Factors Affecting Transcription Elongation and DNA Repair: A New Role for PAF and Ccr4-Not in Transcription-Coupled Repair

RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide. Our data provide evidence that subunits of the SAGA and Ccr4-Not complexes, Mediator, Bre1, Bur2, and Fun12 affect transcription elongation to different extents. Given the dependency of TC-NER on RNA Polymerase II transcription and the fact that the few proteins known to be involved in TC-NER are related to transcription, we performed an in-depth TC-NER analysis of a selection of mutants. We found that mutants of the PAF and Ccr4-Not complexes are impaired in TC-NER. This study provides evidence that PAF and Ccr4-Not are required for efficient TC-NER in yeast, unraveling a novel function for these transcription complexes and opening new perspectives for the understanding of TC-NER and its functional interconnection with transcription elongation

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Assessment of the HER2DX Assay in Patients with ERBB2 -Positive Breast Cancer Treated with Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab

Importance: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy. Objective: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+BC who are receiving deescalated neoadjuvant therapy. Design, Setting, and Participants: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles. Interventions and Exposures: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial. Main Outcomes and Measures: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0). Results: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P <.001). The pCR rates in the HER2DX high, medium, and low pCR score groups were 92.6%, 63.6%, and 29.0%, respectively (high vs low odds ratio, 30.6; P <.001). The HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, ERBB2 immunohistochemistry score, HER2DX ERBB2 expression score, and prediction analysis of microarray 50 ERBB2-enriched subtype. The correlation between the HER2DX pCR score and prognostic risk score was weak (Pearson coefficient, -0.12). Performance of the risk score could not be assessed due to lack of recurrence events. Conclusions and Relevance: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches

Assessment of a Genomic Assay in Patients with ERBB2 -Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy with or Without Pertuzumab

Importance: Biomarkers to guide the use of pertuzumab in the treatment of early-stage ERBB2 (formerly HER2)-positive breast cancer beyond simple ERBB2 status are needed. Objective: To determine if use of the HER2DX genomic assay (Reveal Genomics) in pretreatment baseline tissue samples of patients with ERBB2-positive breast cancer is associated with response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. Design, Setting, and Participants: This is a retrospective diagnostic/prognostic analysis of a multicenter academic observational study in Spain performed during 2018 to 2022 (GOM-HGUGM-2018-05). In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts with results from the assay (DAPHNe and I-SPY2) was performed. All patients had stage I to III ERBB2-positive breast cancer, signed informed consent, and had available formalin-fixed paraffin-embedded tumor specimens obtained prior to starting therapy. Exposures: Patients received intravenous trastuzumab, 8 mg/kg, loading dose, followed by 6 mg/kg every 3 weeks in combination with intravenous docetaxel, 75 mg/m2, every 3 weeks and intravenous carboplatin area under the curve of 6 every 3 weeks for 6 cycles, or this regimen plus intravenous pertuzumab, 840 mg, loading dose, followed by an intravenous 420-mg dose every 3 weeks for 6 cycles. Main Outcome and Measures: Association of baseline assay-reported pathologic complete response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to pertuzumab. Results: The assay was evaluated in 155 patients with ERBB2-positive breast cancer (mean [range] age, 50.3 [26-78] years). Clinical T1 to T2 and node-positive disease was present in 113 (72.9%) and 99 (63.9%) patients, respectively, and 105 (67.7%) tumors were hormone receptor positive. The overall pCR rate was 57.4% (95% CI, 49.2%-65.2%). The proportion of patients in the assay-reported pCR-low, pCR-medium, and pCR-high groups was 53 (34.2%), 54 (34.8%), and 48 (31.0%), respectively. In the multivariable analysis, the assay-reported pCR score (as a continuous variable from 0-100) showed a statistically significant association with pCR (odds ratio [OR] per 10-unit increase, 1.43; 95% CI, 1.22-1.70; P <.001). The pCR rates in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (OR, 7.85; 95% CI, 2.67-24.91; P <.001). In the combined analysis (n = 282), an increase in pCR rate due to pertuzumab was found in the assay-reported pCR-high tumors (OR, 5.36; 95% CI, 1.89-15.20; P <.001) but not in the assay-reported pCR-low tumors (OR, 0.86; 95% CI, 0.30-2.46; P =.77). A statistically significant interaction between the assay-reported pCR score and the effect of pertuzumab in pCR was observed. Conclusions and Relevance: This diagnostic/prognostic study demonstrated that the genomic assay predicted pCR following neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. This assay could guide therapeutic decisions regarding the use of neoadjuvant pertuzumab