Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

BACKGROUND: Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. MATERIALS AND METHODS: Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. RESULTS: In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4 months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. CONCLUSION: After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Pet dogs potential transmitters of pathogenic Escherichia coli with resistance to antimicrobials.

Escherichia coli strains are part of the normal biota of humans and animals; however, several clinical reports have implicated E. coli as the etiological agent of diarrhea in humans and companion animals. Thus, the aim of the present study was to know if companion dogs in the city of San Luis Potosi are colonized with virulent potentially harmful E. coli strains. Rectal swabs from 30 dogs, 13 with and 17 without diarrhea were analyzed. Phylogenetic and virulence genes analysis was performed to the E. coli isolates. Additionally, the Kirby-Bauer test was used to analyze the sensitivity to 32 different antimicrobials from 14 families. Eighty-five isolates were identified as E. coli and detected in 97% of healthy and diarrheic dog samples. E. coli isolates from healthy dogs carried several virulence genes, in contrast with those from diarrheic animals that presented only eaeA. In healthy dogs, phylogenetic analysis showed that 57% and 43% of E. coli isolates belonged to commensal (A and B1) and virulent (B2 and D) groups respectively. Meanwhile, diarrheic dogs showed that 69% of the isolates were identified as virulent B2 and D phylogroups. Moreover, E. coli resistant to ß-lactams, aminoglycosides, tetracycline, quinolones, and folate inhibitors were detected in both groups of dogs. The presence of E. coli with eaeA virulence gene in diarrheic dogs, suggest that these strains are associated with the animal´s condition. Finally, major attention must be drawn to the careful handling of dogs because of their capability to harbor and disseminate virulent E. coli strains.

Medical Oncology Workload in Europe: One Continent, Several Worlds.

AIMS: The workload pressure on medical oncologists will increase in the near future. There are no comprehensive data available about the current workload of medical oncologists in Europe. Here we report the European results of a global survey of the workload of medical oncologists. MATERIALS AND METHODS: An online survey was distributed through a snowball method via national oncology societies to chemotherapy-prescribing physicians in 21 European countries. We compared the workload of medical oncologists in Eastern European countries (EECs) and Western European countries (WECs). The primary measure of workload was the annual number of new cancer patient consults seen per oncologist. RESULTS: In total, 495 oncologists from 16 European countries completed our survey: 100 from seven EECs and 395 from nine WECs. The median number of annual consults per medical oncologist was 225 in EECs compared with 175 in WECs (P < 0.001). The proportion of medical oncologists seeing more than 300 consults/year was 35% (35/100) in EECs compared with 18% (68/395) in WECs. The median number of patients seen in a full day clinic was 25 in EECs and 15 in WECs (P < 0.001). Eastern European medical oncologists reported spending a median of 25 min per new consultation compared with 45 min in WECs (P < 0.001). The top two reported barriers in both EECs and WECs to patient care were high clinical volumes and insufficient time for reading. CONCLUSION: The clinical workload of medical oncologists in EECs was substantially higher than in WECs. European health policymakers and educators need to address existing disparities in the workload of medical oncologist, undertake plans for future workforce supply and consider alternative models of care.

Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy

Purpose: Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. Patients and methods: This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. Results: The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. Conclusion: Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer

No disponible

Use of emerging technologies in the extraction of lupeol, α-amyrin and ß-amyrin from sea grape (Coccoloba uvifera L.).

Emerging technologies are being explored to improve extraction yields of phytochemicals or high-value biological compounds. The aim of this study was to evaluate the extraction of lupeol, α-, and ß-amyrin from fruit, leaf and stem of the sea grape tree (Coccoloba uvifera L.) using technologies such as Ultrasound Assisted Extraction (UAE) and High Hydrostatic Pressure Extraction (HHPE). Results were compared to conventional extraction (maceration). Analysis with thin-layer chromatography revealed the presence of lupeol in all studied parts of the tree. Optimal extraction conditions for UAE and HHPE were found; the highest concentration of triterpenes was obtained by UAE after evaluating conventional and non-conventional techniques. Finally, analysis of different tree parts and other vegetable sources showed that the best source of triterpenes was the leaf.

Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy.

PURPOSE: Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. PATIENTS AND METHODS: This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. RESULTS: The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. CONCLUSION: Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer. TRIAL REGISTRATION: EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7-11, 2016, Copenhagen, Denmark (oral presentation).

Outcomes of single versus double hormone receptor-positive breast cancer. A GEICAM/9906 sub-study.

BACKGROUND: Retrospective data suggest better outcomes for patients with double hormonal receptor (oestrogen [ER] and progesterone receptor [PgR])-positive (dHR+) early breast cancer, compared with single hormonal receptor-positive, sHR+, (ER+/PgR- or ER-/PgR+) disease. Here, we evaluate the classification according to intrinsic subtypes and clinical outcomes of sHR+ versus dHR+ in HER2-negative breast cancer patients enrolled in GEICAM/9906 study (NCT00129922). METHODS: Archival tumours were retrieved retrospectively for the analysis of ER, PgR and HER2 status and classified into intrinsic subtypes using the PAM50 gene expression assay. Disease-free survival (DFS) and overall survival (OS) were explored using a Cox proportional hazard analysis. RESULTS: Data on intrinsic subtypes were available in 571 (50%) patients with ER+ and/or PR+, and HER2-negative primary tumours. The incidence of luminal A and luminal B subtypes were 52%/36% in dHR+ tumours (ER+/PgR+), and 15%/58% in ER+/PgR-tumours. ER-/PgR+ tumours were mainly luminal A (52%). Compared with ER+/PgR+ patients, DFS was similar in ER-/PgR+ (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.57-2.34, p = 0.70) but worse in ER+/PgR- patients (HR 1.60, 95% CI 1.12-2.28, p < 0.01). Similar results were observed for OS (HR 1.50, p = 0.30 and HR 1.86, p < 0.01, respectively). CONCLUSIONS: The ER+/PgR- group is characterised by higher proliferation and worse outcomes. In spite of the ER-/PgR+ subgroup resembles ER+/PgR+ disease in terms of molecular subtypes and outcomes, the small number of patients in this subgroup prevents from drawing any conclusions. TRIAL REGISTRATION: EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). CLINICALTRIALS. GOV IDENTIFIER: NCT00129922 (retrospectively registered 10/08/2005).

Hyperglycaemia and Survival in Solid Tumours: A Systematic Review and Meta-analysis.

AIMS: Diabetes is associated with adverse cancer outcomes. However, the effect of hyperglycaemia in non-diabetic cancer patients is unclear. MATERIALS AND METHODS: A systematic search of electronic databases identified publications exploring the effect of hyperglycaemia on overall survival, disease-free survival (DFS) or progression-free survival (PFS). Data from studies reporting a hazard ratio and 95% confidence interval and/or a P-value were pooled in a meta-analysis using generic inverse-variance and random effects modelling. Subgroup analyses were conducted based on method of hyperglycaemia measurement (HbA1c, other) and stage (early, advanced, mixed). Meta-regression was performed to evaluate the influence of clinical characteristics including baseline diabetes status on the hazard ratio for overall survival. RESULTS: Twelve studies comprising a total of 9872 patients were included. All studies reported hazard ratios for overall survival. Three studies reported DFS; two reported PFS outcomes. Definitions of hyperglycaemia and cut-offs varied between studies. Hyperglycaemia was associated with worse overall survival (hazard ratio 2.05, 95% confidence interval 1.67-2.51; P < 0.001) and DFS (hazard ratio 1.98, 95% confidence interval 1.20-3.27; P = 0.007), but did not affect PFS (hazard ratio 1.08, 95% confidence interval 0.72-1.62; P = 0.71). The association with worse overall survival was maintained in subgroups based on method of hyperglycaemia measurement (subgroup difference P = 0.46) and stage (P = 0.14). Meta-regression showed a significantly greater magnitude of association between hyperglycaemia and decreased overall survival in studies with higher proportions of women and diabetic patients. CONCLUSIONS: Hyperglycaemia is associated with adverse overall survival and DFS in patients with cancer. The therapeutic role of glycaemic control in cancer patients warrants further investigation.

Gas phase kinetics of the OH + CH3CH2OH reaction at temperatures of the interstellar medium (T = 21-107 K).

Ethanol, CH3CH2OH, has been unveiled in the interstellar medium (ISM) by radioastronomy and it is thought to be released into the gas phase after the warm-up phase of the grain surface, where it is formed. Once in the gas phase, it can be destroyed by different reactions with atomic and radical species, such as hydroxyl (OH) radicals. The knowledge of the rate coefficients of all these processes at temperatures of the ISM is essential in the accurate interpretation of the observed abundances. In this work, we have determined the rate coefficient for the reaction of OH with CH3CH2OH (k(T)) between 21 and 107 K by employing the pulsed and continuous CRESU (Cinétique de Réaction en Ecoulement Supersonique Uniforme, which means Reaction Kinetics in a Uniform Supersonic Flow) technique. The pulsed laser photolysis technique was used for generating OH radicals, whose time evolution was monitored by laser induced fluorescence. An increase of approximately 4 times was observed for k(21 K) with respect to k(107 K). With respect to k(300 K), the OH-reactivity at 21 K is enhanced by two orders of magnitude. The obtained T-expression in the investigated temperature range is k(T) = (2.1 ± 0.5) × 10-11 (T/300 K)-(0.71±0.10) cm3 molecule-1 s-1. In addition, the pressure dependence of k(T) has been investigated at several temperatures between 21 K and 90 K. No pressure dependence of k(T) was observed in the investigated ranges. This may imply that this reaction is purely bimolecular or that the high-pressure limit is reached at the lowest total pressure experimentally accessible in our system. From our results, k(T) at usual IS temperatures (∼10-100 K) is confirmed to be very fast. Typical rate coefficients can be considered to range within about 4 × 10-11 cm3 molecule-1 s-1 at 100 K and around 1 × 10-10 cm3 molecule-1 s-1 at 20 K. The extrapolation of k at the lowest temperatures of the dense molecular clouds of ISM is also discussed in this paper.

Robotic versus laparoscopic distal pancreatectomy: A comparative study of clinical outcomes and costs analysis.

BACKGROUND: The robotic surgery cost presents a critical issue which has not been well addressed yet. This study aims to compare the clinical outcomes and cost differences of robotic distal pancreatectomy (RDP) versus laparoscopic distal pancreatectomy (LDP). METHODS: Data were abstracted prospectively from 2011 to 2017. An independent company performed the financial analysis. RESULTS: A total of 28 RDP and 26 LDP were included. The mean operative time was significantly lower in the LDP (294 vs 241 min; p = 0.02). The main intra and post-operative data were similar, except for the conversion rate (RDP: 3.6% vs LDP: 19.2%; p = 0.04) and hospital stay (RDP: 8.9 vs LDP 13.1 days; p = 0.04). The mean total costs were similar in both groups (RDP: 9198.64 € vs LDP: 9399.74 €; p > 0.5). CONCLUSIONS: RDP showed lower conversion rate and shorter hospital stay than LDP at the price of longer operative time. RDP is financially comparable to LDP.

Robotic versus laparoscopic surgery for rectal cancer: a comparative study of clinical outcomes and costs.

PURPOSE: The costs involved in performing robotic surgery present a critical issue which has not been well addressed yet. The aims of this study are to compare the clinical outcomes and cost differences of robotic versus laparoscopic surgery in the treatment of rectal cancer and to conduct a literature review of the cost analysis. METHODS: This is an observational, comparative study whereby data were abstracted from a retrospective database of patients who underwent laparoscopic and robotic rectal resection from October 2010 to March 2017, at Sanchinarro University Hospital, Madrid. An independent company performed the financial analysis, and fixed costs were excluded. RESULTS: A total of 86 robotic and 112 laparoscopic rectal resections were included. The mean operative time was significantly lower in the laparoscopic approach (336 versus 283 min; p = 0.001). The main pre-operative data, overall morbidity, hospital stay and oncological outcomes were similar in both groups, except for the readmission rate (robotic: 5.8%, laparoscopic: 11.6%; p = 0.001). The mean operative costs were higher for robotic surgery (4285.16 versus 3506.11€; p = 0.04); however, the mean overall costs were similar (7279.31€ for robotic and 6879.8€ for the laparoscopic approach; p = 0.44). We found four studies reporting costs, three comparing robotic versus laparoscopy costs, with all of them reporting a higher overall cost for the robotic rectal resection. CONCLUSION: Robotic rectal resection has similar clinical outcomes to that of the conventional laparoscopic approach. Despite the higher operative costs of robotic rectal resection, overall mean costs were similar in our series.

Atmospheric degradation of 2-chloroethyl vinyl ether, allyl ether and allyl ethyl ether: Kinetics with OH radicals and UV photochemistry.

Unsaturated ethers are oxygenated volatile organic compounds (OVOCs) emitted by anthropogenic sources. Potential removal processes in the troposphere are initiated by hydroxyl (OH) radicals and photochemistry. In this work, we report for the first time the rate coefficients of the gas-phase reaction with OH radicals (kOH) of 2-chloroethyl vinyl ether (2ClEVE), allyl ether (AE), and allyl ethyl ether (AEE) as a function of temperature in the 263-358 K range, measured by the pulsed laser photolysis-laser induced fluorescence technique. No pressure dependence of kOH was observed in the 50-500 Torr range in He as bath gas, while a slightly negative T-dependence was observed. The temperature dependent expressions for the rate coefficients determined in this work are: The estimated atmospheric lifetimes (τOH) assuming kOH at 288 K were 3, 2, and 4 h for 2ClEVE, AE and AEE, respectively. The kinetic results are discussed in terms of the chemical structure of the unsaturated ethers by comparison with similar compounds. We also report ultraviolet (UV) and infrared (IR) absorption cross sections (σλ and σ(ν˜), respectively). We estimate the photolysis rate coefficients in the solar UV actinic region to be less than 10-7 s-1, implying that these compounds are not removed from the atmosphere by this process. In addition, from σ(ν˜) and τOH, the global warming potential of each unsaturated ether was calculated to be almost zero. A discussion on the atmospheric implications of the titled compounds is presented.

Is the gas-phase OH+H2CO reaction a source of HCO in interstellar cold dark clouds? A kinetic, dynamic and modelling study.

Chemical kinetics of neutral-neutral gas-phase reactions at ultralow temperatures is a fascinating research subject with important implications on the chemistry of complex organic molecules in the interstellar medium (T∼10-100K). Scarce kinetic information is currently available for this kind of reactions at T<200 K. In this work we use the CRESU (Cinétique de Réaction en Ecoulement Supersonique Uniforme, which means Reaction Kinetics in a Uniform Supersonic Flow) technique to measure for the first time the rate coefficients (k) of the gas-phase OH+H2CO reaction between 22 and 107 K. k values greatly increase from 2.1×10-11 cm3 s-1 at 107 K to 1.2×10-10 cm3 s-1 at 22 K. This is also confirmed by quasi-classical trajectories (QCT) at collision energies down to 0.1 meV performed using a new full dimension and ab initio potential energy surface, recently developed which generates highly accurate potential and includes long range dipole-dipole interactions. QCT calculations indicate that at low temperatures HCO is the exclusive product for the OH+H2CO reaction. In order to revisit the chemistry of HCO in cold dense clouds, k is reasonably extrapolated from the experimental results at 10K (2.6×10-10 cm3 s-1). The modeled abundances of HCO are in agreement with the observations in cold dark clouds for an evolving time of 105-106 yrs. The different sources of production of HCO are presented and the uncertainties in the chemical networks discussed. This reaction can be expected to be a competitive process in the chemistry of prestellar cores. The present reaction is shown to account for a few percent of the total HCO production rate. Extensions to photodissociation regions and diffuse clouds environments are also commented.

Evolution in the eligibility criteria of randomized controlled trials for systemic cancer therapies.

BACKGROUND: Eligibility criteria in randomized controlled trials (RCTs) reduce inter-patient heterogeneity, but may reduce generalizability of results. Here, we explore temporal changes in eligibility criteria of practice-changing RCTs for systemic cancer therapies and in the proportion of patients excluded from these trials after application of eligibility criteria. METHODS: An electronic search identified practice-changing RCTs published in six major journals between July 2010 and December 2012. Trial protocols were identified through journal websites and communication with authors or study sponsors. Eligibility criteria were extracted from protocols. The number of patients excluded after application of eligibility criteria was extracted from the CONSORT diagrams and text of publications. Changes in eligibility criteria over time were assessed by logistic regression and meta-regression was carried out to evaluate the impact of year of protocol on the proportion of patients who were excluded after screening. RESULTS: Eighty-six protocols written between 1987 and 2012 were included. Over time, there has been an increasing frequency of exclusion of patients with prior cerebrovascular events (OR 1.34, p=0.003), coagulation/bleeding disorders (OR 1.34, p=0.006), prior gastrointestinal bleeding (OR 1.33, p=0.01), cardiac co-morbidities (OR 1.24, p=0.004) and exclusion based on concurrent medication (OR 1.19, p=0.01). There has been a decrease in upper age limit usage (OR 0.83, p=0.01) and leukopenia (OR 0.83, p=0.009). The proportion of patients excluded from trials has increased from 9% prior to 2000 to 18% after 2010 (p-value for trend <0.001). CONCLUSIONS: RCTs have become less representative of cancer patients treated in routine practice with increased use of organ-specific and co-morbidity-based exclusion criteria.

Impact of Geographic Region on Benefit of Approved Anticancer Drugs Evaluated in International Phase III Clinical Trials.

AIMS: International collaboration allows for enhanced accrual and more generalisable results of phase III randomised controlled trials (RCTs). The impact of geographic region on the outcomes of new anticancer agents is unclear. MATERIALS AND METHODS: International RCTs evaluating approved systemic therapy for advanced solid tumours that reported efficacy of new anticancer drugs based on geographic regions were eligible. Data for overall (OS) or progression-free survival (PFS) were pooled in a meta-analysis. The primary analysis was the comparison of developed versus developing countries. A meta-regression analysis explored the impact of differences in gross national income (GNI) per capita on the hazard ratio comparing developed and developing countries. Secondary analyses compared geographic regions irrespective of GNI. RESULTS: Of the 63 identified studies, 12 independent RCTs were eligible; five reported data for OS and nine for PFS. Improvements in overall survival were greater in developed as compared with developing countries (hazard ratio 0.82, 95% confidence interval 0.68-0.99, P = 0.04). This effect was seen only among studies of cytotoxic chemotherapy and not among those of targeted agents. No difference was seen for PFS (hazard ratio 0.93, 95% confidence interval 0.79-1.09, P = 0.36). Meta-regression showed a significant negative association between GNI per capita and overall survival, but a non-significant negative association with PFS (ß = -0.774, P = 0.05 and ß = -0.211, P = 0.29, respectively). No differences were observed in PFS between Asian and non-Asian countries or North America and Western Europe. CONCLUSION: Compared with patients from developing countries, those from developed countries derive greater improvement in overall survival from cytotoxic chemotherapy, but similar benefit from targeted drugs.

Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node.

Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis.

Screening antimutagenic and antiproliferative properties of extracts isolated from Jackfruit pulp (Artocarpus heterophyllus Lam).

The present focused on the study of the antimutagenic and antiproliferative potential of pulp Jackfruit (Artocarpus heterophyllus Lam) extract, using Salmonella typhimurium tester strains TA98 and TA100 with metabolic activation (S9) and a cancer cell line M12.C3.F6 (murine B-cell lymphoma), respectively. Jackfruit pulp extract was sequentially fractionated by chromatography (RP-HPLC) and each fraction was tested for antimutagenic and antiproliferative activities. The organic extracts obtained from Jackfruit pulp reduced the number of revertants caused by aflatoxin B1 (AFB1) and proliferation of cells M12.C3.F6; a dose-response relationship was showed. Sequential RP-HPLC fractionation of the active extracts produced both antimutagenic and/or antiproliferative fractions. These results suggested that the Jackfruit contained compounds with chemoprotective properties to reduce the mutagenicity of AFB1, also proliferation of a cancer cell line.

Evaluation of extraction methods for preparative scale obtention of mangiferin and lupeol from mango peels (Mangifera indica L.).

Bioactive compounds have become very important in the food and pharmaceutical markets leading research interests seeking efficient methods for extracting these bioactive substances. The objective of this research is to implement preparative scale obtention of mangiferin and lupeol from mango fruit (Mangifera indica L.) of autochthonous and Ataulfo varieties grown in Nayarit, using emerging extraction techniques. Five extraction techniques were evaluated: maceration, Soxhlet, sonication (UAE), microwave (MAE) and high hydrostatic pressures (HHP). Two maturity stages (physiological and consumption) as well as peel and fruit pulp were evaluated for preparative scale implementation. Peels from Ataulfo mango at consumption maturity stage can be considered as a source of mangiferin and lupeol using the UEA method as it improves extraction efficiency by increasing yield and shortening time.

Functional roles of the nuclear localization signal of parathyroid hormone-related protein (PTHrP) in osteoblastic cells.

PTHrP is an important regulator of bone remodelling, apparently by acting through several sequence domains. We here aimed to further delineate the functional roles of the nuclear localization signal (NLS) comprising the 88-107 amino acid sequence of PTHrP in osteoblasts. PTHrP mutants from a human PTHrP (-36/+139) cDNA (wild type) cloned into pcDNA3.1 plasmid with deletion (Δ) of the signal peptide (SP), NLS, T(107), or T107A replacing T(107) by A(107) were generated and stably transfected into osteoblastic MC3T3-E1 cells. In these cells, intracellular trafficking, cell proliferation and viability, as well as cell differentiation were evaluated. In these transfected cells, PTHrP was detected in the cytoplasm and also in the nucleus, except in the NLS mutant. Meanwhile, the PTH type 1 receptor (PTH1R) accumulates in the cytoplasm except for the ΔSP mutant in which the receptor remains at the cell membrane. PTHrP-wild type cells showed enhanced growth and viability, as well as an increased matrix mineralization, alkaline phosphatase activity, and osteocalcin gene expression; and these features were inhibited or abolished in ΔNLS or ΔT(107) mutants. Of note, these effects of PTHrP overexpression on cell growth and function were similarly decreased in the ΔSP mutant after PTH1R small interfering RNA transfection or by a PTH1R antagonist. The present in vitro findings suggest a mixed model for PTHrP actions on osteoblastic growth and function whereby this protein needs to be secreted and internalized via the PTH1R (autocrine/paracrine pathway) before NLS-dependent shuttling to the nucleus (intracrine pathway).

Association of aromatase inhibitors with coronary heart disease in women with early breast cancer.

As compared to tamoxifen aromatase inhibitors (AIs) may increase the risk of heart disease. Here we explored the association between the use of AIs and coronary artery disease (CAD) in a population-based observational study. In a small and heterogeneous population of 74 women with early breast cancer who received adjuvant hormonal therapy and subsequently underwent cardiac angiography, AIs significantly increased the hazard for CAD (HR 3.23, 95% confidence intervals [CI] 1.26-8.25, p = .01) compared to tamoxifen. Our results suggest that therapy with AIs may increase the risk for CAD.