Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer

BRCA; Cáncer de mama triple negativo: Antígeno 2 de la superficie celular del trofoblastoBRCA; Càncer de mama triple negatiu; Antigen 2 de la superfície cel·lular del trofoblastBRCA; Triple-negative breast cancer; Trophoblast cell-surface antigen 2Background The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.This work was supported by Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc. (no grant number)

Urinary levels of monohydroxyl PAH metabolites in portuguese firefighters: background levels and impact of tobacco smoke

Firefighting occupational exposure is classified as possible carcinogen to humans by the International Agency for Research on Cancer and the US National Institute for Occupational Safety and Health [1,2]. Tobacco smoke is a very important factor in the assessment of occupational exposure of workers, since the prolonged exposure to tobacco smoke is by itself the major cause of lung cancer [3]. The consumption of tobacco is responsible for the exposure to many smoke components including more than sixty known carcinogens, including some polycyclic aromatic hydrocarbons (PAHs) [4]. PAHs are ubiquitous compounds formed during pyrolysis or incomplete combustion of organic matter, being well-known for their toxic, mutagenic, and carcinogenic properties to humans [5,6]. So far, the impact of tobacco smoke on firefighters’ total exposure to PAHs is very limited.info:eu-repo/semantics/publishedVersio

Monitoring training load in beach volleyball players: a case study with an Olympic team

Abstract AIM Describe and compare training load dynamics of two Olympic beach volleyball players. METHODS Two Olympic beach volleyball players participated in this study (specialist defender and blocker: both aged 34 years, holding 14 years of competitive experience, height: 1.74 m and 1.81 m, weight: 69 kg and 65 kg, respectively). Internal training load (ITL), total weekly training load (TWTL), monotony and strain were obtained through the session rating of perceived exertion (session-RPE) for three training mesocycles (10 weeks). Lower limb explosive power was assessed through the counter movement jump (CMJ). RESULTS Mean ITL, TWTL, monotony and strain during the 10-week period were: 370 ± 156; 1997 ± 838; 2.7 ± 1.3; 5621 ± 1802 arbitrary units (AU) (Defender) and 414 ± 153; 2392 ± 892; 2.7 ± 1.1; 6894 ± 3747 (AU) (Blocker). Mean of CMJ height was 47.0 ± 1.3 and 40.3 ± 1.6 cm, for the defender and blocker, respectively. The defender player presented higher ITL in the second (effect size (ES) = 0.90; 92/5/3, likely) and in the third (ES = 0.91; 94/4/2, likely) mesocycles when compared to the first. Monotony raised from the first to the third mesocycle (ES = 2.91; 98/1/1, very likely). Blocker's ITL was higher in the third mesocycle than the first (ES = 1.42. 98/1/1, very likely) and the second (ES = 1.49; 98/1/1, likely) ones. CONCLUSION ITL magnitude increased from the first to the third mesocycle, in both players

Comparison of two peptide radiotracers for prostate carcinoma targeting

OBJECTIVES: Scintigraphy is generally not the first choice treatment for prostate cancer, although successful studies using bombesin analog radiopeptides have been performed. Recently, a novel peptide obtained using a phage display library demonstrated an affinity for prostate tumor cells. The aim of this study was to compare the use of a bombesin analog to that of a phage display library peptide (DUP-1) radiolabeled with technetium-99m for the treatment of prostate carcinoma. The peptides were first conjugated to S-acetyl-MAG3 with a 6-carbon spacer, namely aminohexanoic acid. METHODS: The technetium-99m labeling required a sodium tartrate buffer. Radiochemical evaluation was performed using ITLC and was confirmed by high-performance liquid chromatography. The coefficient partition was determined, and in vitro studies were performed using human prostate tumor cells. Biodistribution was evaluated in healthy animals at various time points and also in mice bearing tumors. RESULTS: The radiochemical purity of both radiotracers was greater than 95%. The DUP-1 tracer was more hydrophilic (log P = -2.41) than the bombesin tracer (log P = -0.39). The biodistribution evaluation confirmed this hydrophilicity by revealing the greater kidney uptake of DUP-1. The bombesin concentration in the pancreas was greater than that of DUP-1 due to specific gastrin-releasing peptide receptors. Bombesin internalization occurred for 78.32% of the total binding in tumor cells. The DUP-1 tracer showed very low binding to tumor cells during the in vitro evaluation, although tumor uptake for both tracers was similar. The tumors were primarily blocked by DUP1 and the bombesin radiotracer primarily targeted the pancreas. CONCLUSION: Further studies with the radiolabeled DUP-1 peptide are recommended. With further structural changes, this molecule could become an efficient alternative tracer for prostate tumor diagnosis

Rhythmicity of mood symptoms in individuals at risk for psychiatric disorders

Despite emerging evidence that disruption in circadian rhythms may contribute to the pathophysiology of psychiatric disorders, there is a significant knowledge gap on the rhythmicity of psychological symptoms. Here, we aimed at investigating the rhythmicity of mood symptoms in individuals at risk for psychiatric disorders. 391 Brazilian and 317 Spanish participants completed the Self-Reporting Questionnaire-20 for non-psychotic mental disorders; the Mood Rhythm Instrument was used to assess rhythmicity of mood symptoms and the Munich ChronoType Questionnaire to assess sleep patterns. We found that the rhythmicity of specific mood-related symptoms and behaviors, particularly pessimism and motivation to exercise, were associated with being at risk for psychiatric disorders, even after controlling for sleep timing, sleep deficit, and season of data collection. We also found that the peak of some mood symptoms and behaviors were different between individuals at high vs. low risk for psychiatric disorders, with specific differences between countries. These results are consistent with previous research showing that circadian misalignment is associated with higher risk for mental health conditions. These findings also suggest that lifestyle changes preventing circadian misalignment might be useful to reduce the risk of psychiatric disorders, where cultural differences must be taken into account

Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells

Targeting urothelial tumors of upper urinary tract with drug-eluting stents impregnated by supercritical fluids

Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide and it has been considered as one of the more expensive to treat due of its long-term propensity of recurrence. The current standard therapy to prevent recurrence is intravesical Bacillus Calmette–Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, that has been reported to be generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term[1], [2]. These failings can be partially attributed to the short residence time and low penetration of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation [3]. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced (figure 1). Four types of drug-eluting biodegradable stents were studied, impregnated with paclitaxel, epirubicin, doxorubicin and gemcitabine. The release kinetics of the impregnated drugs from the anti-cancer drug-eluting stents was measured in artificial urine solution (AUS) for 9 days. The in vitro drugs release from the impregnated biodegradable ureteral stents was analyzed using a microplate reader. The in vitro release study in AUS showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degrades after 9 days. Regarding the amount of impregnated drugs by SCF the gemcitabine showed higher amount (109 μg) and the lower amount was obtained for paclitaxel (67 ng). The diffusion coefficient and the impregnation yield were calculated. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) - T24 cell lines was evaluated. T24 cell line was exposed to graded concentrations (0.01 to 2000 ng/ml) of the four drugs for both 4 and 72 hours to determine the sensitivities to each drug (IC50). Toxicity as a result of both direct and indirect contact of the cell lines with the different material conditions of biodegradable stent were studied. The four anti-cancer drugs showed a concentrationdependent inhibitory effect on the T24 and HUVEC cell lines with IC50’s for paclitaxel of 7.30ng and 501.50ng, respectively. The T24 cell line shows to be more sensitive than HUVEC cell line for all the anti-cancer drugs tested. The direct and indirect contact of the anti-cancer biodegradable stents with the T24 and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the T24 cell line after 72h and no killing effect in the HUVEC cells. Finally, this study has shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the T24 cell lines, with no toxicity observed in the control, non-cancerous cells.Luso­- American Foundation's Grant for Internships in the University of California, Berkeley, 2015/CON5/CAN8; FCT PhD Grant (SFRH/BD/97203/2013); European Union's Seventh Framework Programme (FP7/2007­2013) under grant agreement n° REGPOT­CT2012­316331­ POLARIS; Project “Novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 ­ ABMR ­ NORTE­01­0124­FEDER­000016)” cofinanced by North Portugal Regional Operational Programme (ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF

Ultrasound enhances lipase-catalyzed synthesis of poly (ethylene glutarate)

The present work explores the best conditions for the enzymatic synthesis of poly (ethylene glutarate) for the first time. The start-up materials are the liquids; diethyl glutarate and ethylene glycol diacetate, without the need of addition of extra solvent. The reactions are catalyzed by lipase B from Candida antarctica immobilized on glycidyl methacrylate-ter-divinylbenzene-ter-ethylene glycol dimethacrylate at 40 °C during 18 h in water bath with mechanical stirring or 1 h in ultrasonic bath followed by 6 h in vacuum in both the cases for evaporation of ethyl acetate. The application of ultrasound significantly intensified the polyesterification reaction with reduction of the processing time from 24 to 7 h. The same degree of polymerization was obtained for the same enzyme loading in less time of reaction when using the ultrasound treatment. The degree of polymerization for long-term polyesterification was improved approximately 8-fold due to the presence of sonication during the reaction. The highest degree of polymerization achieved was 31, with a monomer conversion of 96.77%. The ultrasound treatment demonstrated to be an effective green approach to intensify the polyesterification reaction with enhanced initial kinetics and high degree of polymerization.This study was supported by Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684). The work was also supported by Bioprocess and Bionanotechnology Research Group (BBRG) of Minho University and the Post Graduate Funding Program of Jiangnan University for Overseas Study. All authors also acknowledge the funding of Department of Science and Technology and Portuguese Science Foundation under the Indo-Portuguese collaborative program

Ecdysone promotes growth of imaginal discs through the regulation of Thor in D. melanogaster

Animals have a determined species-specific body size that results from the combined action of hormones and signaling pathways regulating growth rate and duration. In Drosophila, the steroid hormone ecdysone controls developmental transitions, thereby regulating the duration of the growth period. Here we show that ecdysone promotes the growth of imaginal discs in mid-third instar larvae, since imaginal discs from larvae with reduced or no ecdysone synthesis are smaller than wild type due to smaller and fewer cells. We show that insulin-like peptides are produced and secreted normally in larvae with reduced ecdysone synthesis, and upstream components of insulin/insulin-like signaling are activated in their discs. Instead, ecdysone appears to regulate the growth of imaginal discs via Thor/4E-BP, a negative growth regulator downstream of the insulin/insulin-like growth factor/Tor pathways. Discs from larvae with reduced ecdysone synthesis have elevated levels of Thor, while mutations in Thor partially rescue their growth. The regulation of organ growth by ecdysone is evolutionarily conserved in hemimetabolous insects, as shown by our results obtained using Blattella germanica. In summary, our data provide new insights into the relationship between components of the insulin/insulin-like/Tor and ecdysone pathways in the control of organ growth.Spanish Ministry of Science and Consolider program grants: (BFU-2008-01884, BFU2011-25986, CSD2007-008-25120, BFU2009-10571 and BES-2009-016077); Departments of Education and Industry of the Basque Government grant: (PI2012/42); Bizkaia County; Instituto Gulbenkian de Ciência/Fundação Calouste Gulbenkian; Fundação Para a Ciência e a Tecnologia fellowship: (SFRH/BD/51181/2010)