314 research outputs found
Mechanism of citrate metabolism in Lactococcus lactis:Resistance against lactate toxicity at low pH
DSO Road Traffic Data Report & Advice
Met de Omgevingswet komt er Ă©Ă©n integrale wet om de fysieke leefomgeving te beschermen en effectief te gebruiken. De Omgevingswet beoogt onder andere de besluitvorming te versnellen en te verbeteren. Het gebruik van de Omgevingswet zal worden ondersteund door het Digitaal Stelsel Omgevingswet (DSO). Om de besluitvorming te kunnen versnellen en verbeteren, is het van belang dat alle gegevens over de fysieke leefomgeving zowel eenvoudig beschikbaar als consistent zijn. Gegevens over wegverkeer vormen een belangrijke bron voor de domeinen Lucht en Geluid binnen de fysieke leefomgeving. Het is dan ook essentieel dat via het DSO consistente wegverkeersgegevens beschikbaar komen. Om dit te realiseren heeft het RIVM - vanuit haar verantwoordelijkheid voor de domeinen Lucht en Geluid binnen het DSO - een verkenning uitgevoerd. Het RIVM heeft de verkenning uitgevoerd samen met gebruikers en bronhouders. Deze partijen constateren dat het belangrijk is om de wegverkeersgegevens (zowel over het gebruik als eigenschappen van de weg) beter beschikbaar, toegankelijk en consistent te maken. Dit versterkt bij de inwerkingtreding van de Omgevingswet de juridische houdbaarheid van beslissingen. Ook verbetert het een integrale afweging van beslissingen over de leefomgeving. Alle partijen hebben aangegeven gezamenlijk aan verbetering te willen werken. Op basis van de verkenning heeft het RIVM een advies opgesteld, waarin een voorlopig streefbeeld en de vervolgstappen zijn geformuleerd om consistente, landsdekkende wegverkeersgegevens te realiseren.The Environment and Planning Act [Omgevingswet] brings us one integral environmental law to protect and effectively plan the living environment. Amongst others, the Environmental and Planning Act means to accelerate and improve decision making. This proces will be supported by the Digital System for the Environment and Planning Act (DSO). To accelerate and improve decision making, it is important that all data regarding the living environment are easy accessible as well as consistent. Data on road traffic are an important source for the domains air and noise within the living environment. It is therefore essential that consistent road trafic data are made available via the Digital System for the Environment and Planning Act. To realise this, RIVM, responsible for the domains air and noise in the Digital System for the Environment and Planning Act, made an investigation. In the investigation, RIVM involved both users and source data owners. These parties acknowledge the importance of improving the availibility, accessibility and consistency of road traffic data (both the use of roads as well as the properties of the roads). This enforces the legal tenability of decisions when the Environmental and Planning Act is inforced. Also, it improves a proper weighing up of decisions relating to the living environment. All parties indicated the will to work together on improvement. Based on the investigation, RIVM has drawn up specific recommendations with a temporary envisaged objective and follow-up steps to realize consistent nationwide road traffic data.Ministerie van I&
Phase II study (KAMELEON) of single-agent T-DM1 in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma
HER2-positive; Pancreatic cancer; Urothelial bladder cancerHER2 positivo; Cáncer de páncreas; Cáncer de vejiga urotelialHER2-positiu; Cà ncer de pà ncrees; Cà ncer de bufeta urotelialThe antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types
A Compendium of AR Splice Variants in Metastatic Castration-Resistant Prostate Cancer
Treatment-induced AR alterations, including AR alternative splice variants (AR-Vs), have been extensively linked to harboring roles in primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer and therefore have gained momentum. Our aim was to uniformly determine recurrent AR-Vs in metastatic castration-resistant prostate cancer (mCRPC) using whole transcriptome sequencing in order to assess which AR-Vs might hold potential diagnostic or prognostic relevance in future research. This study reports that in addition to the promising AR-V7 as a biomarker, AR45 and AR-V3 were also seen as recurrent AR-Vs and that the presence of any AR-V could be associated with higher AR expression. With future research, these AR-Vs may therefore harbor similar or complementary roles to AR-V7 as predictive and prognostic biomarkers in mCRPC or as proxies for abundant AR expression.</p
Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model
Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents
Identifying patient values impacting the decision whether to participate in early phase clinical cancer trials: a systematic review
Background For many patients with advanced cancer, the decision whether to participate in early phase clinical trials or not is complex. The decision-making process requires an in-depth discussion of patient values. We therefore aimed to synthesize and describe patient values that may affect early phase clinical trial participation. Methods We conducted a systematic search in seven electronic databases on patient values in relation to patients’ decisions to participate in early phase clinical cancer trials. Results From 3072 retrieved articles, eleven quantitative and five qualitative studies fulfilled our inclusion criteria. We extracted ten patient values that can contribute to patients’ decisions. Overall, patients who seek trial participation usually report hope, trust, quantity of life, altruism, perseverance, faith and/or risk tolerance as important values. Quality of life and humanity are main values of patients who refuse trial participation. Autonomy and social adherence can be reported by both trial seekers or refusers, dependent upon how they are manifested in a patient. Conclusions We identified patient values that frequently play a role in the decision-making process. In the setting of discussing early phase clinical trial participation with patients, healthcare professionals need to be aware of these values. This analysis supports the importance of individual exploration of values. Patients that become aware of their values, e.g. by means of interventions focused on clarifying their values, could feel more empowered to choose. Subsequently, healthcare professionals could improve their support in a patients’ decision-making process and reduce the chance of decisional conflict
Identifying patient values impacting the decision whether to participate in early phase clinical cancer trials: a systematic review
Realizing better doctor-patient dialogue about choices in palliative care and early phase clinical trial participation: towards an online value clarification tool (OnVaCT)
Realizing better doctor-patient dialogue about choices in palliative care and early phase clinical trial participation: towards an online value clarification tool (OnVaCT)
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