Despite recent advances in the treatment of metastatic castration‐resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are ...urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non‐malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR‐V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase‐dependent or ‐independent apoptosis. Up‐regulation or induction of several pro‐apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase‐3 and down‐regulation of anti‐apoptotic proteins (survivin and Bcl‐2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL‐1β and cathepsin B. Inhibition of pro‐survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC‐3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro‐survival autophagy, and immune modulatory effects are suspected modes of actions.
What's new?
Prognosis of patients with metastatic castration‐resistant prostate cancer (CRPC) remains poor due to the development of drug resistance. Here, the authors investigated the efficacy, toxicity and mechanism of action of the novel marine compound triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. They found that FrA inhibits human prostate cancer cells, including those resistant to docetaxel, abiraterone and enzalutamide. Remarkably, FrA simultaneously induces apoptosis and cell cycle arrest and suppresses pro‐survival autophagy. FrA also decreases local tumor growth and metastatic spread in vivo without significant toxicities, with immune‐modulating effects potentially contributing to the activity.
For patients with refractory or relapsed Burkitt lymphoma (BL), no standard therapy is available for second-line treatment to date. Nonfunctional caspases-dependent apoptosis pathways, inactivating ...p53 mutations and pro-survival autophagy prevent activity of conventional chemotherapy. Thus, new drugs bypassing these mechanisms of resistance are required. Here, we investigated the efficacy of the marine natural compound frondoside A (FrA) in eight BL cell lines. FrA revealed cytotoxic effects in all cell lines tested including the multiresistant CA46 cells. Remarkably, FrA induced caspases- and p53-independent apoptosis, which was characterized by decreased expression of antiapoptotic survivin and Bcl-2, mitochondria targeting (release of cytochrome C, HtrA2/Omi and the apoptosis-inducing factor (AIF), and altered production of ROS) and translocation of AIF to the nuclei. In addition, signs of inhibition of pro-survival autophagy were observed. Thus, FrA is a promising candidate for the treatment of refractory or relapsed BL revealing resistances to standard therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Imaging spectroscopy, also known as hyperspectral remote sensing, is based on the characterization of Earth surface materials and processes through spectrally-resolved measurements of the light ...interacting with matter. The potential of imaging spectroscopy for Earth remote sensing has been demonstrated since the 1980s. However, most of the developments and applications in imaging spectroscopy have largely relied on airborne spectrometers, as the amount and quality of space-based imaging spectroscopy data remain relatively low to date. The upcoming Environmental Mapping and Analysis Program (EnMAP) German imaging spectroscopy mission is intended to fill this gap. An overview of the main characteristics and current status of the mission is provided in this contribution. The core payload of EnMAP consists of a dual-spectrometer instrument measuring in the optical spectral range between 420 and 2450 nm with a spectral sampling distance varying between 5 and 12 nm and a reference signal-to-noise ratio of 400:1 in the visible and near-infrared and 180:1 in the shortwave-infrared parts of the spectrum. EnMAP images will cover a 30 km-wide area in the across-track direction with a ground sampling distance of 30 m. An across-track tilted observation capability will enable a target revisit time of up to four days at the Equator and better at high latitudes. EnMAP will contribute to the development and exploitation of spaceborne imaging spectroscopy applications by making high-quality data freely available to scientific users worldwide.
Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection ...pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure.
From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria-based algorithm (PCT-pyuria group). The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days.
Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 IQR, 5.0-14.0 vs. 10.0 IQR, 7.0-16.0 days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different.
A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Imaging spectroscopy, also known as hyperspectral remote sensing, is based on the characterization of Earth surface materials and processes through spectrally-resolved measurements of the light ...interacting with matter. The potential of imaging spectroscopy for Earth remote sensing has been demonstrated since the 1980s. However, most of the developments and applications in imaging spectroscopy have largely relied on airborne spectrometers, as the amount and quality of space-based imaging spectroscopy data remain relatively low to date. The upcoming Environmental Mapping and Analysis Program (EnMAP) German imaging spectroscopy mission is intended to fill this gap. An overview of the main characteristics and current status of the mission is provided in this contribution. The core payload of EnMAP consists of a dual-spectrometer instrument measuring in the optical spectral range between 420 and 2450 nm with a spectral sampling distance varying between 5 and 12 nm and a reference signal-to-noise ratio of 400:1 in the visible and near-infrared and 180:1 in the shortwave-infrared parts of the spectrum. EnMAP images will cover a 30 km-wide area in the across-track direction with a ground sampling distance of 30 m. An across-track tilted observation capability will enable a target revisit time of up to four days at the Equator and better at high latitudes. EnMAP will contribute to the development and exploitation of spaceborne imaging spectroscopy applications by making high-quality data freely available to scientific users worldwide.
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