Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly ...or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations.
In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 RECIST 1.1), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing.
Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 31% of 127 patients), thrombocytopenia (11 9%), and neutropenia (ten 8%). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths.
Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations.
Pfizer/Medivation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure ...hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure.
The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin.
Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
When peanuts germinate, bioactive compounds such as resveratrol (RES), γ-aminobutyric acid (GABA), isoflavones, and polyphenol compounds are generated. Peanut kernels were germinated in the dark for ...two days, and stimuli including soaking liquid, rice koji, high-pressure processing (HPP), and ultrasonic treatment were tested for their ability to activate the defense mechanisms of peanut kernels, thus increasing their bioactive compound content. The results of this study indicate that no RES was detected in ungerminated peanuts, and only 5.58 μg/g of GABA was present, while unstimulated germinated peanuts contained 4.03 µg/g of RES and 258.83 μg/g of GABA. The RES content of the germinated peanuts increased to 13.64 μg/g after soaking in 0.2% phenylalanine solution, whereas a higher GABA content of 651.51 μg/g was observed after the peanuts were soaked in 0.2% glutamate. Soaking peanuts in 5% rice koji produced the highest RES and GABA contents (28.83 µg/g and 506.34 μg/g, respectively). Meanwhile, the RES and GABA contents of HPP-treated germinated peanuts (i.e., treated with HPP at 100 MPa for 10 min) increased to 7.66 μg/g and 497.09 μg/g, respectively, whereas those of ultrasonic-treated germinated peanuts (for 20 min) increased to 13.02 μg/g and 318.71 μg/g, respectively. After soaking peanuts in 0.5% rice koji, followed by HPP treatment at 100 MPa for 10 min, the RES and GABA contents of the germinated peanuts increased to 37.78 μg/g and 1196.98 μg/g, while the RES and GABA contents of the germinated peanuts treated with rice koji followed by ultrasonic treatment for 20 min increased to 46.53 μg/g and 974.52 μg/g, respectively. The flavonoid and polyphenol contents of the germinated peanuts also increased after exposure to various external stimuli, improving their DPPH free radical-scavenging ability and showing the good potential of germinated peanuts as functional products.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This article presents a fractional-<inline-formula> <tex-math notation="LaTeX">{N} </tex-math></inline-formula> digital multiplying delay-locked loop (MDLL) that uses a digital-to-time converter ...(DTC) for controlling the reference injection timing to support the fractional-<inline-formula> <tex-math notation="LaTeX">{N} </tex-math></inline-formula> operation. This fractional-<inline-formula> <tex-math notation="LaTeX">{N} </tex-math></inline-formula> MDLL features an injection-error scrambling scheme for DTC error randomization and a background third-order DTC delay equalizer for DTC error calibration, to mitigate reference-injection-induced spurs while keeping a low phase noise floor. The MDLL prototype demonstrates 800-fs rms jitter, −67 dBc fractional spur, and −58 dBc reference spur. With the proposed schemes, the fractional and reference spurs are suppressed by 29 and 32 dB, respectively.
To further improve the performance of all-inkjet-printing ZnO UV photodetector and maintain the advantages of inkjet printing technology, the inkjet printing Ag nanoparticles (NPs) were deposited on ...the inkjet printing ZnO UV photodetector for the first time. The inkjet printing Ag NPs can passivate the surface defects of ZnO and work as surface plasmons from the characterization of photoluminescence (PL), X-ray photoelectron spectroscopy (XPS), and finite difference time domain method (FDTD) simulation. The normalized detectivity (
D
*
) of the Ag NP-modified detector reaches to 1.45 × 10
10
Jones at 0.715 mW incident light power, which is higher than that of 5.72 × 10
9
Jones of the bare ZnO photodetector. The power-law relationship between the photocurrent and the incident light power of the Ag NP-modified ZnO detector is
I
pc
∝
P
2.34
, which means the photocurrent is highly sensitive to the change of incident light power.
Wind turbines generate low-frequency noise (LFN, 20-200 Hz), which poses health risks to nearby residents. This study aimed to assess heart rate variability (HRV) responses to LFN exposure and to ...evaluate the LFN exposure (dB, L
) inside households located near wind turbines. Thirty subjects living within a 500 m radius of wind turbines were recruited. The field campaigns for LFN (L
) and HRV monitoring were carried out in July and December 2018. A generalized additive mixed model was employed to evaluate the relationship between HRV changes and LFN. The results suggested that the standard deviations of all the normal to normal R-R intervals were reduced significantly, by 3.39%, with a 95% CI = (0.15%, 6.52%) per 7.86 dB (L
) of LFN in the exposure range of 38.2-57.1 dB (L
). The indoor LFN exposure (L
) ranged between 30.7 and 43.4 dB (L
) at a distance of 124-330 m from wind turbines. Moreover, households built with concrete and equipped with airtight windows showed the highest LFN difference of 13.7 dB between indoors and outdoors. In view of the adverse health impacts of LFN exposure, there should be regulations on the requisite distances of wind turbines from residential communities for health protection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, ...morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC.
Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC.
Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.
Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN.
Global precipitation is becoming increasingly intense due to the extreme climate. Therefore, creating new technology to manage water resources is crucial. To create a sustainable urban and ecological ...environment, a water level and water quality control system implementing artificial intelligence is presented in this research. The proposed smart monitoring system consists of four sensors (two different liquid level sensors, a turbidity and pH sensor, and a water oxygen sensor), a control module (an MCU, a motor, a pump, and a drain), and a power and communication system (a solar panel, a battery, and a wireless communication module). The system focuses on low-cost Internet of Things (IoT) devices along with low power consumption and high precision. This proposal collects rainfall from the preceding 10 years in the application region as well as the region’s meteorological bureau’s weekly weather report and uses artificial intelligence to compute the appropriate water level. More importantly, the adoption of dynamic adjustment systems can reserve and modify water resources in the application region more efficiently. Compared to existing technologies, the measurement approach utilized in this study not only achieves cost savings exceeding 60% but also enhances water level measurement accuracy by over 15% through the successful implementation of water level calibration decisions utilizing multiple distinct sensors. Of greater significance, the dynamic adjustment systems proposed in this research offer the potential for conserving water resources by more than 15% in an effective manner. As a result, the adoption of this technology may efficiently reserve and distribute water resources for smart cities as well as reduce substantial losses caused by anomalous water resources, such as floods, droughts, and ecological concerns.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have ...investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac‐specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria‐permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease.
Synopsis
Modulation of mitochondrial iron is shown to be a viable therapeutic approach against ischemic heart disease and heart failure, highlighting the need to develop more targeted iron chelators.
Mitochondrial iron increases during and after I/R injury.
Baseline mitochondrial iron contributes to ischemia/reperfusion injury.
Decreasing mitochondrial iron at baseline is sufficient to protect against ischemia/reperfusion injury.
Lower baseline mitochondrial iron is associated with decreased ROS production during cellular and tissue injury.
Modulation of mitochondrial iron is shown to be a viable therapeutic approach against ischemic heart disease and heart failure, highlighting the need to develop more targeted iron chelators.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Five iridium bis(carbene) complexes, Ir(pmi)2(pypz) (1), Ir(mpmi)2(pypz) (2), Ir(fpmi)2(pypz) (3), Ir(fpmi)2(pyim) (4), and Ir(fpmi)2(tfpypz) (5) (pmi=1‐phenyl‐3‐methylimdazolin‐2‐ylidene‐C,C2′; ...fpmi=1‐(4‐fluorophenyl)‐3‐methylimdazolin‐2‐ylidene‐C,C2′; mpmi=1‐(4‐methyl‐phenyl)‐3‐methylimdazolin‐2‐ylidene‐C,C2′; pypz=2‐(1H‐pyrazol‐5‐yl)pyridinato; pyim=2‐(1H‐imidazol‐2‐yl)pyridinato; and tfpypz=2‐(3‐(trifluoromethyl)‐1H‐pyrazol‐5‐yl)pyridinato), were synthesized and their structures were characterized by NMR spectroscopy, mass spectroscopy and X‐ray diffraction. These complexes showed phosphorescent emission with the emission maxima between 453 and 490 nm. Various spectrophotometric measurements, cyclic voltammetric studies, and density functional theory (DFT) calculations show that, unlike most of the phosphorescent cyclometalated iridium complexes, the lowest unoccupied molecular orbital (LUMO) energy and the emissive state of these iridium complexes are mainly controlled by the N,N′‐heteroaromatic (N^N) ligand. Despite the fact that the LUMO levels of these complexes are mainly on the N^N ligands, the efficiencies of the electroluminescent (EL) devices are very high. For example, the EL devices using Ir(mpmi)2(pypz), Ir(fpmi)2(pypz), and Ir(fpmi)2(tfpypz) as the dopant emitters exhibited light‐ to deep‐blue electrophosphorescence with external quantum efficiencies of 15.2, 14.1, and 7.6 % and Commission Internationale d’Énclairage (x,y) coordinates (CIEx,y) of (0.14, 0.27), (0.14, 0.18) and (0.14, 0.10), respectively.
Simple and effective! Experimental and theoretical studies show that the emissive state of the iridium complexes (see figure) is mainly controlled by the single conjugated N,N′‐heteroaromatic ligand. Their emission color can be systematically tuned from light to deep blue by simple ligand modulation. The blue electrophosphorescent devices using these complexes as the emitter show very high external quantum efficiencies of 7.6–15.2 %.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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