BCR–ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is ...currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDxTMBCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR–ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR–ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The present study investigates whether epigenetic differences emerge in the heart of patients undergoing cardiac surgery for an aortic valvular replacement (AVR) or coronary artery bypass graft ...(CABG). An algorithm is also established to determine how the pathophysiological condition might influence the human biological cardiac age.
Blood samples and cardiac auricles were collected from patients who underwent cardiac procedures: 94 AVR and 289 CABG. The CpGs from three independent blood-derived biological clocks were selected to design a new blood- and the first cardiac-specific clocks. Specifically, 31 CpGs from six age-related genes, ELOVL2, EDARADD, ITGA2B, ASPA, PDE4C, and FHL2, were used to construct the tissue-tailored clocks. The best-fitting variables were combined to define new cardiac- and blood-tailored clocks validated through neural network analysis and elastic regression. In addition, telomere length (TL) was measured by qPCR. These new methods revealed a similarity between chronological and biological age in the blood and heart; the average TL was significantly higher in the heart than in the blood. In addition, the cardiac clock discriminated well between AVR and CABG and was sensitive to cardiovascular risk factors such as obesity and smoking. Moreover, the cardiac-specific clock identified an AVR patient's subgroup whose accelerated bioage correlated with the altered ventricular parameters, including left ventricular diastolic and systolic volume.
This study reports on applying a method to evaluate the cardiac biological age revealing epigenetic features that separate subgroups of AVR and CABG.
New fentanyl analogues have been constantly emerging into the illegal drug market as cheap substitutes of heroin posing a serious health threat for consumers because of their high toxicity. ...Analytical methods to disclose the presence of these compounds in biological fluids of intoxicated individuals need to be updated to keep up with the new trends. In this study, we updated an ultra-high-performance liquid chromatography-tandem mass spectrometry method previously developed, for detecting some new fentanyl analogues and metabolites (sufentanil and norsufentanil, cis-3-methylnorfentanyl, trans-3-methylnorfentanyl, metabolites of cis and transmethylfentanyl, beta-phenylfentanyl, phenylfentanyl, para-fluoro furanyl fentanyl, isobutyryl fentanyl and ocfentanil) in urine sample.
Urine samples were simply diluted before injection in the chromatograph equipped with a reversed phase microcolumn. Detection was achieved with a triple quadrupole mass spectrometer with an electrospray ionization source in positive ion mode and operated in multiple reaction monitoring.
The chromatographic separation was short (5 min) and the method was fully validated with a high sensitivity being limits of quantifications from 0.003 to 0.006 µg/L urine for the analytes under investigation.
The suitability of the method was tested with urine specimens from former heroin addicts, which resulted positive by immunological screening to the class of fentanyl analogues. This method represents a valid tool to document recent exposure to the above-reported compounds for clinical and forensic purposes.
Small wonder: Atrop‐abyssomicin C is a small, yet complex spirotetronate (see scheme) that is active against Gram‐positive bacteria, such as MRSA. Feeding studies and genetic manipulation of its ...producer, Verrucosispora maris AB‐18‐032, for the first time give insight into its biosynthesis and demonstrate how closely related the members of this important class of molecules are.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent applications require vertical chip stacking to increase the performance of many devices without the need of advanced node components. Image sensors and vision systems will embed more and more ...smart functions, for instance, image processing, object recognition, and movement detection. In this perspective, the combination of Cu-to-Cu direct hybrid bonding technology with Through-Silicon-Via (TSV) will allow 3D interconnection between pixels and the associated computing and memory structures, each function fabricated on a separate wafer. Wafer-to-wafer hybrid bonding was achieved with multi-pitch design—1–4 μm—of single levels of Cu damascene patterned on 300 mm silicon substrates. Defect-free bonding, as far as the extreme edge of the wafer, was demonstrated on a stack with three wafers. Middle wafers thinning was done with grinding only and with a thickness uniformity (TTV) <2 μm to an ultimate thinning as low as 3 μm. Alignment performance was characterized by post-bonding for two superposed hybrid bonding interfaces. In our set of wafers, modeling the alignment with translation, rotation, and scaling components enables us to optimize the residuals down to 3σ < 100 nm. A process flow of thin TSV with a fine pitch of 2 μm for high-density vertical interconnect through a three-wafer stack was developed. Via-last TSV architecture was adopted with 1 μm TSV diameter and 10 μm thickness. Lithography, etching solutions, Ti/TiN barrier deposition, and void-free Cu filling solutions were demonstrated. TSV cross sections after CMP and connections with top and bottom Cu damascene lines show good profile control. Process developments are matured and can be reliably used in the fabrication of an electrical test vehicle including vertical interconnects associating multi-wafers stacking with a hybrid bonding process and high-density thin TSV applicable to low pitches (<5 μm).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A 128 times 64 pixel programmable vision sensor performs real-time analog image processing over high dynamic range images is reported. The pixel-parallel single instruction multiple data (SIMD) ...architecture executes real-time spatio-temporal filtering with 2.8 GOPS/mm 2 and large flexibility in coefficient assignment. The sensor uses time-based and pulse-based operating modalities to execute spatio-temporal filtering on images with dynamic range up to about 100 dB. The in-pixel processing is based on two operations: the absolute value of voltage difference and accumulation of partial results. Feature extraction from the entire image is also possible without the need for image dispatching, thus optimizing both processing speed and video bandwidth. The 32.6 mum square pixel, with a fill-factor of 24%, consists of two analog memories and 28 transistors. The sensor, fabricated in 0.35 mum CMOS technology, gives a fixed pattern noise (FPN) of 0.8% and power consumption of 14 mW at 3.3 V.
In this work we discuss a novel design concept of energy harvester (EH), based on Microsystem (MEMS) technology, meant to convert mechanical energy, available in the form of vibrations scattered in ...the surrounding environment, into electrical energy by means of the piezoelectric conversion principle. The resonant structure, named four-leaf clover (FLC), is circular and based on four petal-like double mass-spring systems, kept suspended through four straight beams anchored to the surrounding Silicon frame. Differently from standard cantilever-type EHs that typically convert energy uniquely in correspondence with the fundamental vibration frequency, this particular shape is aimed to exploit multiple resonant modes and, thereby, to increase the performance and the operation bandwidth of the MEMS device. A preliminary non-optimized design of the FLC is discussed and physical samples of the sole mechanical resonator, fabricated at the DIMES Technology Center (Delft University of Technology, the Netherlands), are experimentally characterized. Their behaviour is compared against simulations performed in ANSYS Workbench™, confirming good accuracy of the predictive method. Furthermore, the electromechanical multiphysical behaviour of the FLC EH is also analysed in Workbench, by adding a layer with piezoelectric conversion properties in the simulation. The measured and simulated data reported in this paper confirm that the MEMS converter exhibits multiple resonant modes in the frequency range below 1 kHz, where most of the environmental vibration energy is scattered, and extracted power levels of 0.2 μW can be achieved as well, in closed-loop conditions. Further developments of this work are expected to fully prove the high-performance of the FLC concept, and are going to be addressed by the authors of this work in the on-going activities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to ...treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This paper reports the design, fabrication and assessment of a low-cost uncooled infrared imager that has been conceived as a general purpose system to be used in a wide range of infrared ...applications. The imager has been fabricated using the AMS 0.8
μm CYE CMOS process together with a compatible front-side bulk micromachining post-process provided by the CMP service of the TIMA laboratory. The adopted fabrication approach does not involve any lithography step, material deposition or particular etch-stop technique after the CMOS process, so that the imager cost is almost equal to the CMOS chip cost. The infrared imager is composed of a focal plane array (FPA) with 16
×
16 thermopile pixels, which are monolithically integrated with the addressing and readout electronics. Each pixel consists of a thermally isolated micromachined membrane suspended by two arms that contain the polysilicon/aluminium thermocouples of the embedded thermopile sensor. The pixel membrane also includes a heating resistor intended to implement a self-test function that allows an electrical test of the FPA without need of specific infrared equipment. Since the voltage levels generated by the thermopile pixels are in the range of a few μV the readout channel consists of a low-noise voltage amplifier with a high variable gain that can be tuned for different operation conditions. The readout circuit makes use of the chopper principle and the correlated double sampling technique to reduce the noise floor and the amplifier offset levels. Optical measurements performed with the fabricated prototypes have shown a pixel responsivity of 15.0
V/W, a noise equivalent power of 1.37
nW and a normalized detectivity of 1.05
×
10
7
cm
Hz
1/2
W
−1, values that are in line with current state of the art. The readout channel features a maximum gain of 85
dB with a 4.3
kHz bandwidth and an equivalent input noise of 22
nV/Hz
1/2. An infrared imager based on the FPA has been build and thermal imaging has been demonstrated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Drug testing in hair usually requires a rather complex sample treatment before drugs are amenable to analysis by either immunological and/or chromatographic coupled to mass spectrometry ...methods. Immunological methods applied are usually dedicated to hair analysis as analytes present in this matrix are not always the same present in urine. Comedical s.a.s. laboratories recently commercialized reagents (VMA-T) purposely designed for hair sample treatment which are compatible with current immunometric methods used for urine drug testing. This is possible as some analytes (6-MAM and cocaine) present in hair after sample treatment are converted to those detected in urine (morphine and benzoylecgonine). A correlation study for several drug classes performed in two laboratories with 32 clinical and 12 spiked drug free (controls) hair samples shows that implementation of the method on clinical chemistry analyzers is easy and that results obtained by different operators and instruments are comparable and reproducible. The main advantage of VMA-T method is the possibility to simultaneously extract from hair main drug classes, in a period of time lower than 2 h and its compatibility with immunological methods applied in urine drug testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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