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Digital droplet PCR (ddPCR) is an implementation of conventional PCR, with the potential of overcoming some limitations of real-time quantitative PCR (RQ-PCR). To evaluate if ddPCR may improve the quantification of disease levels and refine patients' risk stratification, 116 samples at four time points from 44 (35 B-lineage and 9 T-lineage) adult Philadelphia-negative acute lymphoblastic leukemia patients enrolled in the GIMEMA LAL1913 protocol were analyzed by RQ-PCR and ddPCR. A concordance rate between RQ-PCR and ddPCR of 79% (P 0.0001) was observed; discordances were identified in 21% of samples, with the majority being RQ-PCR-negative (NEG) or positive not quantifiable (PNQ). ddPCR significantly reduced the proportion of PNQ samples-2.6% versus 14% (P = 0.003)-and allowed disease quantifiability in 6.6% of RQ-PCR-NEG, increasing minimal residual disease quantification in 14% of samples. Forty-seven samples were also investigated by next-generation sequencing, which confirmed the ddPCR results in samples classified as RQ-PCR-PNQ or NEG. By reclassifying samples on the basis of the ddPCR results, a better event-free survival stratification of patients was observed compared to RQ-PCR; indeed, ddPCR captured more true-quantifiable samples, with five relapses occurring in three patients who resulted RQ-PCR-PNQ/NEG but proved ddPCR positive quantifiable. At variance, no relapses were recorded in patients whose follow-up samples were RQ-PCR-PNQ but reclassified as ddPCR-NEG. A broader application of ddPCR in acute lymphoblastic leukemia clinical trials will help to improve patients' stratification.

Some low-temperature magnetic sensors are based on the Hall effect in thin metallic films. However, their sensitivity is more than one order of magnitude smaller than that of silicon-based Hall sensors operating at room temperature. Furthermore, in order to avoid significant Joule heating, only very small bias currents can be injected at low temperatures. Here, we show that a sensor based on a photoinduced Hall effect, in which charge is photogenerated in a semiconductor and injected into an adjacent metallic layer, can be used as a bias-free, cryogenic sensor. The system consists of a platinum thin film deposited on intrinsic-silicon substrate. The film forms a Schottky interface with the semiconductor. At room temperature, carriers photogenerated in the semiconductor are injected into the metal, because of rounding-off of the Schottky barrier, and are deflected by a magnetic field applied in the film plane. At cryogenic temperatures, and well below the freeze-out temperature for silicon, the photogenerated electrons can tunnel through the barrier, and the sensor recovers the same sensitivity as that obtained at room temperature.

Magnetostrictive properties of Iron-Gallium alloys, such as the saturation of magnetic induction and magnetostriction can be derived from experimental measurements. It is known that, in order to exhibit the largest saturation magnetostriction, Galfenol requires the application of a suitable external compressive stress. In order to avoid a bulky system to provide such stress, a built-in stress could be added to the material through a technological process known as stress annealing. In this paper an experimental method to evaluate the stress applied to Galfenol rods is presented. Then, the method can be exploited either to evaluate the built-in stress or to develop a stress sensor. A concept device exploiting the method and its experimental characterization are presented.

Summary Copy number aberrations (CNAs) represent cooperating events in B-lineage acute lymphoblastic leukaemia (B-ALL); however, their clinical relevance across different age cohorts is unclear. We analysed the recurrent CNAs in 157 age-stratified B-ALL negative cases for recurrent rearrangements (B-NEG ALL), and their association with patients’ clinico-biological features. We found that: (i) CDKN2A/RB1-deleted and EBF1-deleted adults had a shorter disease-free survival than those with wild-type, (ii) among the unfavourable markers, CDKN2A/RB1 deletions and K/NRAS mutations retained their impact in multivariate analysis, encouraging the evaluation of CDKN2A/RB1 deletions and RAS mutations in the diagnostic/prognostic workflow to refine ALL risk assessment.

Minimal residual disease (MRD) is the strongest prognostic factor in both childhood and adult acute lymphoblastic leukemia (ALL). Tumor load reduction during/after induction treatment predicts resp...

Because of its low-cost, silicon is the standard material for photovoltaic conversion. Yet, its band-edge absorption spectrum is narrower than the spectrum of the solar radiation, which reduces its conversion efficiency. In this paper, it is shown that the spectrum of absorbance of silicon can be extended to longer wavelengths by proximity to a two-dimensional (2D) semiconductor. Photo-induced Hall effect, together with standard absorption spectroscopy, was employed to estimate the increase of photo-conversion efficiency of a 2D-platinum-diselenide/intrinsic-silicon heterostructure. The system shows a significantly higher absorption in the infrared as compared to the single films. Angle resolved X-ray Photoelectron Spectroscopy (XPS) confirm that a change of the band structure occurs in the silicon substrate at the interface between the two semiconductors. The results are interpreted in the framework of band-gap narrowing due to hole-confinement in the Si, induced by electron-confinement in the 2D film. This allows us to claim that the increase of photo-conversion efficiency in the Pt/PtSe2/Si sample is due to an enhancement of the light absorbance of silicon near the interface. Possible application of the effect in photo-voltaic cells is discussed.

The requirement of self-powered stand-alone sensors or wireless sensor networks (WSN) with a “fit and forget” paradigm, that is, without the need of batteries, seems to have attracted the interest of technological research in last years. Activity in development of devices, Known as Energy Harvesters, able to transform ambient energy into a kind of usable energy were boosted. Among this quite large set of solutions, those able to transform mechanical vibrations into electric power and referred to as Kinetic Energy Harvesters (KEH) are among the most known and studied, [1]. Such special set of self powered systems found a noteworthy interest in the health monitoring of civil structures or in automotive or railway applications, where, in the latter, the KEH potentialities have been identified for low cost self power sensors in freight railway wagons, [2]. Among them, one solution is represented by the cantilever configuration exploiting magnetostrictive materials, [3], based on Fe-Ga (Galfenol) alloys, showing interesting mechanical and magnetostrictive properties, [4]. Vibrations energy spectrums are complex and usually distributed over a quite large frequency range, while, conversely, cantilever KEH work in a relatively narrow band and this requires both modelling and experimental effort in order to provide an “optimal” system tuning. In this paper as a first step, different configurations employing one or more Fe-Ga strips over an Al substrate have been developed and tested through the analysis of a converted RMS power vs. frequency in order to detect the geometric and physical parameters affecting resonance frequency, bandwidth and converted power by Villari effect, [2]. The selected cantilever is implemented by bonding two single Galfenol strips 120X15X0,3 mm to a 120X15X2 mm Aluminium foil. The latter guarantees a better mechanical resistance to cyclic loads and provides a larger stiffness yielding to a consequent increase of the resonance frequency. The device has been equipped by a 300 turns coil, as it can be observed in Fig. 1. Experimental tests were performed with an electrodynamic shaker (Fig. 2a) in the 50–200 Hz frequency interval with sinusoidal acceleration in the ${1-4 g}$ amplitude range [5]. The excitation level has been detected by a reference accelerometer, while the beam bending is measured by a strain gauge based system. The effect of a resistive load on the RMS converted power is shown in Fig. 2b) where the power response with different resistive loads and 4g acceleration is shown. The best result of 305mW is achivied with a 9,9 W. The low energy conversion required the design of a suitable magnets set in order to supply a sufficient magnetic bias to the active material with the aim to increase the converted power [6]. In order to increase the flux captured by the coil, two magnets were attached to the structure [7]. The field generated by two magnets was measured spanning from 43 kA/m on the upper strip down to 3 kA/m on the lower strip. In Fig. 2c) the effect of the magnetic bias on the RMS converted power is shown. However, it should be outlined that the applied bias is the result of an optimization procedure since, as known, high magnetic biases pushes the material towards saturation and energy conversion is no longer observed [6]. Considering the importance of the bias, tests were carried out by varying the number of magnets (Fig. 2d). In this case it is important to evaluate the position of the magnet on the beam as it influences the resonance frequency and the magnetoelatic coupling [8]. These results seem quite encouraging, due to the relatively high converted energy (37mW) and the simple device structure. However, a thorough and accurate modelling analysis in connection to the experimental data, in order to quantitatively show the dependence of the converted power on geometric and physical parameters will be discussed in the full paper.

BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.

Magnetostrictive actuators play an important role in the perception of usefulness of smart materials and devices. Their applications are potentially wider than that of piezoelectric actuators because of the higher energy density and intrinsic robustness. However, the non-negligible hysteresis and complexity of their characteristics make the design and control quite difficult and has limited their diffusion in industrial applications. Nevertheless, the scientific literature presents a wide offer of results in design and geometries, modeling and control that may be exploited for applications. This paper gives a reasoned review of the main results achieved in the literature about design, modeling and control of magnetostrictive actuators exploiting the direct effects of magnetostriction (Joule and Wiedemann). Some perspectives and challenges about magnetostrictive actuators development are also gathered.

Background. Minimal residual disease (MRD) is the strongest prognostic factor in both children and adults with acute lymphoblastic leukemia (ALL). Currently, it is most widely monitored by molecular methods based on real-time-quantitative-PCR (RQ-PCR). Digital-droplet-PCR (ddPCR) and next-generation-sequencing (NGS) represent advanced tools that have the potential to overcome some limitations of standard approaches and potentially provide additional benefits. We analyzed adult ALL follow-up (FU) samples by RQ-PCR, ddPCR and NGS in order to better define the discriminating power of these novel methods. Patients and Methods. Thirty adult ALL patients enrolled in the GIMEMA LAL 1913 protocol and their 83 FU bone marrow (BM) samples were studied. All patients received homogeneous induction/early consolidation chemotherapy, with concurrent MRD analysis at four time-points, to optimize risk classification and support risk/MRD-oriented therapy. RQ-PCR analyses followed the EuroMRD Consortium guidelines (van der Velden, 2007), ddPCR was performed as published (Della Starza, 2016; Cavalli, 2017) and NGS, as previously described (Faham, 2012; Kotrova M, 2017). Results. By MRD RQ-PCR analysis, 19/83 samples were positive and quantifiable (Q), 9/83 were positive not-quantifiable (PNQ) and 55/83 were negative (NEG). By MRD ddPCR analysis, 27/83 samples were Q, 1/83 sample was PNQ and 55/83 proved NEG. Comparing the results of the two methods, we observed that MRD detection was concordantly positive or negative in 81% (67/83) of FU samples, while 19% (16/83) samples were classified as discordant. Most of the discordances occurred in samples with low levels of disease, i.e. PNQ or NEG: 9/83 were RQ-PCR PNQ, 4 of which were Q by ddPCR and 5 were ddPCR NEG. In the remaining 7 discordant FU samples, 5 were RQ-PCR NEG/ddPCR Q, 1 sample was RQ-PCR Q /ddPCR NEG and 1 sample was RQ-PCR NEG/ddPCR PNQ. The use of ddPCR significantly reduced the proportion of PNQ samples if compared to RQ-PCR - 1/83 (3%) vs 9/83 (15%) - respectively (p=0.0179), increasing the proportion of Q samples: 27/83 (33%) vs 19/83 (23%). It is worth noting that ddPCR also quantified the levels of disease in 9% (5/55) of samples, that were RQ-PCR NEG (Table 1). MRD analysis was also performed by NGS in 41 samples from 15 patients: 18/41 samples proved Q and 23/41 were NEG. Comparing the MRD detection obtained by both ddPCR and NGS, we observed a concordant result in 98% (40/41) of samples; only 1 sample was ddPCR NEG and NGS Q with a MRD level of 1x10-5. The concordance between RQ-PCR and NGS was 78% (32/41 samples). Moreover, among these 41 samples 9 (from 7 patients) were discordant between RQ-PCR and ddPCR in the first comparative analysis: in 4 RQ-PCR-NEG FU samples, 3 were Q by both ddPCR and NGS, 1 was ddPCR NEG and NGS Q, with a MRD level of 10- 5; 1 subsequent relapse was observed; 4 FU samples that were RQ-PCR-PNQ/ddPCR-Q, were Q also by NGS; 1 subsequent relapse was observed. Finally, 1 RQ-PCR-PNQ sample was negative by both ddPCR and NGS, and no recurrence has so far been observed. Moreover, in the cohort of samples analyzed only by RQ-PCR and ddPCR, in 1 RQ-PCR NEG/ddPCR Q sample a relapse was observed, while the only case that was RQ-PCR Q/ddPCR NEG has so far not relapsed. Notably, 2 of the 3 relapses were documented in patients who were, at decisional treatment TPs, RQ-PCR PNQ or NEG and ddPCR/NGS Q. Conclusions. When MRD levels are very low, it can be difficult to dissect if the not-quantifiable signal observed by PCR is due to few residual leukemic cells or to a non-specific amplification of normal DNA. The superior sensitivity and accuracy of ddPCR and NGS could be instrumental to univocally define these samples, which presently represent a problematic gray area in the clinical practice of MRD-driven protocols and might be associated with clinical relapse: indeed, among 83 FU samples analyzed we observed 3 relapses, whose FU samples were classified as PNQ or NEG by RQ-PCR, but proved Q by ddPCR and/or NGS. At variance, no relapses were recorded in patients whose FU samples were defined RQ-PCR-PNQ, but proved ddPCR/NGS NEG. Moreover, in 2/3 relapsed cases the change of MRD status (PNQ or NEG vs Q) could have led to a switch in risk classification and therefore in a treatment change. Further studies with a larger number of discrepant cases and a longer FU time will allow to conclusively define the clinical application and implication of these new methods. Disclosures Chiaretti: Shire: Consultancy; Pfuzer: Consultancy; Amgen: Consultancy; Incyte: Consultancy. Foà:NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau.