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T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.

A copper-based metal-organic framework (MOF) was prepared using a new linker, a 5-substituted isophthalic acid bearing a propargyl carbamate group, intended to provide a terminal alkyne function protruding from the material surface to generate supported gold species for potential catalytic applications. The novel material was fully characterized by spectroscopic analyses of different kinds: FTIR, Raman, EDX, and XPS, as well as by thermal and surface area measurements. Synchrotron X-ray diffraction data analysis, in particular, revealed that this MOF, labelled [Cu(1,3-YBDC)]xH2O (x ca. 2), where Y stands for the pendant alkYne and BDC for benzene dicarboxylate, contains a complex network of 5-substituted isophthalate anions bound to Cu(II) centers, arranged in pairs within paddlewheel (or "Chinese lantern") fragments of Cu2(mu-COO)4(D)2 formulation (D being a neutral Lewis base), with a short Cu/Cu distance of 2.633(4) Angstrom. Quite unexpectedly, the apical atom in the paddlewheel structure belongs to the carbamate carbonyl oxygen atom. Such extra coordination by the propargyl carbamate groups drastically reduces the MOF porosity, a feature that was also confirmed by BET measurements. However, the MOF functionality is retained at the external crystal surface where 2% of active terminal alkynes is located.

High-performance thermoplastic polymers, such as Poly(aryl ether ketone)s (PAEK)s, can be used in various space applications due to their high mechanical properties, low density, and low outgassing properties. Polyether ether ketone (PEEK) is a thermoplastic semi-crystalline polymer belonging to the PAEKs family, which, together with its composites, has been proved to be processable via Additive Manufacturing, in particular via Fused Filament Fabrication (FFF), enabling the production of parts both on-ground and possibly even for out-of-earth. In the past years, extensive efforts have been spent on the improvement of 3D-printed polymeric structures, extending the applications of high-performance polymers from purely mechanical to functional ones. It is possible to confer new properties to polymers by mixing and blending tailored fillers and different additives (e.g., clays, NdFeB powders, magnetite, and carbon fillers). Composite and nanocomposite polymers present customized functional properties such as electrical conductivity, thermal conductivity, soft and hard magnetic properties absent or utterly different from the ones of pure polymer. In this paper, we report the state of the art on 3D-printed PEEK composites, their mechanical properties, and functionalities in view of the production of parts made of PEEK composites and nanocomposites, and their possible space applications (e.g., electromagnetic devices, magnetic shielding, thermal protection system and sensors).

The synthesis and reactivity of a gallium(I) cationic complex using [12]crown-4 as a stabilizing ligand were explored. The synthesis of [Ga([12]crown-4)][GaCl4] was achieved in one step from commercially available starting materials. Anion exchange was utilized to replace the reactive tetrachlorogallate anion for the perfluorophenylborate anion. [Ga([12]crown-4)][B(C6F5)4] was analyzed using XPS, which allowed for the classification of the gallium(I)-crown ether complex as electron-deficient. Reactions of the gallium(I)-crown ether complex with Cp*K and cryptand[2.2.2] demonstrated the facile synthesis of a known gallium(I) compound as well as the generation of new gallium(I) complexes, highlighting the use of the gallium(I)-crown ether complex as an effective starting material for new gallium(I) complexes.

Objective Our objective was to evaluate the effects of providing shade and shade combined with evaporative cooling on production, cow activity, metabolism, and hepatic gene expression of late-lactation Holstein dairy cows under moderate heat-stress conditions. Materials and Methods Forty-eight multiparous Holstein cows were used in a completely randomized block-design trial and randomly assigned to 1 of 3 treatments: control (CTL), without access to shade; access to artificial shade (SH); and shade combined with evaporative cooling (SHplus). Results were analyzed using a mixed procedure with repeated measures. Results and Discussion No differences were observed in DMI. Milk yield was not different among treatments, but lactose concentration was greater in SHplus. Treatments CTL and SH had greater BW losses than SHplus. Control cows spent less time grazing. The CTL and SH had higher p.m. rectal temperatures than SHplus, whereas CTL had the highest p.m. respiration rate. Control cows had greater serum insulin levels. Control and SH had greater BHB and urea concentrations and lower glucose concentration compared with SHplus. The hepatic expression of PCK1, PDK4, and HP genes was downregulated in SH and SHplus relative to control. Hepatic expression of NFKB1 was downregulated, whereas SOCS2 was upregulated, for SHplus compared with CTL. Implications and Applications Despite the absence of treatment effects on productive variables, changes in blood profiles and hepatic expression of target genes were observed among treatments. These results suggest that the provision of shade combined with evaporative cooling was effective in alleviating the negative effects of heat stress.

Highly stable gold nanoparticles anchored on propynylcarbamate-functionalized silica (Au/SiO2@Yne) have been efficiently utilized for the heterogeneous hydroamination of phenylacetylene with aniline under different reaction conditions. In order to ascertain the eventual influence of surface silanol groups on the system activity and selectivity tailored modifications of Au/SiO2@Yne catalysts were pursued according to two different strategies, involving respectively functionalization with trimethylethoxysilane (Au/SiO2@Yne-TMS) or post-treatment with triethylamine (Au/SiO2@Yne-NEt3). The prepared materials were analysed by several complementary techniques such as Solid State NMR (SS NMR), Transmission Electron Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS), X-ray Diffraction (XRD). A comparison of the resulting catalytic activities with that of the pristine Au/SiO2@Yne revealed a significant improvement for Au/SiO2@Yne-NEt3 in terms of both conversion and selectivity. Recycling and stability studies showed a catalytic activity decrease after the first run, due to the formation of polyphenylacetylene (PPhA) oligomers shielding the active sites. PPhA removal by sonication in acetone fully restored the catalytic activity and empowered the system with a good operational stability, a very crucial issue in view of eventual practical applications.

Background & Aims A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. Methods Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. Results Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50–0.79), cabozantinib (HR = 0.76, 95% CI = 0.63–0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70–0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36–0.52), regorafenib (HR = 0.46, 95% CI = 0.37–0.56), ramucirumab (HR = 0.54, 95% CI = 0.43–0.68), brivanib (HR = 0.56, 95% CI = 0.42–0.76), S-1 (HR = 0.60, 95% CI = 0.46–0.77), axitinib (HR = 0.62, 95% CI = 0.44–0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57–0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients’ stratification. Conclusions The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

A simple and industrially scalable method for making a PANI-modified cellulose touch sensor. Ragazzini a, I. Gualandi a, *, S. Selli b, C. Polizzi a, M.C. Cassani a, D. Nanni a, F. Gambassi a, F. Tarterini a, D. Tonelli a, E. Scavetta a, B. Ballarin a, * a Department of Industrial Chemistry “Toso Montanari”, Bologna University, Viale Risorgimento 4, I-40136, Bologna, Italy; b Cromatos s.r.l., via G. Cardano, 6B/C/D, 47122, Forlì, Italy Nowadays, alternatives to the traditional electronics that should be low cost, degradable, compostable and made from environmentally nontoxic substances are of great interest in research. As candidate, we propose bare fibers of cellulose made conductive by an in situ oxidative polymerization of aniline. The resulting composite fibers were emplojed to fabricate electroactive sheets using a pilot plant of a typical paper industry. The resistivity of the obtained sheets is 14 ± 1 Ω sq-1, a value around 1000 times lower than those reported in literature. The higher electronic performances of the sheets were demonstrated by assembling a capacitive touch sensor device with optimized geometry. The touch sensor shows an increase of 3–4 % of the starting electric capacity after compression and a fast response time of 52 ms. To our knowledge this is the first time that a device is prepared in this way and therefore, the herein presented results can bring a significant improvement in the development of low-cost, green and high-tech electronic devices 1. [1] Ragazzini, I. et al. A simple and industrially scalable method for making a PANI-modified cellulose touch sensor. Carbohydr. Polym. (2020) doi: 10.1016/j.carbpol.2020.117304.

Purpose: Develop a quantitative LC–MS/MS method for FDG, FDG-monophosphate, glucose and glucose-monophosphate in mouse tumor models to assist in validating the use of [18F]FDG-positron emission tomography (PET) imaging for anticancer therapies in a clinical setting. Methodology/results: Analytes were isolated from tumors by protein precipitation and detected on a Sciex API-5500 mass spectrometer. Improved assay robustness and selectivity were achieved through chromatographic separation of FDG-monophosphate from glucose-monophosphate, selection of a unique ion transition and incorporation of stable isotope labeled internal standards. In a mouse JIMT-1 tumor model, FDG-monophosphate levels measured by LC–MS/MS correlated with [18F]FDG-PET imaging results. Conclusion: LC–MS/MS analysis of FDG-monophosphate accumulation in tumors is a cost-effective tool to gauge the translational potential of [18F]FDG-PET imaging as a noninvasive biomarker in clinical studies.

Signalling of the epithelial splicing variant of fibroblast growth factor receptor 2 (FGFR2b) triggers both differentiation and autophagy, while the aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells induces impaired differentiation, inhibition of autophagy as well as the induction of the epithelial‐mesenchymal transition (EMT). In light of the widely proposed negative loop linking autophagy and EMT in the early steps of carcinogenesis, here we investigated the possible involvement of FGFR2c aberrant expression and signalling in orchestrating this crosstalk in human keratinocytes. Biochemical, molecular, quantitative immunofluorescence analysis and in vitro invasion assays, coupled to the use of specific substrate inhibitors and transient or stable silencing approaches, showed that AKT/MTOR and PKCε are the two hub signalling pathways, downstream FGFR2c, intersecting with each other in the control of both the inhibition of autophagy and the induction of EMT and invasive behaviour. These results indicate that the expression of FGFR2c, possibly resulting from FGFR2 isoform switch, could represent a key upstream event responsible for the establishment of a negative interplay between autophagy and EMT, which contributes to the assessment of a pathological oncogenic profile in epithelial cells.

Brazil is one of the largest producers of maize worldwide. However, this production is threatened due to low soil fertility, especially low levels of potassium (K+). K+ is one of the most important...

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin.

Pre-slaughter conditions and their effects on carcass quality have been largely addressed for pigs of 90–100 kg live weight, while few studies consider the effects of pre-slaughter conditions on the quality of the carcasses obtained from heavy pigs intended for Protected Designation of Origin (PDO) production. A total of 1680 heavy pigs were transported in 72 batches from a farm to a commercial abattoir on 16 different days, avoiding mixing unfamiliar animals. Slaughterhouse conditions, animal behaviors, and human–animal interactions were annotated at unloading and during the race toward the stunning cage. Carcass lesions on the rear, middle, and shoulder parts of the carcasses were scored. The prevalence of carcasses with severe lesions was 6.92%, 11.87%, and 6.83%, for the rear, middle, and shoulder parts, respectively. Among the pre-slaughter events, waiting before unloading and improper handling practices at the abattoir were the major factors affecting carcass lesion severity. Lairage pen space allowance was also found to affect severe rear and shoulder lesions, and the batches that were transported in the trailer had an increased prevalence of severe shoulder lesions. Our results suggest waiting time before unloading should be shortened as much as possible, and educational programs to train operators for more careful management of animals in the abattoir are greatly required to avoid improper animal handling practices.

Objective: Several studies have reported about the performance of C-choline-PET/computed tomography (CT) (choline) in patients with biochemical recurrent (BCR) prostate cancer, but there is a lack of information regarding negative choline in the same clinical setting. Our aim was to retrospectively analyse negative choline in a cohort of BCR-patients with high prostate-specific antigen (PSA). Methods and results: We retrospectively analysed all choline-scans performed at two high-volume imaging centres between 2005 and 2018, selecting those of interest according to the following inclusion criteria: (1) proven prostate cancer treated either with radical prostatectomy or primary external beam radiation therapy (EBRT), (2) BCR after radical prostatectomy or EBRT, (3) PSA serum values >20 ng/mL at the time of scan and (4) scan reported as negative for active disease. Overall, among 5792 scans performed for BCR-prostate cancer, 14 matched the inclusion criteria and were classified as follows: 5/14(36%) inaccurate reports, 3/14(21%) questionable underestimation of positive findings, originally described as unclear, 6/14(43%) negatives. Choline showed a high detection rate in BCR-prostate cancer patients with PSA >20 ng/mL. Conclusions: Although negative reports can be found in this clinical setting, in our review various disease-relevant findings were identified in more than half of the cases originally reported as negative warranting a double reading in such cases to avoid false-negative reports.

Magnetic Fe 3 O 4 (magnetite) nanoparticles are synthesized via a chemical precipitation route in different alkaline environments (NH 3 or NaOH) and subsequently functionalized with a (propynylcarbamate)triethoxysilane moiety, with the aim of promoting the nucleation and subsequent stabilization of gold nanoparticles. The propynylcarbamate group is able to capture the gold precursor (HAuCl 4 ), spontaneously reduce it, and stabilize the resulting Au nanoaggregates. The obtained results show that though the dimensions of the starting magnetite substrate depend on the base used in the preparation, they remain unaltered upon the subsequent modification. Conversely, the average Au nanoparticle dimensions can be conveniently tailored as a function of the base used in Fe 3 O 4 preparation and the presence/absence of the organic functionalization. The smallest dimensions (15 nm) are obtained for AuNP supported on propynylcarbamate-functionalized Fe 3 O 4 prepared in the presence of ammonia. Magnetization measurements highlight that all the Au/Fe 3 O 4 nanocomposites display a superparamagnetic behavior and those obtained using ammonia showed consistently smaller Hc and Mr values (av. values of 7.4 Oe and 0.8 emu/g) than those prepared with sodium hydroxide (av. values of 28 Oe and 2.8 emu/g).

The aim of the study was to evaluate the levels of lactate, pro-, macro-, and total glycogen in two different muscles, and meat quality traits (pH, colour, drip loss, cooking loss and shear force) across three different pig breeds, in the presence and absence of physical short-term pre-slaughter stress. Twenty-eight halothane-free pigs of the Italian Large White, Duroc and Pietrain breeds were subjected to different kinds of pre-slaughter handling: rough (RPH) or gentle (GPH). Before stunning, RPH group of pigs were subjected to a fast driving supported by the use of electric prods, whereas GPH group pigs were driven slowly without electric prods. Handling procedure influenced the contents of macroglycogen, lactate and pH at 45-min post-mortem with no effect on meat quality traits at 24 and 72 h post-mortem. Irrespective of the handling procedure, breed significantly affected L* and b* colour coordinates, Pietrain pigs showing slightly paler meat.

The aim of this study was to evaluate the use of mining co-products from the Irati (rhythmite and bituminous shale) and Corumbatai Formations (clayey siltstone) as sources of multi-nutrients for the cultivation of Brachiaria ruziziensis. The treatments were arranged within the double factorial scheme (7 × 2), completely randomized with 10 replications and placed into pots inside a greenhouse. Two factors were evaluated: the type of co-product and the soil class (Arenosol and Ferralsol). The mining co-products were applied in their isolated form and in composite (blended) form. At 60 and 140 days after the application of treatments, the ions available in the soil were determined. After that, four Brachiaria ruziziensis plants were cultivated per pot. After 40 days of cultivation, the aerial part of the plants was cut. Afterward, the macronutrients, as well as the production of shoot dry mass of the plants, were determined. The application of co-products, in general, increased the pH and the contents of ions available: K+ (Mehlich-1), Mg2+, Ca2+, P, SO42− and Si. As a highlight, at 140 days, rhythmite was the most efficient co-product in increasing pH, Ca2+ and Mg2+, with increases of 23%, 241% and 722% in Arenosol, respectively. Also at 140 days, bituminous shale increased the contents of SO42− by 72% and 427% in Ferralsol and Arenosol, respectively. Moreover, the accumulation of K, Ca, Mg and S, as well as the production of shoot dry mass of Brachiaria improved with the application of the co-products. In conclusion, the application of mining co-products alters the chemical attributes of both the soil and the plant, and this favors the production of shoot dry mass of Brachiaria, which demonstrates the potential to be a clean environmental solution to soil fertilization.

Background & Aims Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. Methods We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. Results Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. Conclusions These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. Lay summary Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib’s efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (

Simple Summary We aimed to validate the correlation between tumour glycolysis/acidosis and inflammation in osteosarcoma-associated mesenchymal stromal cells and investigate the role of acidity-induced inflammation in the development of metastasis in this very aggressive cancer. We confirmed the presence of an acidic microenvironment in osteosarcoma xenografts, both subcutaneous and orthotopic, using state-of-the-art imaging technologies; corroborated the correlation between tumour glycolysis, acidosis, and inflammatory markers in human patients; and finally, explored the use of anti-IL6 antibody to target these pathogenic pathways, using advanced 3D microfluidic models. In the future, advanced imaging systems for the measurement of tumour glycolysis and/or pH may help identify osteosarcoma patients who would benefit from anti-IL6 therapies to complement conventional therapy. Abstract Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and 18F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.

Nanocellulose (NC) is getting ahead as a renewable, biodegradable and biocompatible biomaterial. The NCs for this study were recovered from industrial cotton waste (CFT) by acid hydrolysis (HNC) and by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) mediated oxidation (ONC). They were functionalized by radical based glycidyl methacrylate (GMA) grafting providing crystalline HNC-GMA and ONC-GMA, and by allylation (ALL) providing amorphous HNC-ALL and ONC-ALL. HNC, ONC and their derivatives were chemically and morphologically characterized. Crystalline NCs were found capable to adsorb, from diluted water solution (2 × 10−3 M), the antibiotics vancomycin (VC), ciprofloxacin (CP), amoxicillin (AM) and the disinfectant chlorhexidine (CHX), while amorphous NCs did not show any significant adsorption properties. Adsorption capability was quantified by measuring the concentration change in function of the contact time. The adsorption kinetics follow the pseudo-second order model and show complex adsorption mechanisms investigated by an intraparticle diffusion model and interpreted by structure-property relationships. ONC and ONC-GMA loaded with VC, and HNC and HNC-GMA loaded with CP were not colonized by Staphylococcus aureus and by Klebsiella pneumonia and suggested long lasting release capability. Our results can envisage developing CFT derived NCs for environmental applications (water remediation) and for biomedical applications (antibacterial NC). Among the future developments, it could also be of interest to take advantage of acidic, glycidyl and allyl groups’ reactivity to provide other NCs from the NC object of this study.

SummaryMidbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.HighlightsThe study provides the first direct evidence of the role of neurexins in dopaminergic neurons.The synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals.Neurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion.Deletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons.

Despite the broad occurrence of carbohydrate-protein interactions in biology, the low binding affinities of such interactions hamper the characterization of carbohydrate binding sites in the absence of three-dimensional structural models. To allow the identification of proteins interacting with specific carbohydrate epitopes, we have developed new photoactivable oligosaccharide probes. Oligosaccharides containing the 1,2-cyclic carbamate group were attached to building blocks with a primary amino group to yield the corresponding urea derivatives. Cyclic carbamates of lactose, and 3- and 2′-fucosyl lactose, were used for the conjugation with building blocks containing photoactivable diazirine, benzophenone or aryl azido groups. The resulting oligosaccharide derivatives were tested for binding to Erythrina cristagalli lectin (ECL), Aleuria aurantia lectin (AAL) and Ulex europaeus agglutinin-I (UEA I). We found that ligands containing an aryl azido photoactivable group were successfully attached to lectins. The photoactivation reaction preserved lectin integrity, as no sign of protein degradation was visible. Mass spectrometric analysis confirmed the covalent binding of between one to three oligosaccharide probes, which matched with the expected carbohydrate-binding properties of the lectins tested. The conjugation of cyclic carbamate-derivatized oligosaccharides with photoactivable aryl azido groups thus represents a convenient approach to study protein-carbohydrate interactions.

This paper gives an overview on the development of microwave phototransistors within SiGe Bipolar and BiCMOS technologies. The physics and design of SiGe/Si Heterojunction Bipolar Phototransistors (HPT) are covered. A comprehensive analysis of the photodetection mechanisms and its localization into the structure is provided. After a description of the scaling rules, applications are presented in the field of Microwave-Photonics for short range and low-cost applications. Perspectives are then highlighted that includes the frequency increase, the enlargement of functionality and even on-chip optical links.

Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (-syn) also called -synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting -syn will therefore provide valuable insights into the disease progression of -synucleinopathies. In particular, -syn imaging can quantify changes in monomeric, oligomeric, and fibrillic -syn over time and improve early diagnosis of various -synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel -syn PET tracers are highly sought after. The development of an -syn PET tracer faces several challenges. For example, the low abundance of -syn within the brain necessitates the development of a high-affinity ligand. Moreover, -syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with -syn pathology. The lack of a defined crystal structure of -syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective -syn PET tracers.

Fixed-duration treatment with venetoclax (Ven), a highly selective Bcl-2 inhibitor combined with an anti-CD20 monoclonal antibody, showed high efficacy inducing high rates of deep responses with undetectable minimal residual disease (uMRD) in patients with previously treated and untreated chronic lymphocytic leukemia (CLL). The efficacy and safety of the Ven and rituximab (VenR) combination have been investigated in a multicenter, prospective study of the GIMEMA group that included young patients with previously untreated CLL (LLC 1518, VERITAS, NCT03455517). The primary endpoint of this study was the CR rate assessed according to the iwCLL criteria. Inclusion criteria were: treatment requirement per iwCLL criteria, age ≤65 years, cumulative Illness rating scale score ≤6, creatinine clearance ≥30 mL/min, and an unfavorable biologic profile with IGHV unmutated and or TP53 disruption. Treatment consisted of the Ven dose ramp-up (from 20 to 400 mg daily, during 5-weeks) followed by Ven 400 mg daily, combined with R for six 28-day courses (375 mg/m2, course 1; 500 mg/m2, courses 2-6). Patients continued with Ven single agent, 400 mg daily, until month 13. Tumor lysis syndrome (TLS) prophylaxis measures included hydration, allopurinol, or rasburicase. All patients received PneumocystisJirovecii prophylaxis. G-CSF was given in patients with recurrent and severe granulocytopenia. Adverse events (AEs) were graded according to the CTCAE criteria v.5, TLS events were classified according to Howard's criteria. Response was assessed at months 7 and 15 and included clinical examination, PB evaluation, BM aspirate, BM biopsy, and CT scan. MRD was checked centrally in the PB and BM by a 6/4-color flow-cytometry assay with a sensitivity of at least 10-4 according to the internationally standardized European Research Initiative on CLL. Quantitative MRD results assessed by flow-cytometry were categorized as uMRD (uMRD4; Between October 2018 and May 2020, 77 patients with CLL were included in this study. Two patients were off study before the start of treatment (withdrawal of consent, 1; Covid-19 infection, 1) and were not included in the analysis. The median age was 53.5 years (range 38-65). Binet stage B/C was present in 84% of patients, increased beta-2 microglobulin in 41%. Seventy-one (96%) of patients were IGHV unmutated, while 3 (4%) were IGHV mutated and showed TP53 mutation (Table 1). At the data cutoff of June 30, 2020, 65 (87%) patients completed the ramp-up phase. The planned 400 mg dose of Ven was reached within 5 weeks in 78.5% of patients. Response was assessed in 34 patients at the end of the VenR combination therapy. A response was achieved by 32 (94%) patients. Responses included 20 (59%) CRs, 1 CRi (3%) and 11 (32%) PRs due to residual enlarged nodes (median maximum size, 1.9 cm). Treatment failure due to toxicity was recorded in 2 (6%) patients. Overall, a response with uMRD4 by flow-cytometry in the PB was observed in 26 (76.5%) cases, and in the PB and BM, in 17 (50.0%). The rates of patients with CR and uMRD4 by flow-cytometry in the PB, and both in the PB and BM, were 44%, and 35%, respectively (Table 2). No detectable disease by PCR, both in the PB and BM, was observed in 4 (12%) patients. With a median follow-up of 4.5 months from the start of therapy, no patient has progressed or died. Fifty-three percent of patients were hospitalized during the first seven days of the Ven ramp-up phase. A transient laboratory TLS was observed in 3 patients. Treatment was discontinued after the first dose of Ven in 1 patient with evidence of laboratory TLS associated with severe neurologic toxicity due to the concomitant administration of fentanyl. Selected grade ≥3 AEs included neutropenia in 10 patients (ramp-up phase, 5) and neutropenic fever in 4. Grade ≥3 infection was recorded in 3 patients and was the reason for treatment discontinuation in 1 who developed COVID-19 pneumonia. In conclusion, the preliminary results of this study demonstrate the high efficacy of the front-line VenR combination, which resulted in a high proportion of CRs and responses with uMRD4 in young patients with CLL and an unfavorable biologic profile. Disclosures Mauro: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Consultancy. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Trentin:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Coscia:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sportoletti:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laurenti:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano:Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Membership on an entity's Board of Directors or advisory committees. Marasca:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Murru:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scarfo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Marchetti:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Levato:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galieni:Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Liberati:Verastem: Research Funding; Onconova: Research Funding; Janssen: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Takeda: Research Funding. Molica:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Visentin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale:Janssen: Honoraria. Del Giudice:Janssen: Other: grant for meeting participation; Tolero: Membership on an entity's Board of Directors or advisory committees; Roche: Other: grant for meeting partecipation; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Cuneo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.

Background: Despite the benefits of physical activity on cardiovascular risk in kidney transplant recipients (KTRs), the long-term effects of exercise have been poorly investigated. This is a three-year observational study comparing graft function and cardiovascular risk factors in active KTRs (AKTRs) vs. sedentary KTRs (SKTRs). Methods: KTRs with stable renal function were assigned to active or sedentary group in relation to the level of daily physical activity based on World Health Organization (WHO) recommendations (&lt, 150 or &gt, 150 minutes/week, respectively). Complete blood count, renal function indices, lipid profile, blood pressure and anthropometric measures were collected yearly for an observation period of three years. The comparisons between the two groups were performed by repeated measures analyses of covariance (ANCOVAs), with age as a covariate. Results: Fifty-four subjects were included in the study. Thirty of them were identified as AKTRs (M/F 26/4, aged 45 &plusmn, 12 years) and 24 as SKTRs (M/F 18/6, aged 51 &plusmn, 14 years). Baseline characteristics were similar between the groups except body mass index (BMI) that was significantly higher in SKTRs (p = 0.043). Furthermore, over the three-year observation period, BMI decreased in AKTRs and increased in SKTRs (p = 0.006). Graft function was stable in AKTRs, while it showed a decline over time in SKTRs, as indicated by the rise in serum creatinine levels (p = 0.006) and lower eGFR (p = 0.050). Proteinuria, glucose and uric acid levels displayed a decrease in AKTRs and an increase in SKTRs during the three-year period (p = 0.015, p = 0.004 and p = 0.013, respectively). Finally, concerning lipid profiles, AKTRs had a significant reduction over time of triglycerides levels, which conversely showed a clinically relevant increase in SKTRs (p = 0.014). Conclusions: Our findings indicate that regular weekly exercise training may counteract the increased cardiovascular risks and also prevent graft function decline in KTRs.

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The aim of this study was to investigate the fatty acid profile of thelongissimus thoracismuscle in two genetictypes of pigs. Fifty one pigs of the Italian local breed Apulo-Calabrese and 52 crossbreeds [Duroc x (Landrace xLarge White)] were fed the same commercial diet and reared in the same indoor system. Fatty acid compositionwas assessed through Folch method and the obtained data were analysed with a mixed model to identify possibledifferences between the two genetic types. The Apulo-Calabrese pigs showed significantly higher contents ofheptadecenoic acid (P< 0.0001), myristic (P= 0.03), arachidic (P= 0.04), myristoleic (P= 0.004), palmi-toleic (P= 0.01) and gondoic (P= 0.01) acids. On the other hand, crossbreed samples presented highercontents of docosahexaenoic (P= 0.01) and arachidonic acid (P= 0.01). Except for heptadecenoic acid, there were no great differences inlongissimus thoracismuscle fatty acid profile between the two genetic types, suggesting that when Apulo-Calabrese pigs are managed in the same rearing conditions as crossbreeds their longissimus thoracis muscle fatty acid composition is similar.

A grape pomace extract (GPext) and a grape seed extract (T) have been melt mixed within poly(butylene succinate) (PBS) and tested as natural stabilizers. Their effect on the PBS stabilization has been evaluated trough thermo-mechanical degradative tests (reprocessing), thermo-oxidation (oven aging), thermogravimetric analysis (TGA) and biodegradation tests. GPext and T have been deeply analyzed in terms of polyphenolic profile and bioactivity to connect the stabilization's results with the antioxidant's structures. Additive T exhibited the best results, maintaining unaltered the PBS molecular weight both after six reprocessing steps and after 300 h of oven aging and to increase the degradation temperature of more than 20 °C. These encouraging results have been explained by the long-chains polyphenols present within T (medium degree of polymerization of 10.8), by the excellent radical scavenger activity of T (6.0 mM TEAC) and by the low releases of peroxides from T (0.06 µM H2O2).

PRKAG3 is a major gene for meat quality and production in pigs. In this study, we investigated two single nucleotide polymorphisms (SNPs) of the PRKAG3 promoter region (g.-995A>G and g.-311A>G) in 381 pigs of different breeds. Association between these SNPs and three major haplotypes, constructed including other three substitutions (c.89C>A, c.154A>G and c.595G>A) and different traits (meat quality parameters: pH2h, pHu, glycogen and lactate content, glycolytic potential and cathepsin B activity of Semimembranosus muscle; estimated breeding values and random residuals for growth performances and carcass traits) were analysed in 271 Italian Large White performance tested pigs. A significant effect (P = 0.043) of the g.-995A>G SNP on cathepsin B activity and a suggestive effect (P = 0.067) of the g.-311A>G SNP on pHuwere found. The haplotype [g.-995G:g.-311G:c.89A:c.154G:c.595G] was associated with pHu(P = 0.024), glycolytic potential (P = 0.040) and cathepsin B activity (P = 0.086). This study on haplotypes, including promoter region SNPs, contribute to explain the effect of this gene on meat quality traits in pigs.

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.

Immiscible blends of ethylene‐propylene‐diene‐monomer (EPDM) and polyoxymethylene (POM), when EPDM is the major phase were compatibilized on the addition of an ionomer, poly(ethylene‐co‐methacrylic acid). The inclusion of the ionomer reduced the interfacial tension between the two phases, such that the diameter of the POM domains were significantly reduced to between 0.5 and 2 μm, typical of that required to toughen ductile polymers. The mechanical properties of the resultant compatibilized blends were significantly enhanced with increases in Young's modulus (↑54%), tensile strength (σ, ↑139%), elongation at break (e, ↑97%), and tensile toughness (↑500%) with increasing ionomer content, relative to EPDM rubber alone. The ShoreA hardness of the compatibilized blend was 70.1 compared with 56.8 for the immiscible binary blend and, 50.2 for neat EPDM rubber.

Visible (V), Near Infrared (NIR) and Short Waves Infrared (SWIR) spectroscopy has been indicated as a promising tool in soil studies, especially in the last decade. However, in order to apply this method, it is necessary to develop prediction models with the capacity to capture the intrinsic differences between agricultural areas and incorporate them in the modeling process. High quality estimates are generally obtained when these models are applied to soil samples displaying characteristics similar to the samples used in their construction. However, low quality predictions are noted when applied to samples from new areas presenting different characteristics. One way to solve this problem is by recalibrating the models using selected samples from the area of interest. Based on this premise, the aim of this study was to use the spiking technique and spiking associated with hybridization to expand prediction models and estimate organic matter content in a target area undergoing different uses and management. A total of 425 soil samples were used for the generation of the state model, as well as 200 samples from a target area to select the subsets (10 samples) used for model recalibration. The spectral readings of the samples were obtained in the laboratory using the ASD FieldSpec 3 Jr. Sensor from 350 to 2500 nm. The spectral curves of the samples were then associated to the soil attributes by means of a partial least squares regression (PLSR). The state model obtained better results when recalibrated with samples selected through a cluster analysis. The use of hybrid spectral curves did not generate significant improvements, presenting estimates, in most cases, lower than the state model applied without recalibration. The use of the isolated spiking technique was more effective in comparison with the spiked and hybridized state models, reaching r2, square root of mean prediction error (RMSEP) and ratio of performance to deviation (RPD) values of 0.43, 4.4 g dm−3, and 1.36, respectively.

Glass fiber–reinforced polymer (GFRP) bars have been used in concrete structures as an alternative to steel bars due to their noncorrosive behavior. However, due to the lack of full unders...

This Letter presents the impact of silicon substrate resistivity on SiGe phototransistors. SiGe phototransistors were fabricated on the commercially available SiGe/Si bipolar technology. The performances of the phototransistors fabricated based on low- and the high-resistive silicon substrate are compared. The phototransistor based on low-resistivity (LR) silicon substrate provides a responsivity of more than double compared to the phototransistor based on a high-resistivity silicon substrate that is fabricated by using the same bipolar transistor technology. The phototransistor fabricated on LR substrate exhibits low-frequency responsivity up to 1.35 A/W (at 50 MHz).