Usefulness of ambulatory blood pressure monitoring in predicting the presence of autonomic neuropathy in type I diabetic patients.

This study investigated whether nondipping (defined as a day–night change in blood pressure (BP) <=0%) could be assumed as a diagnostic index for autonomic neuropathy, and assessed its accuracy in discriminating between type I diabetic patients with and without autonomic neuropathy. In 87 type I diabetic patients with normal renal function (age 36+-11, duration 17+-9 years, serum creatinine 67.2+-15.9 mcmol/l), four cardiovascular tests and 24-h BP monitoring were performed, and the percentage day–night change (Delta) in systolic (SBP) and diastolic BP (DBP) was calculated. Sixteen patients had Delta SBP and/or Delta DBP <=0%. In a multiple logistic regression with adjustment for sex, age, and body mass index, the odds ratio for having autonomic neuropathy was seven times higher in patients with DSBP <=0% as opposed to those without (odds ratio 6.97, CI 1.4–34.9, P=0.018). Using Receiver Operating Characteristic (ROC) analysis, DBP showed an acceptable accuracy in discriminating between patients with and without autonomic neuropathy (area under the ROC curve 0.69+-0.06 and 0.72+-0.05 for Delta SBP and Delta DBP, respectively). Adequate cutoff values were 0% for Delta SBP (sensitivity, 26%; specificity, 95%; positive predictive value, 87%) and 5% for Delta DBP (sensitivity, 26%; specificity, 92%; positive predictive value, 81%). In type I diabetic patients with normal renal function, a value of Delta SBP p0% identifies the presence of autonomic neuropathy with a very high chance. Nondipping at the cutoff proposed could be considered an adjunctive marker of autonomic neuropathy provided with a high specificity and low sensitivity

Anti-PD-L1 immunoconjugates for cancer therapy: Are available antibodies good carriers for toxic payload delivering?

Immune checkpoint mechanisms are important molecular cell systems that maintain tolerance toward autoantigens in order to prevent immunity-mediated accidental damage. It is well known that cancer cells may exploit these molecular and cellular mechanisms to escape recognition and elimination by immune cells. Programmed cell death protein-1 (PD-1) and its natural ligand programmed cell death ligand-1 (PD-L1) form the PD-L1/PD-1 axis, a well-known immune checkpoint mechanism, which is considered an interesting target in cancer immunotherapy. In fact, the expression of PD-L1 was found in various solid malignancies and the overactivation of PD-L1/PD-1 axis results in a poor patient survival rate. Breaking PD-L1/PD-1 axis, by blocking either the cancer side or the immune side of the axis, is currently used as anti-cancer strategy to re-establish a tumor-specific immune response. For this purpose, several blocking antibodies are now available. To date, three anti-PD-L1 antibodies have been approved by the FDA, namely atezolizumab, durvalumab and avelumab. The main advantages of anti-PD-L1 antibodies arise from the overexpression of PD-L1 antigen by a high number of tumor cells, also deriving from different tissues; this makes anti-PD-L1 antibodies potential pan-specific anti-cancer molecules. Despite the good results reported in clinical trials with anti-PD-L1 antibodies, there is a significant number of patients that do not respond to the therapy. In fact, it should be considered that, in some neoplastic patients, reduced or absent infiltration of cytotoxic T cells and natural killer cells in the tumor microenvironment or presence of other immunosuppressive molecules make immunotherapy with anti-PD-L1 blocking antibodies less effective. A strategy to improve the efficacy of antibodies is to use them as carriers for toxic payloads (toxins, drugs, enzymes, radionuclides, etc.) to form immunoconjugates. Several immunoconjugates have been already approved by FDA for treatment of malignancies. In this review, we focused on PD-L1 targeting antibodies utilized as carrier to construct immunoconjugates for the potential elimination of neoplastic cells, expressing PD-L1. A complete examination of the literature regarding anti-PD-L1 immunoconjugates is here reported, describing the results obtained in vitro and in vivo. The real potential of anti-PD-L1 antibodies as carriers for toxic payload delivery is considered and extensively discussed

Impact of radar data assimilation for the simulation of a heavy rainfall case in central Italy using WRF–3DVAR

Abstract. The aim of this study is to investigate the role of the assimilation of Doppler weather radar (DWR) data in a mesoscale model for the forecast of a heavy rainfall event that occurred in Italy in the urban area of Rome from 19 to 22 May 2008. For this purpose, radar reflectivity and radial velocity acquired from Monte Midia Doppler radar are assimilated into the Weather Research Forecasting (WRF) model, version 3.4.1. The general goal is to improve the quantitative precipitation forecasts (QPF): with this aim, several experiments are performed using the three-dimensional variational (3DVAR) technique. Moreover, sensitivity tests to outer loops are performed to include non-linearity in the observation operators. In order to identify the best initial conditions (ICs), statistical indicators such as forecast accuracy, frequency bias, false alarm rate and equitable threat score for the accumulated precipitation are used. The results show that the assimilation of DWR data has a large impact on both the position of convective cells and on the rainfall forecast of the analyzed event. A positive impact is also found if they are ingested together with conventional observations. Sensitivity to the use of two or three outer loops is also found if DWR data are assimilated together with conventional data

Net gain: Low-cost, trawl-associated eDNA samplers upscale ecological assessment of marine demersal communities

Marine biodiversity stewardship requires costly and time-consuming capture-based monitoring techniques, which limit our understanding of the distribution and status of marine populations. Here, we reconstruct catch and demersal community compo- sition in a set of 24 fishing sites in the central Tyrrhenian Sea by gathering environ- mental DNA (eDNA) aboard commercial bottom-trawl fishing vessels. We collected genetic material from two sources: the water draining from the net after the end of hauling operations (“slush”), and custom-made rolls of gauze tied to a hollow perfo- rated sphere placed inside the fishing net (“metaprobe”). Species inventories were generated using a combination of fish-specific (Tele02 12S) and universal metazoan (COI) molecular markers. DNA metabarcoding data recovered over 90% of the caught taxa and accurately reconstructed the overall structure of the assemblages of the examined sites, reflecting expected differences linked to major drivers of community structure in Mediterranean demersal ecosystems, such as depth, distance from the coast, and fishing effort. eDNA also returned a “biodiversity bonus” mostly consisting of pelagic species not catchable by bottom trawl but present in the surrounding en- vironment. Overall, the “metaprobe” gauzes showed a greater biodiversity detection power as compared to “slush” water, both qualitatively and quantitatively, strengthen- ing the idea that these low-cost sampling devices can play a major role in upscaling the gathering of data on both catch composition and the broader ecological charac- teristics of marine communities sustaining trawling activities. This approach has the potential to drastically expand the reach of ecological monitoring, whereby fishing vessels operating across the oceans may serve as opportunistic scientific platforms to increase the strength and granularity of marine biodiversity data

High-dose chemotherapy as initial salvage treatment in relapsed testicular cancer patients

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Sequence, structure, and binding site analysis of kirkiin in comparison with ricin and other type 2 rips

Kirkiin is a new type 2 ribosome-inactivating protein (RIP) purified from the caudex of Adenia kirkii with a cytotoxicity compared to that of stenodactylin. The high toxicity of RIPs from Adenia genus plants makes them interesting tools for biotechnology and therapeutic applications, particularly in cancer therapy. The complete amino acid sequence and 3D structure prediction of kirkiin are here reported. Gene sequence analysis revealed that kirkiin is encoded by a 1572 bp open reading frame, corresponding to 524 amino acid residues, without introns. The amino acid sequence analysis showed a high degree of identity with other Adenia RIPs. The 3D structure of kirkiin preserves the overall folding of type 2 RIPs. The key amino acids of the active site, described for ricin and other RIPs, are also conserved in the kirkiin A chain. Sugar affinity studies and docking experiments revealed that both the 1α and 2γ sites of the kirkiin B chain exhibit binding activity toward lactose and D-galactose, being lower than ricin. The replacement of His246 in the kirkiin 2γ site instead of Tyr248 in ricin causes a different structure arrangement that could explain the lower sugar affinity of kirkiin with respect to ricin

Enhanced Carrier Collection in Cd/In-Based Dual Buffers in Kesterite Thin-Film Solar Cells from Nanoparticle Inks

Increasing the power conversion efficiency (PCE) of kesterite Cu2ZnSn­(S,Se)4 (CZTSSe) solar cells has remained challenging over the past decade, in part due to open-circuit voltage (V OC)-limiting defect states at the absorber/buffer interface. Previously, we found that substituting the conventional CdS buffer layer with In2S3 in CZTSSe devices fabricated from nanoparticle inks produced an increase in the apparent doping density of the CZTSSe film and a higher built-in voltage arising from a more favorable energy-band alignment at the absorber/buffer interface. However, any associated gain in V OC was negated by the introduction of photoactive defects at the interface. This present study incorporates a hybrid Cd/In dual buffer in CZTSSe devices that demonstrate an average relative increase of 11.5% in PCE compared to CZTSSe devices with a standard CdS buffer. Current density–voltage analysis using a double-diode model revealed the presence of (i) a large recombination current in the quasi-neutral region (QNR) of the CZTSSe absorber in the standard CdS-based device, (ii) a large recombination current in the space-charge region (SCR) of the hybrid buffer CZTSSe–In2S3–CdS device, and (iii) reduced recombination currents in both the QNR and SCR of the CZTSSe–CdS–In2S3 device. This accounts for a notable 9.0% average increase in the short-circuit current density (J SC) observed in CZTSSe–CdS–In2S3 in comparison to the CdS-only CZTSSe solar cells. Energy-dispersive X-ray, secondary-ion mass spectroscopy, and grazing-incidence X-ray diffraction compositional analysis of the CZTSSe layer in the three types of kesterite solar cells suggest that there is diffusion of elemental In and Cd into the absorbers with a hybrid buffer. Enhanced Cd diffusion concomitant with a double postdeposition heat treatment of the hybrid buffer layers in the CZTSSe–CdS–In2S3 device increases carrier collection and extraction and boosts J SC. This is evidenced by electron-beam-induced current measurements, where higher current generation and collection near to the p–n junction is observed, accounting for the increase in J SC in this device. It is expected that optimization of the heat treatment of the hybrid buffer layers will lead to further improvements in the device performance

Reflectivity and velocity radar data assimilation for two flash flood events in central Italy: A comparison between 3D and 4D variational methods

The aim of this study is to provide an evaluation of the impact of two largely used data assimilation techniques, namely three- and four-dimensional variational data assimilation systems (3D-Var and 4D-Var), on the forecasting of heavy precipitation events using the Weather Research and Forecasting (WRF) model. For this purpose, two flash flood events in central Italy are analysed. The first occurred on September 14, 2012 during an Intensive Observation Period of the Hydrological cycle in the Mediterranean experiment (HyMeX) campaign, while the other occurred on May 3, 2018. Radial velocity and reflectivity acquired by C-band weather radars at Mt. Midia (central Italy) and San Pietro Capofiume (northern Italy), as well as conventional observations (SYNOP and TEMP), are assimilated into the WRF model to simulate these damaging flash flood events. In order to evaluate the impact of the 3D-Var and 4D-Var assimilation systems on the estimation of short-term quantitative precipitation forecasts, several experiments are carried out using conventional observations with and without radar data. Rainfall evaluation is performed by means of point-by-point and filtering methodologies. The results point to a positive impact of the 4D-Var technique compared to results without assimilation and with 3D-Var experiments. More specifically, the 4D-Var system produces an increase of up to 22% in terms of the Fractions Skill Score compared to 3D-Var for the first flash flood event, while an increase of about 5% is achieved for the second event. The use of a warm start initialization results in a considerable reduction in the spin-up time and a significant improvement in the rainfall forecast, suggesting that the initial precipitation spin-up problem still occurs when using 4D-Var