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Background Tacrolimus trough levels (C0) are used in most transplant centres for therapeutic drug monitoring (TDM) of tacrolimus (Tac). The target range of Tac C0 has been remarkably changed, with a target as low as 3–7 ng/ml in the 2009 European consensus conference and a target of 4–12 ng/ml (preferably to 7–12 ng/ml) following the second consensus report in 2019. Our aim was to investigate whether reaching early Tac therapeutic targets and maintaining time in the therapeutic range (TTR) according to the new recommendations may be necessary for preventing acute rejection (AR) during the first month after transplantation. Methods A retrospective study including 160 adult renal transplant patients (113 men and 47 women) with a median age of 36.3 (20–44) years was conducted between January 2018 and December 2019 at 103 Military Hospital (Vietnam). Tac trough levels were recorded in the first month, and episodes of AR were confirmed by kidney biopsy. Tac TTR was calculated as the percentage of time within the target range of 7–12 ng/ml, according to the 2019 second consensus report. Multivariate Cox analysis was performed to identify the correlation between the Tac target range and TTR with AR. Results In the first month after RT, 14 (8.8%) patients experienced AR. There was a significant difference in the incidence of AR between the Tac level groups of 7 ng/ml (p = 0.0096). In the multivariate Cox analysis, after adjusting for related factors, a mean Tac level > 7 ng/ml was associated with an 86% decreased risk of AR compared with that of 4–7 ng/ml in the first month (HR, 0.14; 95% CI, 0.03–0.66; p = 0.0131). Every 10% increase in TTR was associated with a 28% lower risk of AR (HR, 0.72; 95% CI, 0.55–0.94; p = 0.014). Conclusion Gaining and maintaining Tac C0 according to the 2019 second consensus report might reduce the risk of AR in the first month following transplantation.

This work presents a design of a simple and sensitive sensing interface consisting of a graphene/poly(1,5-diaminonaphthalene) nanocomposite, denoted as Gr/P(1,5DAN), as an immobilization matrix and graphene decorated with silver nanoparticles (Gr-AgNPs) as an electrochemical label for bisphenol A (BPA). The nanocomposite was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and electrochemical techniques (CV and EIS). Immunocomplex formation between the anti-BPA antibody (αBPA) and BPA antigen would induce the square wave voltammetric (SWV) peak current variation of Gr-AgNPs labels, and afterward, the concentration of BPA could be indirectly assayed and qualitatively determined. The results indicated a linear relationship between (SWV) response to the BPA concentration in a range of 1.0–8.0 nM, with a limit of detection (LOD) of 0.6 nM. It is a promising attempt for PBA analysis with a low-cost and easy-to-fabricate sensor.

Wire and arc-based additively manufacturing (WAAM) is a potential metallic additively manufacturing (AM) technologies for producing large-size metallic components. 316L is one of the most common stainless-steel grades used in WAAM. However, most of previous studies normally adopted process parameters for the WAAM process based on recommendations of welding wire manufacturers for traditional welding processes. In this article, we focus on predicting and optimizing process parameters for the WAAM process of 316L stainless steel. The experiment was designed by using Taguchi method and L16 orthogonal array. Three parameters, consisting of voltage (U), welding current (I), and travel speed (v), were considered as the input variables, and the responses are four geometrical characteristics of single weld beads, including width, height, penetration, and dilution of weld beads (WWB, HWB, PWB, and DWB, respectively). The effects of each input variable on the responses were determined through analysis of variance (ANOVA). The optimal process parameters were identified by using GRA (grey-relational analysis) and TOPSIS (techniques for order-preferences by similarity-to-ideal solution) methods. The obtained results show that the travel speed has the most important effect on WWB and HWB, while the voltage has the highest impact on PWB and DWD. Both GRA and TOPSIS methods give the same optimum process parameters, namely U = 22 V, I = 110 A, and v = 0.3 m/min, which are validated by confirmation experiments. The predicted models of WWB, HWB, PWB, and DWB were also demonstrated to be adequate for selecting the process parameters in specific applications.

SummaryCutaneous T cell lymphomas (CTCL) are a heterogeneous group of rare non-Hodgkin lymphomas. The most common type of CTCL is Mycosis fungoides (MF). Much less common but clinically and histopathologically related to MF is Sézary syndrome (SS). CTCL are incurable and associated with a reduced quality of life. While early stage MF has a good prognosis and is usually treated with skin directed therapies, advanced-stages require systemic therapies, including retinoids, interferon, cytotoxic chemotherapeutic drugs, low-dose methotrexate, histone deacetylase inhibitors and alemtuzumab. However, relapses are frequent and long-term remissions are achieved only in few cases, e.g. with allogenic stem cell transplantation. In recent years, new therapeutic options have evolved by the approval of brentuximab vedotin and mogamulizumab. Both recently approved therapies demonstrated superiority with regard to overall response rate and progression free survival over traditional systemic therapies. Other promising treatments such as lacutamab and PD-1/L-1 inhibitors are in the pipeline, and more therapeutic agents are currently investigated in clinical trials.

SummaryCutaneous squamous cell carcinoma (cSCC) accounts for approximately 20% of all skin cancers. Its rising incidence represents a major public health concern. The majority of cSCC are curable by surgical resection. Although less than 5% of cSCC patients develop metastases or local recurrence after complete excision, advanced cSCC is difficult to treat. Until recently, no standard therapeutic regimen for advanced cSCC exists. Traditional therapies include chemotherapy and EGFR-targeted therapy, but their clinical benefit remains modest and has been demonstrated mostly in retrospective studies. On the contrary, PD-1 inhibitors dramatically improve outcomes in many immunocompetent cSCC patients, resulting in the approval of cemiplimab as the first FDA-approved systemic drug for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or radiation. In the coming years combination therapies are an emerging treatment strategy that could improve efficacy of PD-1 inhibitors in advanced cSCC. Moreover, several prospective controlled trials have been designed to explore the potential role of PD-1 inhibitors in the adjuvant and neodjuvant setting. Given the paucity of data, the management of immunocompromised cSCC patients requires a heightened awareness in this new era of cancer therapeutics.

The incidence rates of cutaneous melanoma are continually rising in the Caucasian population with the highest rates in Australia and New Zealand. The genesis of melanoma is a complex interplay between genetic predisposition and exogenous factors. The major known exogenous risk factor of this potentially lethal malignancy is ultraviolet (UV) radiation. In the last decades diverse prevention strategies have been developed which in case of primary prevention are aimed to protect the skin from high-dose UV radiation. Although its effect is only visible after a long period of time and despite the growing awareness in the general population, it seems that primary prevention interventions are often not carried out as recommended. It was proposed that particularly in Europe where incidence rates are still increasing, the development and implementation of primary prevention campaigns should be pursued further. Secondary prevention implies early detection of melanoma by using skin cancer screenings. However, according to recent reviews there is only limited evidence on impact and benefit of routine skin cancer screenings in the adult general population. Thus, it was suggested that future research should focus on effects of targeted screening in population subgroups with increased risk for melanoma.

Quantitative systems pharmacology (QSP) is an emerging discipline that aims to discover how drugs modulate the dynamics of biological components in molecular and cellular networks and the impact of those perturbations on human pathophysiology. The integration of systems-based experimental and computational approaches is required to facilitate the advancement of this field. QSP models typically consist of a series of ordinary differential equations (ODE). However, this mathematical framework requires extensive knowledge of parameters pertaining to biological processes, which is often unavailable. An alternative framework that does not require knowledge of system-specific parameters, such as Boolean network modeling, could serve as an initial foundation prior to the development of an ODE-based model. Boolean network models have been shown to efficiently describe, in a qualitative manner, the complex behavior of signal transduction and gene/protein regulatory processes. In addition to providing a starting point prior to quantitative modeling, Boolean network models can also be utilized to discover novel therapeutic targets and combinatorial treatment strategies. Identifying drug targets using a network-based approach could supplement current drug discovery methodologies and help to fill the innovation gap across the pharmaceutical industry. In this review, we discuss the process of developing Boolean network models and the various analyses that can be performed to identify novel drug targets and combinatorial approaches. An example for each of these analyses is provided using a previously developed Boolean network of signaling pathways in multiple myeloma. Selected examples of Boolean network models of human (patho-)physiological systems are also reviewed in brief.