Editorial: Neuroendocrine tumors: the road to precision medicine

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PBAT based composites reinforced with microcrystalline cellulose obtained from softwood almond shells

This study explores the processability, mechanical, and thermal properties of biocompostable composites based on poly (butylene adipate-co-terephthalate) (PBAT) as polymer matrix and microcrystalline cellulose (MCC) derived from softwood almond (Prunus dulcis) shells (as-MCC) as filler at two different weight concentration, i.e., 10 wt% and 20 wt%. The materials were processed by melt mixing and a commercial MCC (c-MCC) was used as filler comparison. The fibrillar shape of as-MCC particles was found to change the rheological behavior of PBAT, particularly at the highest concentration. The melt mixing processing allowed obtaining a uniform dispersion of both kinds of fillers, slightly reducing the L/D ratio of as-MCC fibers. The as-MCC particles led to a higher increase of the elastic modulus of PBAT if compared to the c-MCC counterparts. Both the MCC fillers caused a drastic reduction of the elongation at break, although it was higher than 120% also at the highest filler concentrations. DSC analysis revealed that both MCC fillers poorly affected the matrix crystallinity, although as-MCC induced a slight PBAT crystallinity increase from 8.8% up to 10.9% for PBAT/as-MCC 20%. Therefore, this work demonstrates the great potential of MCC particles derived from almond shells as filler for biocompostable composites fabrication

Novel and widely spread citrus rootstocks behavior in response to salt stress

Irrigation water salinity is a major limiting factor in arid and semi-arid environments. The use of rootstock is one of the appropriate agronomic techniques that attempt to support and limit the negative effect of salinity. The objective of this study was to evaluate the behavior of eight one-year-old rootstocks grown in pots under salt stress conditions (30 and 60 mM NaCl). Some genotypes, i.e. C35 citrange, Bitters, Carpenter and Furr citrandarins were recently released or spread and poor information on their behavior in saline conditions is available, while Carrizo citrange, Swingle Citrumelo, Citrus volkameriana and Citrus macrophylla are spread since long ago in the Mediterranean basin. The results clearly demonstrated that the most salt sensitive genotypes were Carrizo and C35 citrange, that reduced morphological and gas exchanges performances. Furr, Bitters and Carpenter citrandarins revealed good physiological and hormonal behavior. An intense antioxidant enzymatic activity was noted in C35 and Carrizo citranges, while Furr showed a decrease in malondialdehyde and antioxidant enzymatic activities at 60 mM NaCl. Its tolerance to saline water was also confirmed by transcriptomic analyses

A Novel Tumor on Chip Mimicking the Breast Cancer Microenvironment for Dynamic Drug Screening

In light of the emerging breakthroughs in cancer biology, drug discovery, and personalized medicine, Tumor-on-Chip (ToC) platforms have become pivotal tools in current biomedical research. This study introduced a novel rapid prototyping approach for the fabrication of a ToC device using laser-patterned poly(methyl methacrylate) (PMMA) layers integrated with a polylactic acid (PLA) electrospun scaffold, enabling dynamic drug delivery and the assessment of therapeutic efficacy in cancer cells. Traditional drug screening methods, such as conventional cell cultures, mimic certain aspects of cancer progression but fail to capture critical features of the tumor microenvironment (TME). While animal models offer a closer approximation of tumor complexity, they are limited in their ability to predict human drug responses. Here, we evaluated the ability of our ToC device to recapitulate the interactions between cancer and TME cells and its efficacy in evaluating the drug response of breast cancer cells. The functional design of the proposed ToC system offered substantial potential for a wide range of applications in cancer research, significantly accelerating the preclinical assessment of new therapeutic agents

Environmental and Agro-Economic Sustainability of Olive Orchards Irrigated with Reclaimed Water under Deficit Irrigation

This study explores the effects of the adoption of reclaimed water (RW) as source of irrigation in conjunction with the application of deficit irrigation strategies in an olive orchard (different genotypes) located within the “Valle dei Margi” farmhouse (Eastern Sicily). Specifically, the RW was obtained in situ by treating the wastewater coming from the farmhouse throughout a treatment wetland system (TW). The effects of RW on crop water status (CWS) was assessed by conducting plant-based measurements (i.e., leaf water potential, Ψ, and leaves relative water content, RWC) and determining satellite-based biophysical indicators. An economical and environmental evaluation of the proposed sustainable irrigation practices was carried out by using the life cycle assessment (LCA) approach.The RW quality showed high variability due to fluctuations in the number of customers at the farmhouse during the Covid-19 pandemic period. However, high removal efficiency of the overall TW was reached even if the RW quality did not always accomplish with the limits of the Italian regulations. A strong impact in the variation of Ψ was observed among the olive orchard under the different water regimes, evidencing how CWS performances are greatly conditioned by the genotype. However, no differences in leaves RWC and in satellite-based biophysical indicators were detected, despite the severe water deficit imposed (i.e., 50% of irrigation water reduction). Finally, the results of the LCA analysis underlined that the use of RW may permit to obtain important gains both in economic and environmental terms, thus representing a valid strategy for the olive cultivation

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

IntroductionMedullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.Aim of the studyThis review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC.Materials and methodsWe performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.ResultsOur search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.ConclusionWe found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials’ implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients’ outcome and survival

Antitumor activity of novel POLA1-HDAC11 dual inhibitors

Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72–77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice. © 2021 Elsevier Masson SA

Probabilistic evaluation of process model matching techniques

Process model matching refers to the automatic identification of corresponding activities between two process models. It represents the basis for many advanced process model analysis techniques such as the identification of similar process parts or process model search. A central problem is how to evaluate the performance of process model matching techniques. Often, not even humans can agree on a set of correct correspondences. Current evaluation methods, however, require a binary gold standard, which clearly defines which correspondences are correct. The disadvantage of this evaluation method is that it does not take the true complexity of the matching problem into account and does not fairly assess the capabilities of a matching technique. In this paper, we propose a novel evaluation method for process model matching techniques. In particular, we build on the assessment of multiple annotators to define probabilistic notions of precision and recall. We use the dataset and the results of the Process Model Matching Contest 2015 to assess and compare our evaluation method. We found that our probabilistic evaluation method assigns different ranks to the matching techniques from the contest and allows to gain more detailed insights into their performance