Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies

Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in 60–80% of MCC cases as integrated within the genome and is considered a major risk factor for MCC. Viral negative MCCs have a high mutation burden with a UV damage signature. Aberrations occur in RB1, TP53, and NOTCH genes as well as in the PI3K-AKT-mTOR pathway. MCC is highly immunogenic, but MCC cells are known to evade the host’s immune response. Despite the characteristic immunohistological profile of MCC, the diagnosis is challenging, and it should be confirmed by an experienced pathologist. Sentinel lymph node biopsy is considered the most reliable staging tool to identify subclinical nodal disease. Subclinical node metastases are present in about 30–50% of patients with primary MCC. The basis of MCC treatment is surgical excision. MCC is highly radiosensitive. It becomes chemoresistant within a few months. MCC is prone to recurrence. The outcomes in patients with metastatic disease are poor, with a historical 5-year survival of 13.5%. The median progression-free survival is 3–5 months, and the median overall survival is ten months. Currently, immunotherapy has become a standard of care first-line therapy for advanced MCC.     

Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis

Pre-eclampsia (PE) complicates 2%–8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39–0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.     

Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (M^pro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 M^pro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV M^pro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 M^pro inhibitors, as we report it, was not previously conducted.     

Mechanically Strong Polyurethane Composites Reinforced with Montmorillonite-Modified Sage Filler (Salvia officinalis L.)

Rigid polyurethane (PUR) foams reinforced with 1, 2, and 5 wt.% of salvia filler (SO filler) and montmorillonite-modified salvia filler (MMT-modified SO filler) were produced in the following study. The impact of 1, 2, and 5 wt.% of SO filler and MMT-modified SO filler on the morphological, chemical, and mechanical properties of PUR composites were examined. In both cases, the addition of 1 and 2 wt.% of SO fillers resulted in the synthesis of PUR composites with improved physicomechanical properties, while the addition of 5 wt.% of SO fillers resulted in the formation of PUR composites with a less uniform structure and, therefore, some deterioration in their physicomechanical performances. Moreover, the results showed that the modification of SO filler with MMT improved the interphase compatibility between filler surface and PUR matrix. Therefore, such reinforced PUR composites were characterized by a well-developed closed-cell structure and improved mechanical, thermal, and flame-retardant performances. For example, when compared with reference foam, the addition of 2 wt.% of MMT-modified SO filler resulted in the formation of PUR composites with greater mechanical properties (compressive strength, flexural strength) and improved dynamic-mechanical properties (storage modulus). The PUR composites were characterized by better thermal stability as well as improved flame retardancy—e.g., decreased peak rate of heat release (pHRR), reduced total smoke release (TSR), and increased limiting oxygen index (LOI).     

Highly Porous Crosslinkable PLA‐PNB Block Copolymer Scaffolds

Poly(lactic acid) (PLA)‐block‐poly(norbornene) (PNB) copolymers which bear photocrosslinkable cinnamate side‐chains are synthesized by combining the ring‐opening metathesis polymerization (ROMP) of norbornenes with the ring‐opening polymerization (ROP) of lactides. Highly porous 3D scaffolds with tunable pore sizes ranging from 20 to 300 µm are fabricated through liquid–solid phase separation. Scaffolds with an average pore size around 250 µm, which are under investigation as bone grafting materials, are reproducibly obtained from freeze‐drying 5% w/v benzene solutions of PLA‐b‐PNB copolymers at −10 °C. As a demonstration of the impact of photocrosslinking of cinnamate side‐chains, scaffolds are exposed to UV radiation for 8 h, resulting in a 33% increase in the compressive modulus of the polymeric scaffold. The foams and the methodology described herein represent a new strategy toward polymeric scaffolds with potential for use in regenerative medicine applications.     

Physical identification of gate metal interdiffusion in GaAs PHEMTs

The Ti metal interdiffusion of Ti/Pt/Au gate metal stacks in 0.15-/spl mu/m GaAs PHEMTs subjected to high-temperature accelerated lifetest has been physically identified using scanning transmission electron microscopy. Further energy dispersive analysis with X-ray (EDX) analysis confirms the Ti diffusion into the AlGaAs Schottky barrier layer and the decrease of Schottky barrier height suggests the Ti-AlGaAs intermetallic formation, which is consistent with previous Rutherford backscattering spectroscopy/X-ray photoelectron spectroscopy studies. The Ti metal interdiffusion reduces the separation of the gate metal and InGaAs channel, thus leading to a slight Gm increase, positive shift in pinchoff voltage, and S21 increase during the preliminary portion of the lifetest. Accordingly, the Ti interdiffusion effect implies that the lifetime of GaAs PHEMTs subjected to high-temperature accelerated lifetest could be dependent upon the initial thickness of the Schottky layer underneath the gate metal.     

Semiconducting ferromagnetic spinels

The family of spinel compounds of which CdCr2Se4is the prototype has been found to be simultaneously ferromagnetic and semiconducting. Numerous experiments reveal, moreover, that the electronic states in these materials are strongly coupled to the degree of magnetic order. The interaction between the electronic transport and the magnetic state offers the exciting possibility of constructing electronic devices having magnetic control. This paper presents a review of literature on the magnetic, crystallographic, electrical transport, and optical properties of the chromium chalcogenide spinels as they relate to device applications. The prospects of realizing novel devices utilizing these properties are examined.     

Fortification of low-nitrite canned pork with willow herb (Epilobium angustifolium L.)

Nitrite is a multifunctional additive used for meat products. However, cancerogenic N-nitrosoamines (NAs) can be formed from nitrite. For this reason, nitrite should be reduced or eliminated. This study aimed to (1) determine the phenolic content, composition, and in vitro antioxidant and antimicrobial activity of water lyophilized extracts of willow herb (WH); and (2) assess the effect of the extracts on lipid oxidation, colour, microbiological and chemical safety of canned pork with lower nitrite content during storage. For the preparation of extract, redistilled water at a temp. of 90°C (1:10) was used. The extracts were filtered and freeze-dried for 72 h (−80°C, 0.04 mbar). Five different variants of product were tested in the study: control (with 100 mg kg⁻¹ NaNO₂) and herbal samples (with 50, 100, 150, and 1000 mg kg⁻¹ WH). The samples were assessed for their colour, antioxidant capacity, lipid oxidation, pH, sensory characteristics, and the presence of N-nitrosamines and pathogenic bacteria. Oenothein B was found as the predominating compound in the analysed extract (HPLC) followed by querceti-3-O-rhamnoside and oenothein A, myricetin 3-O-glucoside. The addition of WH extract contributed to maintaining the typical, cured colour of canned meat as well as reducing the NaNO₂ content. Furthermore, fortification with 150 mg kg⁻¹ of Epilobium angustifolium L. extract allowed stabilising the antioxidant properties of canned meat during storage to a greater extent compared to 1000 mg kg⁻¹ of extract.