Gravitationally-induced wave function collapse time for molecules.

The Diósi-Penrose model states that the wave function collapse ending a quantum superposition occurs due to the instability of coexisting gravitational potentials created by distinct geometric conformations of the system in different states. The Heisenberg time-energy principle can be invoked to estimate the collapse time for the energy associated with this instability, the gravitational self-energy. This paper develops atomistic models to calculate the Diósi-Penrose collapse time. It applies them to a range of systems, from small molecules to large biological structures and macroscopic systems. An experiment is suggested to test the Diósi-Penrose hypothesis, and we critically examine the model, highlighting challenges from an atomistic perspective, such as gravitational self-energy saturation and limited extensivity.

Efficacy of Eating Disorder Focused Family Therapy for Adolescents With Anorexia Nervosa: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review and evaluate the efficacy of eating disorder focused family therapy (FT-ED) in comparison to all other forms of psychotherapy for children and adolescents with anorexia nervosa. A secondary aim is to assess the relative efficacy of different variations of FT-ED (e.g., shorter vs. longer dose, parent-focused). METHODS: A search with relevant terms was systematically conducted on four databases. Twenty-three publications across 18 randomized controlled trials met inclusion criteria. Outcomes of interest included variables related to weight, eating psychopathology, and remission status. Study quality was assessed, and data were extracted by two independent researchers. RESULTS: Adolescents receiving FT-ED gained significantly more weight by the end of treatment in comparison to those receiving individual psychotherapy. FT-ED that was delivered just to parents or to parents and child separately offered preferable weight outcomes and rates of recovery at the end of treatment in comparison to conjoint FT-ED. No other outcomes tested in the meta-analysis were statistically significant at the end of treatment or follow-up. DISCUSSION: Currently available data suggest the use of FT-ED in its conjoint or separated/parent focused format is the best outpatient treatment option for adolescents with anorexia nervosa when immediate weight gain is paramount. The variability of outcome measurement, including the tools used and timepoints chosen, limit comparison among no more than a handful of studies. The field would benefit from the standardization of measurement and reporting guidelines for future clinical trials. TRIAL REGISTRATION: PROSPERO number: CRD42023396263.

OBJETIVO: Revisar y evaluar sistemáticamente la eficacia de la terapia familiar centrada en el trastorno de conducta alimentaria (TF­TCA; FT­ED por sus siglas en inglés) en comparación con todas las demás formas de psicoterapia para niños y adolescentes que padecen anorexia nerviosa. Un objetivo secundario es evaluar la eficacia relativa de diferentes variaciones de la TF­TCA (por ejemplo, dosis más corta vs. más larga, centrada en los padres). MÉTODOS: Se realizó una búsqueda sistemática con términos relevantes en cuatro bases de datos. Veintitrés publicaciones de 18 ensayos controlados aleatorios cumplieron con los criterios de inclusión. Los resultados de interés incluyeron variables relacionadas con el peso, la psicopatología alimentaria y el estado de remisión. La calidad del estudio fue evaluada y los datos fueron extraídos por dos investigadores independientes. RESULTADOS: Los adolescentes que recibieron TF­TCA ganaron significativamente más peso al final del tratamiento en comparación con aquellos que recibieron psicoterapia individual. La TF­TCA que se administró solo a los padres o a padres e hijos por separado ofreció mejores resultados en el peso y tasas de recuperación al final del tratamiento en comparación con la TF­TCA conjunta. Ningún otro resultado probado en el metaanálisis fue estadísticamente significativo al final del tratamiento o durante el seguimiento. DISCUSIÓN: Los datos disponibles actualmente sugieren que el uso de la TF­TCA en su formato conjunto o separado/centrado en los padres es la mejor opción de tratamiento ambulatorio para adolescentes que padecen anorexia nerviosa cuando la ganancia de peso inmediata es primordial. La variabilidad en la medición de los resultados, incluyendo las herramientas utilizadas y los puntos temporales elegidos, limita la comparación entre no más de un puñado de estudios. El campo se beneficiaría de la estandarización de la medición y las directrices de reporte para futuros ensayos clínicos.

Treatment of evolving cancers will require dynamic decision support.

Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicling the milestones of the field, we show that the impact of schedule choice crucially depends on processes driving treatment response and failure. As such, cancer heterogeneity and evolution dictate that a one-size-fits-all solution is unlikely-instead, each patient should be mapped to the strategy that best matches their current disease characteristics and treatment objectives (i.e. their 'tumorscape'). To achieve this level of personalization, we need mathematical modeling. In this perspective, we propose a five-step 'Adaptive Dosing Adjusted for Personalized Tumorscapes (ADAPT)' paradigm to integrate data and understanding across scales and derive dynamic and personalized schedules. We conclude with promising examples of model-guided schedule personalization and a call to action to address key outstanding challenges surrounding data collection, model development, and integration.

Genetic diversity of Trypanosoma cruzi infecting raccoons (Procyon lotor) in 2 metropolitan areas of southern Louisiana: implications for parasite transmission networks.

Trypanosoma cruzi, the aetiological agent of Chagas disease, exists as an anthropozoonosis in Louisiana. Raccoons are an important reservoir, as they demonstrate high prevalence and maintain high parasitaemia longer than other mammals. Given the complex nature of parasite transmission networks and importance of raccoons as reservoirs that move between sylvatic and domestic environments, detailing the genetic diversity of T. cruzi in raccoons is crucial to assess risk to human health. Using a next-generation sequencing approach targeting the mini-exon, parasite diversity was assessed in 2 metropolitan areas of Louisiana. Sequences were analysed along with those previously identified in other mammals and vectors to determine if any association exists between ecoregion and parasite diversity. Parasites were identified from discrete typing units (DTUs) TcI, TcII, TcIV, TcV and TcVI. DTUs TcII, TcV and TcVI are previously unreported in raccoons in the United States (US). TcI was the most abundant DTU, comprising nearly 80% of all sequences. All but 1 raccoon harboured multiple haplotypes, some demonstrating mixed infections of different DTUs. Furthermore, there is significant association between DTU distribution and level III ecoregion in Louisiana. Finally, while certain sequences were distributed across multiple tissues, others appeared to have tissue-specific tropism. Taken together, these findings indicate that ongoing surveillance of T. cruzi in the US should be undertaken across ecoregions to fully assess risk to human health. Given potential connections between parasite diversity and clinical outcomes, deep sequencing technologies are crucial and interventions targeting raccoons may prove useful in mitigating human health risk.

The oral microbiota is a reservoir for antimicrobial resistance: resistome and phenotypic resistance characteristics of oral biofilm in health, caries, and periodontitis.

BACKGROUND: Antimicrobial resistance (AMR) is an ever-growing threat to modern medicine and, according to the latest reports, it causes nearly twice as many deaths globally as AIDS or malaria. Elucidating reservoirs and dissemination routes of antimicrobial resistance genes (ARGs) are essential in fighting AMR. Human commensals represent an important reservoir, which is underexplored for the oral microbiota. Here, we set out to investigate the resistome and phenotypic resistance of oral biofilm microbiota from 179 orally healthy (H), caries active (C), and periodontally diseased (P) individuals (TRN: DRKS00013119, Registration date: 22.10.2022). The samples were analysed using shotgun metagenomic sequencing combined, for the first time, with culture technique. A selection of 997 isolates was tested for resistance to relevant antibiotics. RESULTS: The shotgun metagenomics sequencing resulted in 2,069,295,923 reads classified into 4856 species-level OTUs. PERMANOVA analysis of beta-diversity revealed significant differences between the groups regarding their microbiota composition and their ARG profile. The samples were clustered into three ecotypes based on their microbial composition. The bacterial composition of H and C samples greatly overlapped and was based on ecotypes 1 and 2 whereas ecotype 3 was only detected in periodontitis. We found 64 ARGs conveying resistance to 36 antibiotics, particularly to tetracycline, macrolide-lincosamide-streptogramin, and beta-lactam antibiotics, and a correspondingly high prevalence of phenotypic resistance. Based on the microbiota composition, these ARGs cluster in different resistotypes, and a higher prevalence is found in healthy and caries active than in periodontally diseased individuals. There was a significant association between the resistotypes and the ecotypes. Although numerous associations were found between specific antibiotic resistance and bacterial taxa, only a few taxa showed matching associations with both genotypic and phenotypic analyses. CONCLUSIONS: Our findings show the importance of the oral microbiota from different niches within the oral cavity as a reservoir for antibiotic resistance. Additionally, the present study showed the need for using more than one method to reveal antibiotic resistance within the total oral biofilm, as a clear mismatch between the shotgun metagenomics method and the phenotypic resistance characterization was shown.

Phytochemical profiling, anti-hyperglycemic, antifungal, and radicals scavenging potential of crude extracts of Athyrium asplenioides- an in-vitro approach.

This research was aimed to evaluate the phytochemical profile, antifungal, anti-hyperglycemic, as well as antioxidant activity competence of different extracts of Athyrium asplenioides through in-vitro approach. The A. asplenioides crude methanol extract contained considerable quantity of pharmaceutically precious phytochemicals (saponins, tannins, quinones, flavonoid, phenols, steroid, and terpenoids) than others (acetone, ethyl acetate, and chloroform). Interestingly, the crude methanol extract showed remarkable antifungal activity against Candida species (C. krusei: 19.3 ± 2 mm > C. tropicalis: 18.4 ± 1 mm > C. albicans: 16.5 ± 1 mm > C. parapsilosis: 15.5 ± 2 mm > C. glabrate: 13.5 ± 2 mm > C. auris: 7.6 ± 1 mm) at a concentration of 20 mg mL-1. The crude methanol extract also showed remarkable anti-hyperglycemic activity on concentration basis. Surprisingly, remarkable free radicals scavenging potential against DPPH (76.38%) and ABTS (76.28%) free radicals at a concentration of 20 mg mL-1. According to the findings, the A. asplenioides crude methanol extract contains pharmaceutically valuable phytochemicals and may be useful for drug discovery.

Optimizing engine performance and reducing emissions of greenhouse gases through spirulina microalgae and nano-additive blends.

The shift in focus towards biofuels has led to the attention towards fourth-generation fuels, particularly microalgae, due to its high oil productivity and simple cultivation processes. The current study aimed to examine the effects of spirulina microalgae blends in a naturally aspirated diesel engine by testing two blend percentages (15% and 30%) and incorporating Fe2O3 nanoparticles (75 ppm). A series of test conducted in a single-cylinder engine with an optimum compression ratio of 17.5. The fuels tested include 100% diesel (D0), diesel with Fe2O3 nanoparticles (DF), diesel with 15% microalgae blends (B15), diesel with 15% microalgae blends and Fe2O3 nanoparticles (B15F), diesel with 30% microalgae blends (B30), and diesel with 30% microalgae blends and Fe2O3 nanoparticles (B30F). The results showed that the addition of microalgae blends led to a marginal increase in engine performance, while the addition of Fe2O3 nanoparticles led to a significant increase in brake thermal efficiency and decreased fuel consumption. The emissions rate was also lower compared to diesel, but the addition of Fe2O3 nanoparticles increased the oxygen content in the fuel, thereby improving the combustion rates. By ensuring the complete combustion the formation of CO2, HC and smoke intensity was also found to be significantly lower compared to diesel fuel. On the contrary, NOx increased due to the cylinder temperatures. This research highlights the potential of using microalgae as a sustainable source of biofuel, and the positive effects of adding Fe2O3 nanoparticles to enhance the fuel's efficiency.

Enhancing emission control and analyzing the performance and combustion attributes of vehicular engines with spirulina microalgae diesel Ce2O3 nanoparticles blends.

The current research investigates the utilization of spirulina microalgae biodiesel blends in a naturally aspirated constant speed compression ignition engine with Ce2O3 nanoparticles at the concentration of 50 ppm under diverse engine loading conditions. Blends of microalgae dispersed with neat diesel at the volume of 20% and 40%. A series of tests were conducted to evaluate the combined effects of microalgae and nanoparticles on engine performance, combustion efficiency, and emission characteristics. The study revealed that increasing the microalgae concentration in the diesel fuel resulted in reduced brake thermal efficiency due to less effective atomization and lower calorific value. Surprisingly, the 20% biodiesel blend with nanoparticles exhibited the highest brake thermal efficiency across various engine loads, while the 40% blend showed higher brake specific fuel consumption compared to both the 20% blend and neat diesel, primarily because of its lower heating value necessitating increased fuel consumption. Furthermore, the biodiesel blends led to lower in-cylinder pressure than pure diesel, mainly attributable to suboptimal atomization. In terms of emissions, the utilization of microalgae-based fuel led to a significant reduction in NOx, CO, and smoke emissions, attributed to the lower cylinder temperatures associated with these blends. In conclusion, this study underscores the potential of spirulina microalgae, particularly when combined with nanoparticles at an optimal concentration, as a promising and environmentally friendly alternative for compression ignition engines.

Utilization of the Nannochloropsis microalgae biochar prepared via microwave assisted pyrolysis on the mixed biomass fuel pellets.

Nannochloropsis microalgae biochar has become increasingly attractive due to its potential as a component of microalgae-based biodiesel blends. This biochar is a by-product of the pyrolysis process, but its use in the energy sector has been limited. In this study, pellets were formed using microalgae residues and their physiochemical properties were analyzed to assess the feasibility of using microalgae biochar as a fuel source. Three types of biomasses, namely date seed dust, coconut shell waste, and microalgae biochar, were utilized to produce fuel pellets. These pellets were categorized into three types, B1, B2, and B3, based on the composition of the biomass. The inclusion of microalgae biochar in the pellets resulted in enhanced calorific value, as well as improved heating value and bulk density. Moreover, the mechanical strength of microalgae-based pellets was higher due to their high lignin content compared to another biomass. The moisture absorption test results showed that the use of mixed biomass reduced the moisture content over an extended period. Microalgae pellets exhibited higher young's modulus and greater impact resistance, indicating greater mechanical strength. Furthermore, due to their higher calorific value, the combustion time of microalgae pellets was greater than that of other biomass. In conclusion, the results of this study suggest that microalgae biochar can be a promising alternative fuel source for the energy sector.

Investigation of the photocatalytic and optical properties of the SrMoO4/g-C3N4 heterostructure obtained via sonochemical synthesis with temperature control.

In this work, nanomaterials of the SrMoO4/g-C3N4 heterostructure were synthesized in a single step by the sonochemical method with controlled temperatures. Structural and morphological investigations indicate the formation of heterojunctions, revealing the presence of g-C3N4 (CN) in the heterostructures and an interface region between the phases. Optical analyzes show broadening of the wavelength absorption range and a decrease in the photoluminescence (PL) intensity of the heterojunctions compared to the CN emission spectrum, proving a decrease in the recombination of the photogenerated charges. The results of the photocatalytic tests indicate that the insertion of CN promoted photocatalytic degradation of the Methylene Blue (MB), Rhodamine B (RhB) and Crystal Violet (CV) organic contaminants, up to 99.58%, 100% and 98.65%, respectively. The mixture of dyes used and reuse cycles was performed to analyze the applicability of the compounds in a real situation.

Co-designed weight management intervention for women recovering from oestrogen-receptor positive breast cancer.

BACKGROUND: Weight gain is commonly observed during and after breast cancer treatment and is associated with poorer survival outcomes, particularly in women with oestrogen receptor-positive (ER +) disease. The aim of this study was to co-design (with patients) a programme of tailored, personalised support (intervention), including high-quality support materials, to help female breast cancer patients (BCPs) with ER + disease to develop the skills and confidence needed for sustainable weight loss.  METHODS: ER + BCPs were recruited from two UK National Health Service (NHS) Trusts. The selection criteria included (i) recent experience of breast cancer treatment (within 36 months of completing primary treatment); (ii) participation in a recent focus group study investigating weight management perceptions and experiences; (iii) willingness to share experiences and contribute to discussions on the support structures needed for sustainable dietary and physical activity behaviour change. Co-design workshops included presentations and interactive activities and were facilitated by an experienced co-design researcher (HH), assisted by other members of the research team (KP, SW and JS). RESULTS: Two groups of BCPs from the North of England (N = 4) and South Yorkshire (N = 5) participated in a two-stage co-design process. The stage 1 and stage 2 co-design workshops were held two weeks apart and took place between Jan-March 2019, with each workshop being approximately 2 h in duration. Guided by the Behaviour Change Wheel, a theoretically-informed weight management intervention was developed on the basis of co-designed strategies to overcome physical and emotional barriers to dietary and physical activity behaviour change. BCPs were instrumental in designing all key features of the intervention, in terms of Capability (e.g., evidence-based information, peer-support and shared experiences), Opportunity (e.g., flexible approach to weight management based on core principles) and Motivation (e.g., appropriate use of goal-setting and high-quality resources, including motivational factsheets) for behaviour change. CONCLUSION: This co-design approach enabled the development of a theoretically-informed intervention with a content, structure and delivery model that has the potential to address the weight management challenges faced by BCPs diagnosed with ER + disease. Future research is required to evaluate the effectiveness of the intervention for eliciting clinically-important and sustainable weight loss in this population.

Synthesis of novel thiazolidinic-phthalimide derivatives evaluated as new multi-target antiepileptic agents.

Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures.

3D-printed electrochemical platform with multi-purpose carbon black sensing electrodes.

The 3D printing is described of a complete and portable system comprising a batch injection analysis (BIA) cell and an electrochemical platform with eight sensing electrodes. Both BIA and electrochemical cells were printed within 3.4 h using a multimaterial printer equipped with insulating, flexible, and conductive filaments at cost of ca. ~ U$ 1.2 per unit, and their integration was based on a threadable assembling without commercial component requirements. Printed electrodes were exposed to electrochemical/Fenton pre-treatments to improve the sensitivity. Scanning electron microscopy and electrochemical impedance spectroscopy measurements upon printed materials revealed high-fidelity 3D features (90 to 98%) and fast heterogeneous rate constants ((1.5 ± 0.1) × 10-3 cm s-1). Operational parameters of BIA cell were optimized using a redox probe composed of [Fe(CN)6]4-/3- under stirring and the best analytical performance was achieved using a dispensing rate of 9.0 µL s-1 and an injection volume of 2.0 µL. The proof of concept of the printed device for bioanalytical applications was evaluated using adrenaline (ADR) as target analyte and its redox activities were carefully evaluated through different voltammetric techniques upon multiple 3D-printed electrodes. The coupling of BIA system with amperometric detection ensured fast responses with well-defined peak width related to the oxidation of ADR applying a potential of 0.4 V vs Ag. The fully 3D-printed system provided suitable analytical performance in terms of repeatability and reproducibility (RSD ≤ 6%), linear concentration range (5 to 40 µmol L-1; R2 = 0.99), limit of detection (0.61 µmol L-1), and high analytical frequency (494 ± 13 h-1). Lastly, artificial urine samples were spiked with ADR solutions at three different concentration levels and the obtained recovery values ranged from 87 to 118%, thus demonstrating potentiality for biological fluid analysis. Based on the analytical performance, the complete device fully printed through additive manufacturing technology emerges as powerful, inexpensive, and portable tool for electroanalytical applications involving biologically relevant compounds.

New Pregnane Glycosides from Mandevilla dardanoi and Their Anti-Inflammatory Activity.

Mandevilla Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, Mandevilla species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. Mandevilla dardanoi is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of Mandevilla species, this study aimed to isolate new pregnane glycosides from M. dardanoi. To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of M. dardanoi by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MSn and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1ß and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the Mandevilla genus.

Translation into Spanish and field-testing of a new score for evaluating psoriasis severity: The Simplified Psoriasis Index (SPI). / Traducción al español y ensayos de campo de una nueva escala destinada a la valoración global de la gravedad de la psoriasis: el índice de psoriasis simplificado (SPI).

BACKGROUND: The simplified psoriasis index (SPI) was developed in the United Kingdom to provide a simple summary measure for monitoring changes in psoriasis severity and associated psychosocial impact as well as for obtaining information about past disease behavior and treatment. Two complementary versions of the SPI allow for self-assessment by the patient or professional assessment by a doctor or nurse. Both versions have proven responsive to change, reliable, and interpretable, and to correlate well with assessment tools that are widely used in clinical trials - the Psoriasis Area and Severity Index and the Dermatology Quality of Life Index. The SPI has already been translated into several languages, including French, Brazilian Portuguese, Dutch, Arabic, and Thai. OBJECTIVE: To translate the professional and self-assessment versions of the SPI to Spanish and to field test the translations. METHOD: A medically qualified native Spanish speaker translated both versions of the SPI into Spanish. The Spanish translations were discussed by comparing them to blinded back translations into English undertaken by native English speakers; the Spanish texts were then revised in an iterative process involving the translators, 4 dermatologists, and 20 patients. The patients scored their own experience of psoriasis with the self-assessment version and commented on it. The process involved checking the conceptual accuracy of the translation, language-related differences, and subtle gradations of meaning in a process involving all translators and a panel of both Spanish- and English-speaking dermatologists, including a coauthor of the SPI. RESULTS: The final self-assessment and professional Spanish versions of the SPI are presented in this manuscript. CONCLUSIONS: Castilian Spanish translations of both versions of the SPI are now available for monitoring disease changes in Spanish-speaking patients with psoriasis under routine clinical care.

Angular velocimetry for fluid flows: an optical sensor using structured light and machine learning.

Most velocimetry approaches for fluid flows measure linear components of the velocity vector; yet, the angular velocity components, particularly at small scales in turbulent flows, also need to be resolved to study energy transfer and other important flow characteristics. Here, we detail an optical sensor approach to determine a component of the angular velocity vector. This approach uses beams of structured light and a machine learning-based analysis. We discuss the methodology to train the machine learning model and test it in experimentally validated simulations. This approach represents an interesting new direction for fluid flow velocimetry which may be extended to sense other flow parameters by selecting different light structures.

Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors.

Checkpoint inhibitor (CPI) therapy has vastly improved long-term outcomes in metastatic malignant melanoma (MMM). Therapy takes the form of monoclonal antibody infusions that target immune cell checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1/programmed death ligand 1 (PD1/PDL1). Cutaneous immune-related adverse effects (IrAEs) are frequent in patients with MMM treated with CPIs. Our aim was to review the clinical presentations of cutaneous IrAEs associated with CPI therapy in adult patients with MMM. We carried out a literature review of clinical trials, case series and case reports of patients with melanoma and those with other cancers treated with anti-CTLA4, anti-PD1/PDL1, or a combination of these therapies. Diverse clinical presentations of cutaneous IrAEs are recognized. Anti-CTLA4 therapy has a higher associated rate of cutaneous IrAEs than anti-PD1/PDL1 therapies. Low-grade cutaneous IrAEs are common and are usually managed supportively while continuing CPI therapy. Delayed presentations arising after established use of CPIs can make therapy-associated cutaneous IrAEs difficult to distinguish from coincidental dermatological disease. Vitiligo-like depigmentation is a good prognostic indicator of outcome in patients with melanoma. Life-threatening adverse events including toxic epidermal necrolysis are rare. The identification of predictive biomarkers that highlight patients at risk of life-threatening IrAEs remains an unmet need. The involvement of dermatologists in the multidisciplinary assessment of cutaneous IrAEs is increasingly pertinent in the management and care of CPI-treated patients with melanoma.

High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive, high-grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low- and moderate-grade NETs that express somatostatin receptors (SSTRs). OBJECTIVES: To assess SSTR expression and the efficacy of SSAs in mMCC, a high-grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression-free survival (PFS) of ≥ 120 days after initiation of SSA. RESULTS: Thirty-three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response-evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152-358). Twelve of 19 patients did not have a response-evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143-1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. CONCLUSIONS: In contrast to other high-grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side-effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC.

Steric and Electrostatic Effects on the Diffusion of CH4/CH3OH in Copper-Exchanged Zeolites: Insights from Enhanced Sampling Molecular Dynamics and Free Energy Calculations.

Copper-exchanged zeolites have demonstrated high selectivity in methane-to-methanol conversion carried out on copper-oxo centers. Nevertheless, the reaction can only occur if the methane molecules reach the active site while the methanol molecules must leave the material without high energetic cost for the migration. In this context, we have used force field-based molecular dynamics simulations with the potential of mean force method to estimate the energy barrier in cage to cage diffusion of methane and methanol molecules in the chabazite framework type zeolite. The results show considerably higher energy barrier for methanol diffusion. The steric effect of the active site and the electrostatic environment favors the CH3OH diffusion toward nonactive cages where it tends to accumulate due to the strong interactions with the zeolite. The same behavior is observed in the water molecules distribution, which emphasizes the control of the electrostatic potential over the polar molecules migration. For high concentration of polar molecules, the electrostatic effect is shielded and the driving force is reduced for CH3OH diffusion. The results show that if the electrostatic environment can be controlled, the product migration may be facilitated, which can improve the catalytic process.

Multidimensional redox potential/pKa coupling in multicopper oxidases from molecular dynamics: implications for the proton transfer mechanism.

Bilirubin oxidases (BOD) are metalloenzymes that catalyze the conversion of O2 and bilirubin to biliverdin and water in the metabolism of chlorophyll and porphyrin. In this work we have used the CpHMD method to analyze the effects of the different oxidation states on the BOD trinuclear cluster (TNC). Our results demonstrate that there is a link between the different oxidation states of copper ions and the protonation capacity of nearby titratable residues. Each configuration affects pKa differently, creating proton gradients within the enzyme that act in an extremely orderly manner. This order is closely linked to the catalytic mechanism and leads us to the conclusion of the entry of the O2 molecule and its reduction in water molecules is associated with the probability of the release of protons from nearby acid groups. With this information, we deduce that under the initial reaction conditions the acidic side chains of nearby residues can be protonated; this allows the enzyme to reduce the activation energy of the reaction by coupling the proton transfer to oxidation state changes in the metallic center.