Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion.

PURPOSE: Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M). RESULTS: Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death. CONCLUSION: Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.

The potential of a combination of pungent spices as a novel supplement in gilthead seabream (Sparus aurata) diets to aid in the strategic use of fish oil in aquafeeds: a holistic perspective.

This work studied the potential of a combination of pungent spices (capsicum, black pepper, ginger, and cinnamaldehyde) to be used as a supplement in diets of gilthead seabream (Sparus aurata; 44.1 ± 4.2 g). During 90 days, fish were fed three experimental diets with low inclusion of fish oil and containing poultry fat as the main source of lipids, supplemented with graded levels of the tested supplement: 0 (control), 0.1 (SPICY0.1%), and 0.15% (SPICY0.15%). As a result, the pungent spices enhanced the growth performance, the activity of the bile-salt-activated lipase in the intestine, and decreased fat deposit levels within enterocytes. The SPICY0.1% diet reduced the feed conversion ratio and the perivisceral fat index and lipid deposits in the liver. Moreover, the ratio of docosahexaenoic acid/eicosapentaenoic acid in fillet increased in fish fed the SPICY0.1% diet, while the hepatic levels of docosahexaenoic acid and total n-3 polyunsaturated fatty acids increased in fish fed the SPICY0.15% diet. Furthermore, there was an effect on the expression of some biomarkers related to lipid metabolism in 2-h postprandial fish (fasn, elovl6, scd1b, cyp7a1, lpl, and pparß), and in 48 h fasted-fish fed with the SPICY0.1% diet, a regulation of the intestinal immune response was indicated. However, no significant differences were found in lipid apparent digestibility and proximate macronutrient composition. The spices did not affect biomarkers of hepatic or oxidative stress. No differences in microbial diversity were found, except for an increase in Simpson's Index in the posterior intestine of fish fed the SPICY0.1% diet, reflected in the increased relative abundance of the phylum Chloroflexi and lower relative abundances of the genera Campylobacter, Corynebacterium, and Peptoniphilus. In conclusion, the supplementation of gilthead seabream diets with pungent spices at an inclusion of 0.1% was beneficial to enhance growth performance and feed utilization; reduce fat accumulation in the visceral cavity, liver, and intestine; and improve the fish health status and condition. Results suggest that the tested supplement can be used as part of a nutritional strategy to promote a more judicious use of fish oil in fish diets due to its decreasing availability and rising costs.

Assessment of open-field fluorescence guided surgery systems: implementing a standardized method for characterization and comparison.

Significance: Fluorescence guided surgery (FGS) has demonstrated improvements in decision making and patient outcomes for a wide range of surgical procedures. Not only can FGS systems provide a higher level of structural perfusion accuracy in tissue reconstruction cases but they can also serve for real-time functional characterization. Multiple FGS devices have been Food and Drug administration (FDA) cleared for use in open and laparoscopic surgery. Despite the rapid growth of the field, there has been a lack standardization methods. Aim: This work overviews commonalities inherent to optical imaging methods that can be exploited to produce such a standardization procedure. Furthermore, a system evaluation pipeline is proposed and executed through the use of photo-stable indocyanine green fluorescence phantoms. Five different FDA-approved open-field FGS systems are used and evaluated with the proposed method. Approach: The proposed pipeline encompasses the following characterization: (1) imaging spatial resolution and sharpness, (2) sensitivity and linearity, (3) imaging depth into tissue, (4) imaging system DOF, (5) uniformity of illumination, (6) spatial distortion, (7) signal to background ratio, (8) excitation bands, and (9) illumination wavelength and power. Results: The results highlight how such a standardization approach can be successfully implemented for inter-system comparisons as well as how to better understand essential features within each FGS setup. Conclusions: Despite clinical use being the end goal, a robust yet simple standardization pipeline before clinical trials, such as the one presented herein, should benefit regulatory agencies, manufacturers, and end-users to better assess basic performance and improvements to be made in next generation FGS systems.

Anesthetic management of a child with Loeys-Dietz syndrome undergoing complete aortic arch replacement.

Loeys-Dietz syndrome (LDS) is a connective tissue disease related to ß-transforming growth factor mutations, which causes aneurysms formation, vascular tortuosity and skeletal manifestations. The prognosis is very poor, and mortality occurs at the age of 27 in patients without surgical treatment. Despite being diagnosed in childhood, is not usual surgical aortic replacement in children. We report a case of 12 years old child with LDS and multiple aneurysms in thoracic aorta, undergoing complete aortic arch replacement and our proposal for the anesthetic management, due to surgical complexity and implications in pediatric population.

El síndrome de Loeys-Dietz (SDL) es una enfermedad del tejido conectivo debida a mutaciones del factor de crecimiento transformador beta que provocan formación de aneurismas, malformaciones vasculares y esqueléticas. Tiene mal pronóstico y el fallecimiento sobreviene de media a los 27 años sin tratamiento quirúrgico. A pesar de diagnosticarse en la infancia, es infrecuente la cirugía en niños. Presentamos el caso de una niña de 12 años con SDL y aneurisma múltiple en aorta torácica, programada para recambio completo de arco aórtico, proponiendo estrategias para el manejo anestésico, dada la complejidad y las implicaciones de esta cirugía en la población pediátrica.

Smartphone-based dual radiometric fluorescence and white-light imager for quantification of protoporphyrin IX in skin.

Significance: The quantification of protoporphyrin IX (PpIX) in skin can be used to study photodynamic therapy (PDT) treatments, understand porphyrin mechanisms, and enhance preoperative mapping of non-melanoma skin cancers. Aim: We aim to develop a smartphone-based imager for performing simultaneous radiometric fluorescence (FL) and white light (WL) imaging to study the baseline levels, accumulation, and photobleaching of PpIX in skin. Approach: A smartphone-based dual FL and WL imager (sDUO) is introduced alongside new radiometric calibration methods for providing SI-units of measurements in both pre-clinical and clinical settings. These radiometric measurements and corresponding PpIX concentration estimations are applied to clinical measurements to understand mechanistic differences between PDT treatments, accumulation differences between normal tissue and actinic keratosis lesions, and the correlation of photosensitizer concentrations to treatment outcomes. Results: The sDUO alongside the developed methods provided radiometric FL measurements (nW/cm2) with a demonstrated sub nanomolar PpIX sensitivity in 1% intralipid phantoms. Patients undergoing PDT treatment of actinic keratosis (AK) lesions were imaged, capturing the increase and subsequent decrease in FL associated with the incubation and irradiation timepoints of lamp-based PDT. Furthermore, the clinical measurements showed mechanistic differences in new daylight-based treatment modalities alongside the selective accumulation of PpIX within AK lesions. The use of the radiometric calibration enabled the reporting of detected PpIX FL in units of nW/cm2 with the use of liquid phantom measurements allowing for the estimation of in-vivo molar concentrations of skin PpIX. Conclusions: The phantom, pre-clinical, and clinical measurements demonstrated the capability of the sDUO to provide quantitative measurements of PpIX FL. The results demonstrate the use of the sDUO for the quantification of PpIX accumulation and photobleaching in a clinical setting, with implications for improving the diagnosis and treatment of various skin conditions.

Equivalent efficacy of indoor daylight and lamp-based 5-aminolevulinic acid photodynamic therapy for treatment of actinic keratosis.

Background: Photodynamic therapy (PDT) is widely used as a treatment for actinic keratoses (AK), with new sunlight-based regimens proposed as alternatives to lamp-based treatments. Prescribing indoor daylight activation could help address the seasonal temperature, clinical supervision, and access variability associated with outdoor treatments. Objective: To compare the AK lesion clearance efficacy of indoor daylight PDT treatment (30 min of 5-aminolevulinic acid (ALA) pre-incubation, followed by 2 h of indoor sunlight) versus a lamp-based PDT treatment (30 min of ALA preincubation, followed by 10 min of red light). Methods: A prospective clinical trial was conducted with 41 patients. Topical 10% ALA was applied to the entire treatment site (face, forehead, scalp). Patients were assigned to either the lamp-based or indoor daylight treatment. Actinic keratosis lesion counts were determined by clinical examination and recorded for pre-treatment, 1-month, and 6-month follow-up visits. Results: There was no statistical difference in the efficacy of AK lesion clearance between the red-lamp (1-month clearance = 57 ± 17%, 6-month clearance = 57 ± 20%) and indoor daylight treatment (1-month clearance = 61 ± 19%, 6-month clearance = 67 ± 20%). A 95% confidence interval of the difference of the means was measured between -4.4% and 13.4% for 1-month, and -2.2% and +23.6% for 6-month timepoints when comparing the indoor daylight to the red-lamp treatment, with a priori interval of equivalence of ±20%. Limitations: Ensuring an equivalent dose between the indoor and lamp treatment cohorts limited randomisation since it required performing indoor daylight treatments only during sunny days. Conclusion: Indoor-daylight PDT provided equivalent AK treatment efficacy to a lamp-based regimen while overcoming temperature limitations and UV-block sunscreen issues associated with outdoor sunlight treatments in the winter. Clinical trial registration: Clinicaltrials.gov listing: NCT03805737.

Effective fluence and dose at skin depth of daylight and lamp sources for PpIX-based photodynamic therapy.

SIGNIFICANCE: Skin-based photodynamic therapy (PDT) is used for the clinical treatment of actinic keratosis (AKs) and other skin lesions with continued expansion into the standard of care. Due to the spectral dependency of photosensitizer activation and skin optical fluence, there is a need for more accurate methods to estimate the delivered dose at depth from different PDT light sources and treatment regimens. AIM: Develop radiometric methods for calculating photosensitizer-effective fluence and dose at depth and determine differences between red-lamp, blue-lamp, and daylight-based PDT treatments. METHODS: Radiometric measurements of FDA-approved PDT lamp sources, outdoor daylight, and indoor daylight were performed for clinically relevant AK treatments. The protoporphyrin IX (PpIX) equivalent irradiance, fluence, and dose for each light source were calculated from the PpIX absorption spectrum and a 7-layer skin fluence model. The effective fluence and dose at depth was estimated by combining the spectral attenuation predicted at each wavelength and depth with the source fluence at each wavelength. RESULTS: The red-lamp source had the highest illuminance (112,000 lumen/m2), but lowest PpIX-effective irradiance (9.6 W/m2), and highest effective fluence at depth (10.8 W/m2 at 500 µm). In contrast, the blue light source had the lowest illuminance (2300 lumen/m2), but highest PpIX effective irradiance (37.0 W/m2), and ultimately the lowest effective fluence at depth (0.18 W/cm2 at 500 µm). The daylight source had values of (outdoor | indoor) illuminance of (49,200 | 37,800 lumen/m2), effective irradiance of (19.2 | 10.7 W/m2), and effective fluence of (1.50 | 1.08 W/m2 at 500 µm). The effective fluence and dose at depth facilitated the comparison of treatment regimens, for example, calculating an equivalent dose for a 2 hr indoor daylight treatment and a 10 min red-light treatment for the 300-1000 µm depth range. CONCLUSIONS: The consideration of PpIX-effective fluence at varying depths is necessary to provide adequate comparisons of the delivered dose from PDT light sources. Methods for calculating radiometric fluence and delivered dose at depth were introduced, with open source MATLAB code, to help overcome the limitations of commonly used photometric and irradiance-based reporting.

[Zero Emissions. A shared responsibility. Gas capture and recycling project at the Cruces University Hospital (Spain).] / Emisiones Zero. Una responsabilidad compartida. Proyecto captura de gases y reciclado en el Hospital Universitario de Cruces.

OBJECTIVE: The use of volatile anesthetics plays an important role in the production of greenhouse gases and other environmental pollutants that negatively affect global health. Programs to reduce anesthesia contaminants have been shown to be effective and reduce costs. For this reason, we conducted a study to implementing a Zero Emissions Program for zero carbon dioxide emissions derived from anesthetic gases used in the operating room, as recommended by the Green Deal of the European Union by 2030 and be climate neutral in 2050, maintaining satisfaction and current clinical results. METHODS: A Zero Emissions Program was implemented within the Zero safety programs of the Cruces University Hospital in order to produce zero emissions of carbon dioxide derived from the anesthetic gases used in the operating rooms. The contribution of anesthetic gases to carbon dioxide production before and after implementation of program was determined. Data analysis was conducted descriptively to analyze program effectiveness. RESULTS: The implementation of a Zero Emissions Program allowed us to achieve a reduction in emissions to zero. CONCLUSIONS: Anesthesiologists must understand that minimizing our harmful impact on environmental health sustainability is not only desirable, but ethically necessary. A way to contribute to this ethical responsibility is Zero Emissions Programs which are effective in reducing emissions to zero, probably improving our impact on planet health.

OBJETIVO: El uso de anestésicos volátiles juega un papel importante en la producción de gases de efecto invernadero y otros contaminantes ambientales que afectan negativamente a la salud mundial. Se ha demostrado que los programas para reducir los contaminantes de la anestesia en el medio ambiente son eficaces y también reducen los costes. Por este motivo nos planteamos como objetivo implementar un Programa de Emisiones Zero para producir cero emisiones de dióxido de carbono derivados de los gases anestésicos utilizados en el quirófano, como recomienda el Pacto Verde de la Unión Europea, para 2030 y ser climáticamente neutros en 2050, manteniendo la satisfacción y los resultados clínicos actuales. METODOS: Se implementó un Programa de Emisiones Zero dentro de los programas Zero de seguridad del Hospital Universitario de Cruces (Barakaldo) con la finalidad de producir cero emisiones de dióxido de carbono derivado de los gases anestésicos utilizados en los quirófanos. Se determinó la contribución de los gases anestésicos a la producción de dióxido de carbono previo y posterior a la implementación del programa. El análisis de los datos se llevó a cabo de forma descriptiva para analizar la efectividad del programa. RESULTADOS: La implementación de un Programa de Emisiones de Zero nos permitió conseguir una disminución de las emisiones a cero. CONCLUSIONES: Los anestesiólogos debemos comprender que minimizar nuestro impacto nocivo en la sostenibilidad de la salud ambiental no es solo deseable, sino éticamente necesario. Una de las formas de contribuir con esta responsabilidad ética es con la implementación de Programas de Emisiones Zero que son eficaces en la reducción a cero de estas emisiones con lo que mejoraremos nuestro impacto en la salud del planeta.

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice.

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.

3D-Printed Tumor Phantoms for Assessment of In Vivo Fluorescence Imaging Analysis Methods.

PURPOSE: Interventional fluorescence imaging is increasingly being utilized to quantify cancer biomarkers in both clinical and preclinical models, yet absolute quantification is complicated by many factors. The use of optical phantoms has been suggested by multiple professional organizations for quantitative performance assessment of fluorescence guidance imaging systems. This concept can be further extended to provide standardized tools to compare and assess image analysis metrics. PROCEDURES: 3D-printed fluorescence phantoms based on solid tumor models were developed with representative bio-mimicking optical properties. Phantoms were produced with discrete tumors embedded with an NIR fluorophore of fixed concentration and either zero or 3% non-specific fluorophore in the surrounding material. These phantoms were first imaged by two fluorescence imaging systems using two methods of image segmentation, and four assessment metrics were calculated to demonstrate variability in the quantitative assessment of system performance. The same analysis techniques were then applied to one tumor model with decreasing tumor fluorophore concentrations. RESULTS: These anatomical phantom models demonstrate the ability to use 3D printing to manufacture anthropomorphic shapes with a wide range of reduced scattering (µs': 0.24-1.06 mm-1) and absorption (µa: 0.005-0.14 mm-1) properties. The phantom imaging and analysis highlight variability in the measured sensitivity metrics associated with tumor visualization. CONCLUSIONS: 3D printing techniques provide a platform for demonstrating complex biological models that introduce real-world complexities for quantifying fluorescence image data. Controlled iterative development of these phantom designs can be used as a tool to advance the field and provide context for consensus-building beyond performance assessment of fluorescence imaging platforms, and extend support for standardizing how quantitative metrics are extracted from imaging data and reported in literature.

A Novel PiRNA Enhances CA19-9 Sensitivity for Pancreatic Cancer Identification by Liquid Biopsy.

Pancreatic cancer is one of the deadliest tumours worldwide, and its poor prognosis is due to an inability to detect the disease at the early stages, thereby creating an urgent need to develop non-invasive biomarkers. P-element-induced wimpy testis (PIWI) proteins work together with piwi-interacting RNAs (piRNAs) to perform epigenetic regulation and as such hold great potential as biomarkers for pancreatic cancer. PIWIL2 and PIWIL4 are associated with better prognosis, while PIWIL1 and PIWIL3 involvement appears to be associated with carcinogenesis. We aimed to discover PIWIL3- and PIWIL4-modulated piRNAs and determine their potential mechanisms in pancreatic cancer and the clinical implications. PIWIL3 or PIWIL4 was downregulated in pancreatic cancer-derived cell lines or in a non-tumour cell line. Differentially expressed piRNAs were analysed by next generation sequencing of small RNA. Nine fresh-frozen samples from solid human pancreases (three healthy pancreases, three intraductal papillary mucinous neoplasms, and three early-stage pancreatic cancers) were included in the sequencing analysis. Two piRNAs associated with PIWIL3 (piR-168112 and piR-162725) were identified in the neoplastic cells; in untransformed samples, we identified one piRNA associated with PIWIL4 (pir-366845). After validation in pancreatic cancer-derived cell lines and one untransformed pancreatic cell line, these piRNAs were evaluated in plasma samples from healthy donors (n = 27) or patients with pancreatic cancer (n = 45). Interestingly, piR-162725 expression identified pancreatic cancer patients versus healthy donors in liquid biopsies. Moreover, the potential of the serum carbohydrate antigen 19-9 (CA19-9) biomarker to identify pancreatic cancer patients was greatly enhanced when combined with piR-162725 detection. The enhanced diagnostic potential for the early detection of pancreatic cancer in liquid biopsies of these new small non-coding RNAs will likely improve the prognosis and management of this deadly cancer.

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased ß2 adrenergic agonist.

Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S')-4'-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased ß2-adrenergic receptor (ß2-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and ß2-AR in (R,S')-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S')-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S')-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased ß2-AR/Gαs/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S')-MNF administration significantly reduced PANC-1 tumor growth and circulating L-lactate concentrations. Global metabolic profiling of (R,S')-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S')-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards ß-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased ß2-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

Impact of New Systemic Therapies in Overall Survival in Non-Metastatic Castration Resistant Prostate Cancer: Systematic Review and Meta-Analysis.

There was a high medical need for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) when several next-generation anti-androgens (apalutamide, enzalutamide, and darolutamide) demonstrated clinically relevant delays in metastasis onset. However, to date, few publications have assessed the pooled effect of these treatments on overall survival (OS). We performed a systematic review and meta-analysis of all randomized, placebo-controlled studies investigating a systemic treatment in nmCRPC. Publications were identified by searching several databases on April 7, 2021. The primary objective of this analysis was to determine the OS benefit. Secondary outcomes included the relative risk (RR) of adverse events (AEs) and grade 3-4 AEs. A sensitivity analysis with simulated data was also conducted to examine the influence of the study designs on the results. Three randomized controlled studies (SPARTAN, PROSPER, ARAMIS) met our inclusion criteria. Pooled meta-analyses showed a significant benefit in OS with the active agents versus placebo (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.65-0.83), as well as increased risk of any grade (RR 1.09, 95% CI 1.01-1.17) and grade 3-4 AEs (RR 1.50, 95% CI 1.23-1.83). The sensitivity analysis with SPARTAN-like simulated populations demonstrated that when using ARAMIS statistical design, OS would be statistically significant in 98.1% of the cases, at a shorter follow-up and with lower number of events. First-line treatment of nmCRPC patients with anti-androgens increased OS with an acceptable safety profile. In light of the different study designs and follow-up, results should be interpreted separately.

Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.

Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.

3D printing fluorescent material with tunable optical properties.

The 3D printing of fluorescent materials could help develop, validate, and translate imaging technologies, including systems for fluorescence-guided surgery. Despite advances in 3D printing techniques for optical targets, no comprehensive method has been demonstrated for the simultaneous incorporation of fluorophores and fine-tuning of absorption and scattering properties. Here, we introduce a photopolymer-based 3D printing method for manufacturing fluorescent material with tunable optical properties. The results demonstrate the ability to 3D print various individual fluorophores at reasonably high fluorescence yields, including IR-125, quantum dots, methylene blue, and rhodamine 590. Furthermore, tuning of the absorption and reduced scattering coefficients is demonstrated within the relevant mamalian soft tissue coefficient ranges of 0.005-0.05 mm-1 and 0.2-1.5 mm-1, respectively. Fabrication of fluorophore-doped biomimicking and complex geometric structures validated the ability to print feature sizes less than 200 µm. The presented methods and optical characterization techniques provide the foundation for the manufacturing of solid 3D printed fluorescent structures, with direct relevance to biomedical optics and the broad adoption of fast manufacturing methods in fluorescence imaging.

Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity.

Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that may reduce hepatic steatosis through their effects in adipose tissue and therefore have been assessed as potential therapies to treat nonalcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (PpargΔHep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic triglyceride content only in control mice with severe obesity. Under these conditions, PpargΔHep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated adenosine 5'-monophosphate-activated protein kinase were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the antisteatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.

Alimentación, comportamiento de oviposición, ciclo de vida y enemigos naturales de Hamadryas feronia (Nymphalidae) en la Amazonía del Perú / Feeding, oviposition behavior, life cycle, and natural enemies of Hamadryas Feronia (Nymphalidae) in the Peruvian Amazon

Resumen Introducción: Hamadryas feronia feronia, se mimetiza sobre las cortezas de los árboles y suele emitir sonidos al volar que llaman la atención; posee un buen potencial para los bionegocios (exportación, elaboración de artesanías y centros turísticos de crianza). Sin embargo, aún se desconocen sus aspectos biológicos que obstaculizan su crianza en cautiverio. Objetivos: Determinar los aspectos biológicos de alimentación, comportamiento de oviposición, ciclo de vida y los enemigos naturales de Hamadryas feronia feronia L. en San Rafael-Indiana, Loreto, Perú. Métodos: Los muestreos fueron realizados desde enero 2018 a diciembre 2019 en la comunidad de San Rafael, río Amazonas. Los adultos fueron observados durante el día, se registraron sus plantas alimenticias, su comportamiento de oviposición, su ciclo biológico y sus enemigos naturales. El ciclo de vida fue evaluado en el laboratorio, utilizando 20 huevos recientemente depositados en las hojas de su planta hospedera. Resultados: Las larvas de H. feronia feronia se alimentan de las hojas de Dalechampia juruana y los adultos se alimentan de la savia de la corteza de los árboles de Cedrela odorata, Spondias mombin, Uncaria guianensis y de los frutos fermentados de Syzygium malaccense y Pouteria caimito. Los adultos vuelan en días soleados, los machos emiten un fuerte sonido al volar. Las hembras previo a la oviposición revolotean de forma irregular alrededor de su planta hospedera entre las 8.00 y las 14.00 h y depositan sus huevos en el haz y envés de las hojas de forma aislada con mayor frecuencia en el envés (N= 85). La duración del ciclo, desde huevo hasta adulto fue de 28.24 días. El periodo promedio del huevo fue 3.75 ± 0.40 días. La larva pasa por cinco estadíos larvales: el primero duró 3.21 ± 1.03 días, el segundo 2.78 ± 0.73 días, el tercero 2.67 ± 0.77 días, el cuarto 3.22 ± 0.81 días, y el quinto 4.61 ± 0.70 días. El periodo de la prepupa duró 1.33 ± 0.49 días y el de pupa 6.67 ± 0.80 días; los adultos nacieron entre las 10:00 y 11:00 h. Los machos adultos viven en promedio 31.80 ± 3.29 días, la hembra 42.00 ± 2.14 días y sus huevos son parasitados por un microhimenóptero (Scelionidae). Conclusiones: Este estudio permitió conocer los aspectos biológicos de H. feronia feronia identificando sus plantas alimenticias tanto de las larvas como de los adultos, su comportamiento de oviposición, así mismo se ha determinado que tiene un ciclo biológico relativamente corto con un periodo menor de un mes y sus huevos son consumidos por un pequeño Himenóptero que puede obstaculizar su producción. Este trabajo brinda información necesaria para desarrollar la crianza de H. feronia feronia, orientado a su conservación, la educación ambiental y los bionegocios (turismo y artesanía) en la Amazonia peruana.

Abstract Introduction: Hamadryas feronia feronia, which mimics the bark of trees and often makes attention-grabbing sounds when flying, has good potential for bio-business (export, handicrafts and tourist breeding centers). However, its biological aspects are still unknown, which hinder its captive breeding. Objectives: To determine the biological aspects of feeding, oviposition behavior, life cycle and natural enemies of Hamadryas feronia feronia L. in San Rafael-Indiana, Loreto, Peru. Methods: Sampling was conducted from January 2018 to December 2019 in the community of San Rafael, Amazon River. Adults were observed during the day, their food plants, oviposition behavior, biological cycle and natural enemies were recorded. The life cycle was evaluated in the laboratory, using 20 eggs recently deposited on the leaves of their host plant. Results: The larvae of H. feronia feronia feed on the leaves of Dalechampia juruana and the adults feed on the bark sap of Cedrela odorata, Spondias mombin, Uncaria guianensis and the fermented fruits of Syzygium malaccense and Pouteria caimito. Adults fly on sunny days, males emit a loud sound when flying. Females prior to oviposition flit irregularly around their host plant between 8.00 and 14.00 h and deposit their eggs on the upper and underside of leaves in isolation, most frequently on the underside. The duration of the cycle from egg to adult was 28.24 days. The average egg period was 3.75 ± 0.40 days. The larvae passed through five larval instars: the first instar 3.21 ± 1.03 days, the second 2.78 ± 0.73 days, the third 2.67 ± 0.77 days, the fourth 3.22 ± 0.81 days, and the fifth 4.61 ± 0.70 days. The prepupal period lasted 1.33 ± 0.49 days and the pupal period 6.67 ± 0.80 days; the adults hatched between 10:00 to 11:00 h. Adult males lived on average 31.80 ± 3.29 days, the female 42.00 ± 2.14 days and their eggs were parasitized by a microhymenopteran (Scelionidae). Conclusions: This study allowed to know the biological aspects of H. feronia feronia identifying its food plants of both larvae and adults, its oviposition behavior, as well as it has been determined that it has a relatively short biological cycle with a period of less than one month and its eggs are consumed by a small Hymenoptera that can hinder its production. This work provides necessary information to develop the breeding of H. feronia feronia, oriented to its conservation, environmental education and biotrade (tourism and handicrafts) in the Peruvian Amazon.

Evaluation of bone perfusion during open orthopedic surgery using quantitative dynamic contrast-enhanced fluorescence imaging.

In this study, an indocyanine green (ICG)-based dynamic contrast- enhanced fluorescence imaging (DCE-FI) technique was evaluated as a method to provide objective real-time data on bone perfusion using a porcine osteotomy model. DCE-FI with sequentially increasing injury to osseous blood supply was performed in 12 porcine tibias. There were measurable, reproducible and predictable changes to DCE-FI data across each condition have been observed on simple kinetic curve-derived variables as well variables derived from a novel bone-specific kinetic model. The best accuracy, sensitivity and specificity of 89%, 88% and 90%, have been achieved to effectively differentiate injured from normal/healthy bone.

Effects of music therapy as an adjunct to chest physiotherapy in children with cystic fibrosis: A randomized controlled trial.

Airway clearance therapy (ACT) is considered an important approach to improve airway clearance in children with cystic fibrosis (CF). Daily ACT administration requires substantial commitments of time and energy that complicate ACT and reduce its benefits. It is crucial to establish ACT as a positive routine. Music therapy (MT) is an aspect of integrative strategies to ameliorate the psycho-emotional consequences of chronic diseases, and a MT intervention could help children with CF between the ages of 2 and 17 develop a positive response. The aim of this randomized controlled trial was to evaluate the effects of specifically composed and recorded instrumental music as an adjunct to ACT. We compared the use of specifically composed music (Treated Group, TG), music that the patient liked (Placebo Group, PG), and no music (Control Group, CG) during the usual ACT routine in children with CF aged from 2 to 17. The primary outcomes, i.e., enjoyment and perception of time, were evaluated via validated questionnaires. The secondary outcome, i.e., efficiency, was evaluated in terms of avoided healthcare resources. Enjoyment increased after the use of the specifically composed music (children +0.9 units/parents +1.7 units; p<0.05) compared to enjoyment with no music (0 units) and familiar music (+0.5 units). Perception of time was 11.1 min (±3.9) less than the actual time in the TG (p<0.05), 3.9 min (±4.2) more than the actual time in the PG and unchanged in the CG. The potential cost saving related to respiratory exacerbations was €6,704.87, while the cost increased to €33,524.35 in the CG and to €13,409.74 in the PG. In conclusion, the specifically composed, played and compiled instrumental recorded music is an effective adjunct to ACT to establish a positive response and is an efficient option in terms of avoided costs. Trial registered as ISRCTN11161411. ISRCTN registry (www.isrctn.com).

Topical mitomycin in endoscopic-assisted probing for the treatment of congenital nasolacrimal duct obstruction in older children.

PURPOSE: Mitomycin C has been used in ophthalmic surgery to mitigate postoperative scarring. However, the outcomes of endoscopic-assisted probing for the treatment of congenital nasolacrimal duct obstruction with adjunctive mitomycin C in children remain unknown. Our study was aimed to evaluate the efficacy and safety of adjunctive application of mitomycin C after endoscopic-assisted probing for the treatment of congenital nasolacrimal duct obstruction in children. METHODS: This is a retrospective chart review performed in a tertiary eye care hospital involving children with congenital nasolacrimal duct obstruction, who underwent endoscopic-assisted probing from October 2013 to August 2015. We compared children who underwent endoscopic-assisted probing with mitomycin C (mitomycin C group) versus others who underwent endoscopic-assisted probing without mitomycin C (endoscopic-assisted probing group). The mitomycin C group received 0.2 mg/ml within 4 min to the nasolacrimal duct ostium using a cotton tip applicator immediately after probing. Probing was considered successful when patient complaints of tearing were reduced or the results of the dye disappearance test were normal. Demographic data, clinical features, and intraoperative and postoperative variables were correlated to the success rate. RESULTS: The study sample comprised 68 lacrimal vies. The majority of children had bilateral obstruction and no previous history of probing. The mean age of the patients was approximately 4 years. Most obstructions were considered complex. The success rates were high in both groups (p>0.05). There were no adverse events related to the use of mitomycin C (p>0.05). CONCLUSIONS: Although mitomycin C has no adverse effects when applied to the opening of the nasolacrimal duct, its use after lacrimal probing for the treatment of congenital nasolacrimal duct obstruction does not improve the chance of success.