Early change in apparent diffusion coefficient as a predictor of response to neoadjuvant androgen deprivation and external beam radiation therapy for intermediate- to high-risk prostate cancer.

AIM: To determine the role of serial apparent diffusion coefficient (ADC) as a biomarker for response to neoadjuvant androgen deprivation therapy (nADT) followed by external beam radiation therapy (EBRT) in intermediate- to high-risk prostate cancer (PCa) patients. METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant, institutional review board (IRB)-approved prospective study included 12 patients with intermediate- to high-risk PCa patients prior to nADT and EBRT, who underwent serial serum prostate-specific antigen (PSA) and multiparametric prostate magnetic resonance imaging (mpMRI) at baseline (BL), 8-weeks after nADT initiation (time point [TP]1), 6-weeks into EBRT delivery (TP2), and 6-months after nADT initiation (TP3). Tumour volume (tVOL) and tumour and normal tissue ADC (tADC and nlADC) were determined at all TPs. tADC and nlADC dynamics were correlated with post-treatment PSA using Pearson's correlation coefficient. Paired t-tests compared pre/post-treatment ADC. RESULTS: There was a sequential decrease in PSA at all TPs, reaching their lowest values at TP3 post-treatment completion. Mean tADC increased significantly from baseline to TP1 (917.8 ± 107.7 × 10-6 versus 1033.8 ± 139.3 × 10-6 mm2/s; p<0.01), with no subsequent change at TP2 or TP3. Both percentage and absolute change in tADC from BL to TP1 correlated with post-treatment PSA (r=-0.666, r=-0.674; p=0.02). Post-treatment PSA in good responders (<0.1 ng/ml) versus poor responders (≥ 0.1 ng/ml) was associated with a greater increase in tADC from BL to TP1 (169.2 ± 122.4 × 10-6 versus 22.9 ± 75.5 × 10-6 mm2/s, p=0.03). CONCLUSION: This pilot study demonstrates the potential for early ADC metrics as a biomarker of response to nADT and EBRT in intermediate to high-risk PCA.

Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets.

Malaria, caused by Plasmodium falciparum, remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. Like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.

Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in Plasmodium falciparum.

The Plasmodium proteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinin and related analogues. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible, macrocyclic inhibitors of the Plasmodium falciparum proteasome. We identified compounds with excellent potency and low cytotoxicity; however, the first generation suffered from poor microsomal stability. Further optimization of an existing macrocyclic scaffold resulted in an irreversible covalent inhibitor carrying a vinyl sulfone electrophile that retained high potency and low cytotoxicity and had acceptable metabolic stability. Importantly, unlike the parent reversible inhibitor that selected for multiple mutations in the proteasome, with one resulting in a 5,000-fold loss of potency, the irreversible analogue only showed a 5-fold loss in potency for any single point mutation. Furthermore, an epoxyketone analogue of the same scaffold retained potency against a panel of known proteasome mutants. These results confirm that macrocycles are optimal scaffolds to target the malarial proteasome and that the use of a covalent electrophile can greatly reduce the ability of the parasite to generate drug resistance mutations.

Biotransformation of 1-nitro-2-phenylethane [Formula: see text] 2-phenylethanol from fungi species of the Amazon biome: an experimental and theoretical analysis.

CONTEXT: Natural products and their biotransformation procedures are a powerful source of new chromophores with potential applications in fields like biology, pharmacology and materials science. Thus, this work discusses about the extraction procedure of 1-nitro-2-phenylethane (1N2PE) from Aniba canelilla, its biotransformation setup into 2-phenylethanol (2PE) using four fungi, Lasiodiplodia caatinguensis (phytopathogenic fungus from Citrus sinensis), Colletotrichum sp. (phytopathogenic fungus from Euterpe oleracea), Aspergillus flavus and Rigidoporus lineatus isolated from copper mining waste located in the interior of the Brazilian Amazon. A detailed experimental and theoretical vibrational analysis (IR and Raman) have allowed us to perform some charge transfer effects on the title compounds (push-pull effect) by monitoring specific vibrational modes of their electrophilic and nucleophilic molecular sites. The solvent interactions promote molecular conformations that affect the vibrational spectra of the donor and acceptor groups, as can be seen comparatively in the gas and aqueous solution spectra, an effect possibly related to the bathochromic shift in the calculated optical spectrum of the compounds. The nonlinear optical behavior shows that while the solvent reduces the response of 1N2PE, the response of 2PE increases the optical parameters, which presents low refractive index (n) and first hyperpolarizability. ([Formula: see text]) is almost eight times that reported for urea (42.79 a.u.), a common nonlinear optical material. Furthermore, the bioconversion goes from an electrophilic to a nucleophilic compound, affecting its molecular reactivity. METHODS: 1N2PE was obtained from Aniba canelilla, whose essential oil is constituted of [Formula: see text] of 2PE. The A. canelilla essential oil was extracted under hydrodistillation. The biotransformation reactions were performed in autoclaved liquid media (100 mL) composed of malt extract (2%) in 250 mL Erlenmeyer flask. Each culture was incubated in an orbital shaker (130 rpm) at [Formula: see text]C during 7 days and after that, 50 mg of 1N2PE (80%) were diluted in 100 [Formula: see text]L of dimethylsulfoxide (DMSO) and added to the reactions flasks. Aliquots (2 mL) were removed using ethyl acetate (2 mL) and analyzed by GC-MS (fused silica capillary col1umn, Rtx -5MS 30 m [Formula: see text] 0.25 mm [Formula: see text] 0.25 [Formula: see text]m) in order to determine the amount of 1N2PE biotransformation. FTIR 1N2PE and 2PE spectra were obtained by attenuated total reflectance (ATR), using a Agilent CARY 630 spectrometer, in the spectral region 4000-650 cm[Formula: see text]. The quantum chemical calculations were carried out in the Gaussian 09 program while the DICE code was used to perform the classical Monte Carlo simulations and generate the liquid environment using the classical All-Atom Optimized parameters for Liquid Simulations (AA-OPLS). All nonlinear optical properties, reactive parameters, and electronic excitations were calculated using the Density Functional Theory framework coupled to the standard 6-311++G(d,p) basis set.

Protease Activated Probes for Real-Time Ratiometric Imaging of Solid Tumors.

Surgery is the preferred treatment option for most solid tumors. However, inaccurate detection of cancer borders leads to either incomplete removal of malignant cells or excess excision of healthy tissue. While fluorescent contrast agents and imaging systems improve tumor visualization, they can suffer from low signal-to-background and are prone to technical artifacts. Ratiometric imaging has the potential to eliminate many of these issues such as uneven probe distribution, tissue autofluorescence, and changes in positioning of the light source. Here, we describe a strategy to convert quenched fluorescent probes into ratiometric contrast agents. Conversion of the cathepsin-activated probe, 6QC-Cy5, into a two-fluorophore probe, 6QC-RATIO, significantly improved signal-to-background in vitro and in a mouse subcutaneous breast tumor model. Tumor detection sensitivity was further enhanced using a dual-substrate AND-gate ratiometric probe, Death-Cat-RATIO, that fluoresces only after orthogonal processing by multiple tumor-specific proteases. We also designed and built a modular camera system that was coupled to the FDA-approved da Vinci Xi robot, to enable real-time imaging of ratiometric signals at video frame rates compatible with surgical workflows. Our results demonstrate that ratiometric camera systems and imaging probes have the potential to be clinically implemented to improve surgical resection of many types of cancer.

Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows.

Macrocyclic peptides are attractive for chemoproteomic applications due to their modular synthesis and potential for high target selectivity. We describe a solid phase synthesis method for the efficient generation of libraries of small macrocycles that contain an electrophile and alkyne handle. The modular synthesis produces libraries that can be directly screened using simple SDS-PAGE readouts and then optimal lead molecules applied to proteomic analysis. We generated a library of 480 macrocyclic peptides containing the weakly reactive fluorosulfate (OSF) electrophile. Initial screening of a subset of the library containing each of the various diversity elements identified initial molecules of interest. The corresponding positional and confirmational isomers were then screened to select molecules that showed specific protein labeling patterns that were dependent on the probe structure. The most promising hits were applied to standard chemoproteomic workflows to identify protein targets. Our results demonstrate the feasibility of rapid, on-resin synthesis of diverse macrocyclic electrophiles to generate new classes of covalent ligands.

Pseudo-equivalent deterministic excitation method application for experimental reproduction of a structural response to a turbulent boundary layer excitation.

In the transportation engineering field, the turbulent boundary layer over a structure is one of the most relevant sources of structural vibration and emitted noise. Wind tunnels are still one of the best options for vibroacoustic experimental analyses for this specific problem. However, it is also true that this experimental method is not always affordable, due to several limitations-settings hard to control, time and money consumption, discrepancies among laboratories-that wind tunnel facilities present. It has already developed different methodologies to address this necessity, most of them based on the use of loudspeakers or shakers. In this work, an existing numerical method, called the pseudo-equivalent deterministic excitation method (PEDEM), is further developed for the experimental purpose of reproducing the experimental structural response of a panel subjected to a turbulent boundary layer (TBL) excitation, by using an equivalent rain-on-the-roof excitation instead; different formulations are used for the application of this approximated TBL excitation. The experimental application of PEDEM, here called X-PEDEM, is validated by comparison with experimental results of two different panels analysed in two different wind tunnel facilities.

Pilot study for low-cost model validation in laparoscopic pediatric pyeloplasty simulation. / Estudio piloto para la validación de un modelo de bajo coste en la simulación de la pieloplastia laparoscópica pediátrica.

OBJECTIVE: To describe the creation of an original 3D-printed liquid latex model designed for laparoscopic pyeloplasty (LP) simulation in infants, and to assess its usefulness. MATERIALS AND METHODS: A 3D model of a dilated pelvis and a ureter with ureteropelvic junction obstruction (UPJO) was designed. It was covered in liquid latex, which allowed flexible models to be achieved in order to conduct pyeloplasty in a pelvitrainer. The total price of each model was 6 euros. A nearly-experimental, non-randomized, blind study was carried out, while measuring operating times and OSATS (Objective Structured Assessment of Technical Skills) scores. Following simulation completion, a survey based on Likert scale was conducted to assess overall appearance, texture, usefulness, and probability of recommending the model for regular training. RESULTS: 8 pediatric surgeons spent a median of 71.5 minutes (range: 50-86), and rated the model with a median 20.1/30 (range: 17-24) OSATS score. The model received a 4.25 (range: 3-5) score in terms of overall appearance, a 4.37 (range: 3-5) score in terms of texture, a 4.5 (range: 4-5) score in terms of usefulness, and a 4.6 (range: 4-5) score in terms of probability of recommending the model for regular training. CONCLUSIONS: Our liquid latex model for laparoscopic pyeloplasty simulation is feasible, with favorable preliminary results. Its usefulness in laparoscopic pyeloplasty training is promising.

OBJETIVOS: Describir la creación de un modelo original de látex líquido diseñado para la simulación de la pieloplastia laparoscópica (PL) en lactantes, construido a partir de una impresión tridimensional (3D), y valorar su utilidad. MATERIAL Y METODOS: Se diseñó un modelo 3D de una pelvis dilatada y un uréter con estenosis pieloureteral (EPU), que fue recubierto por látex líquido obteniendo modelos flexibles para realizar la pieloplastia en un pelvitrainer. El precio total de cada modelo fue de 6 euros. Se realizó un estudio cuasiexperimental, ciego y no aleatorizado, midiendo el tiempo quirúrgico y la puntuación OSATS (Objective Structured Assessment of Technical Skills). Tras completar la simulación, se realizó una encuesta utilizando la escala de Likert, en la cual se valoró el aspecto general, la textura, la utilidad del modelo y el grado de recomendación en el entrenamiento habitual. RESULTADOS: 8 cirujanos pediátricos dedicaron una mediana de 71,5 minutos (R 50-86), y puntuaron una mediana de 20,1/30 (R 17-24) en la escala OSATS. El modelo obtuvo una valoración de 4,25 (R3-5) en aspecto general, 4,37 (R3-5) en textura, 4,5 (R 4-5) en utilidad y 4,6 (R 4-5) en recomendación para incorporar al entrenamiento habitual. CONCLUSIONES: El uso de nuestro modelo de látex líquido para la simulación de la pielopalstia laparoscópica es factible y los resultados preliminares han sido favorables. Su utilidad como herramienta en el entrenamiento de la pieloplastia laparoscópica es prometedora.

Estudio piloto para la validación de unmodelo de bajo coste en la simulación de la pieloplastia laparoscópica pediátrica / Pilot study for low-cost model validation in laparoscopic pediatric pyeloplasty simulation

Objetivos: Describir la creación de un modelo original de látex líquido diseñado para la simulación de la pieloplastia laparoscópica (PL) en lactantes, construido a partir de una impresión tridimensional (3D), y valorar su utilidad. Material y métodos: Se diseñó un modelo 3D de una pelvis dilataday un uréter con estenosis pieloureteral (EPU), que fue recubierto por látex líquido obteniendo modelos flexibles para realizar la pieloplastia en un pelvitrainer. El precio total de cada modelo fue de 6 euros. Se realizó un estudio cuasiexperimental, ciego y no aleatorizado, midiendo el tiempo quirúrgico y la puntuación OSATS (Objective Structured Assessment of Technical Skills). Tras completar la simulación, se realizó una encuesta utilizando la escala de Likert, en la cual se valoró el aspecto general, la textura, la utilidad del modelo y el grado de recomendación en el entrenamiento habitual. Resultados: Ocho cirujanos pediátricos dedicaron una mediana de71,5 minutos (R 50-86), y puntuaron una mediana de 20,1/30 (R 17-24)en la escala OSATS. El modelo obtuvo una valoración de 4,25 (R3-5) en aspecto general, 4,37 (R3-5) en textura, 4,5 (R 4-5) en utilidad y 4,6(R 4-5) en recomendación para incorporar al entrenamiento habitual. Conclusiones: El uso de nuestro modelo de látex líquido para lasimulación de la pielopalstia laparoscópica es factible y los resultados preliminares han sido favorables. Su utilidad como herramienta en el entrenamiento de la pieloplastia laparoscópica es prometedora.(AU)

Objective: To describe the creation of an original 3D-printed liquid latex model designed for laparoscopic pyeloplasty (LP) simulation in infants, and to assess its usefulness. Materials and methods: A 3D model of a dilated pelvis and a ureter with ureteropelvic junction obstruction (UPJO) was designed. It was covered in liquid latex, which allowed flexible models to be achieved in order to conduct pyeloplasty in a pelvitrainer. The total price of each model was 6 euros. A nearly-experimental, non-randomized, blind study was carried out, while measuring operating times and OSATS (Objective Structured Assessment of Technical Skills) scores. Following simulation completion, a survey based on Likert scale was conducted to assess overall appearance, texture, usefulness, and probability of recommending the model for regular training. Results.: 8 pediatric surgeons spent a median of 71.5 minutes (range: 50-86), and rated the model with a median 20.1/30 (range: 17-24) OSATS score. The model received a 4.25 (range: 3-5) score in terms of overall appearance, a 4.37 (range: 3-5) score in terms of texture, a 4.5 (range: 4-5) score in terms of usefulness, and a 4.6 (range: 4-5) score in terms of probability of recommending the model for regular training. Conclusions: Our liquid latex model for laparoscopic pyeloplasty simulation is feasible, with favorable preliminary results. Its usefulness in laparoscopic pyeloplasty training is promising.(AU)

The normal and fibrotic mouse lung classified by spatial proteomic analysis.

Single cell classification is elucidating homeostasis and pathology in tissues and whole organs. We applied in situ spatial proteomics by multiplex antibody staining to routinely processed mouse lung, healthy and during a fibrosis model. With a limited validated antibody panel (24) we classify the normal constituents (alveolar type I and II, bronchial epithelia, endothelial, muscular, stromal and hematopoietic cells) and by quantitative measurements, we show the progress of lung fibrosis over a 4 weeks course, the changing landscape and the cell-specific quantitative variation of a multidrug transporter. An early decline in AT2 alveolar cells and a progressive increase in stromal cells seems at the core of the fibrotic process.

Phenotypes of prediabetes and metabolic risk in Caucasian youths with overweight or obesity.

PURPOSE: To assess the prevalence of pre-diabetes phenotypes, i.e., impaired fasting glucose (IFG), impaired glucose tolerance (IGT), increased HbA1c (IA1c), and their association with metabolic profile and atherogenic lipid profile in youths with overweight/obesity (OW/OB). METHODS: This cross-sectional study analyzed data of 1549 youths (5-18 years) with OW/OB followed in nine Italian centers between 2016 and 2020. Fasting and post-load measurements of glucose, insulin, and HbA1c were available. Insulin resistance (IR) was estimated by HOMA-IR and insulin sensitivity (IS) by reciprocal of fasting insulin. The atherogenic lipid profile was assessed by triglycerides-to-HDL ratio or cholesterol-to-HDL ratio. Insulinogenic index was available in 939 youths, in whom the disposition index was calculated. RESULTS: The prevalence of overall pre-diabetes, IFG, IGT and IA1c was 27.6%, 10.2%, 8% and 16.3%, respectively. Analyzing each isolated phenotype, IGT exhibited two- to three-fold higher odds ratio of family history of diabetes, and worse metabolic and atherogenic lipid profile vs normoglycemic youths; IFG was associated only with IR, while IA1c showed a metabolic and atherogenic lipid profile intermediate between IGT and IFG. CONCLUSION: Prevalence of pre-diabetes was high and IA1c was the most prevalent phenotype in Italian youths with OW/OB. The IGT phenotype showed the worst metabolic and atherogenic lipid profile, followed by IA1c. More studies are needed to assess whether HbA1c may help improving the prediction of diabetes.

The fading popularity of a local ecological calendar from Brunei Darussalam, Borneo.

BACKGROUND: Local ecological calendars are ecocultural frameworks that link temporal and spatial scales, contributing to resilience and adaptive management of natural resources and landscapes. They also facilitate management, access and withdrawal of provisioning ecosystem services. In this article, we describe how the ecological calendar of the Kedayan people of Brunei Darussalam links skyscape and biodiversity with sociocultural aspirations to foster adaptive management of landscape, and provide an understanding of the transmission of calendric knowledge in the community. METHODS: In 2018, we collaborated with sixteen purposively sampled knowledge keepers from the Kedayan community of Brunei Darussalam to document the Kedayan local ecological calendar, and develop a calendrical pictogram. Using a structured questionnaire, we then interviewed 107 randomly selected community members, to understand the contemporary relevance and popularity of the Kedayan calendar, and the transmission of calendric knowledge in the community. RESULTS: Our findings reveal that very few respondents (n = 27, 25.3%) are aware of the existence of Kedayan ecological calendar; majority (n = 80, 74.7%) were not aware of its existence. There is no statistically significant correlation between consulting healers, knowledge on appropriate time requisite to consult healers, and awareness and self-professed knowledge of Kedayan calendar. Only 14 (13.1%) of the respondents reported to have received some form of calendric knowledge, while the majority (86.9%; n = 93) never received any calendric knowledge. Only a negligible 1.9% reported to have transmitted calendric knowledge to others indicating a breakdown in transmission of calendric knowledge. CONCLUSION: The calendric pictogram would help the community in revitalizing their calendar. However, the community will have to invest on enhancing transmission of calendric knowledge.

Ecocultural or Biocultural? Towards Appropriate Terminologies in Biocultural Diversity.

Biocultural diversity has made notable contributions that have furthered our understanding of the human culture-nature interrelationship. However, the usage of the term 'biocultural' is not unique to biocultural diversity. It was first used in biocultural studies within anthropology decades ahead of biocultural diversity. The existing literature on biocultural diversity does not acknowledge the prior existence of biocultural studies, or provide a clear demarcation between usages of the two terms. In this article, I discuss the varying contexts in usage of the term 'biocultural' between biocultural diversity and biocultural anthropology. While biocultural diversity deals with the linkages between biological, cultural, and linguistic diversity, biocultural studies in anthropology deal with the deterministic influence of physical and social environment on human biology and wellbeing. In biocultural studies, 'biocultural' refers to the integration of methodically collated cultural data with biological and environmental data. 'Bio' in biocultural anthropology therefore denotes biology, unlike biocultural diversity where it refers to biodiversity. Both biocultural studies and biocultural diversity apply 'biocultural' as descriptor to generate overlapping terminologies such as 'biocultural approach'. Such a confusing scenario is not in the interest of biocultural diversity, as it would impede theoretical advancements. I propose that advocates of biocultural diversity explore its harmonies with ecoculturalism and the possibilities of suitably adapting the term 'ecoculture' in lieu of 'bioculture'. Using 'ecocultural' instead of 'biocultural' as a descriptor to coin terminologies could solve confusions arising from the expanding usage of the term 'bioculture'.

Clinical outcomes of FOLFIRINOX and gemcitabine–nab paclitaxel for metastatic pancreatic cancer in the real world setting

Background/objectives The incidence of pancreatic cancer is increasing in developed countries. The incorporation of new therapies, to the first-line treatment of patients with good performance status led to better survival in clinical trials. However, there is a wide variability in their use and some concerns about the treatment of elderly patients who were not included in the clinical trials. Methods This is a retrospective multicenter study. Data from consecutive patients diagnosed with metastatic pancreatic cancer (mPC) treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) were analysed to evaluate efficacy (overall survival—OS) and toxicity. Results A total of 119 patients were included. 49.6% were treated with FFX and 50.4% with GNP in first-line. The median OS was 12 months with no statistically significant differences between both regimens (12.7 m for FFX vs 10.2 m for GnP). Elevated Ca 19.9 levels and neutrophil–lymphocyte ratio (NLR) increased the risk of death. Patients who received both regimens in first/second line had a median OS longer than 15 months whichever the sequence. 32 patients (27%) were older than 70-y. 54% patients received a second-line treatment, 56% in the FFX group and 44% in the GnP group. The median OS for patients older than 70 was 9.5 m versus 12.3 m for patients younger than 70. Progression of the disease was the cause of death in 67.6% of the patients. Conclusions In our setting, the use of FFX and GnP for treating mPC is quite similar, but superiority could not be demonstrated for any of the schemes in the first line. OS was determined by basal levels of Ca 19.9 and NLR. Patients receiving both regimens in first/second line whichever the sequence, exhibited the best survival rates. In our series, elderly patients had poorer survival rates (AU)

The pathological growth of the prostate gland in atherogenic contexts.

The human prostate is an androgen-dependent gland where an imbalance in cell proliferation can lead to benign prostatic hyperplasia (BPH), which results in voiding lower urinary tract symptoms in the elderly. In the last decades, novel evidence has suggested that BPH might represent an element into the wide spectrum of disorders conforming the Metabolic Syndrome (MS). The dyslipidemic state and the other atherogenic factors of the MS have been shown to induce, maintain and/or aggravate the pathological growth of different organs, with data regarding the prostate being still limited. We here review the available epidemiological and experimental studies about the association of BPH with dyslipidemias. In particular, we have focused on Oxidized Low-Density Lipoproteins (OxLDL) as a potential trigger for vascular disease and cellular proliferation in atherogenic contexts, analyzing their putative molecular mechanisms, including the induction of specific extracellular vesicles (EVs)-derived miRNAs. In addition to the epidemiological evidence, OxLDL is proposed to play a fundamental role in the upregulation of prostatic cell proliferation by activating the Rho/Akt/p27Kip1 pathway in atherogenic contexts. miR-21, miR-141, miR-143, miR-145, miR-155, and miR-221 would be involved in the transcription of genes related to the proliferative process. Although much remains to be investigated regarding the impact of OxLDL, its receptors, and molecular mechanisms on the prostate, it is clear that EVs and miRNAs represent a promising target for proliferative pathologies of the prostate gland.

Clinical outcomes of FOLFIRINOX and gemcitabine-nab paclitaxel for metastatic pancreatic cancer in the real world setting.

BACKGROUND/OBJECTIVES: The incidence of pancreatic cancer is increasing in developed countries. The incorporation of new therapies, to the first-line treatment of patients with good performance status led to better survival in clinical trials. However, there is a wide variability in their use and some concerns about the treatment of elderly patients who were not included in the clinical trials. METHODS: This is a retrospective multicenter study. Data from consecutive patients diagnosed with metastatic pancreatic cancer (mPC) treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) were analysed to evaluate efficacy (overall survival-OS) and toxicity. RESULTS: A total of 119 patients were included. 49.6% were treated with FFX and 50.4% with GNP in first-line. The median OS was 12 months with no statistically significant differences between both regimens (12.7 m for FFX vs 10.2 m for GnP). Elevated Ca 19.9 levels and neutrophil-lymphocyte ratio (NLR) increased the risk of death. Patients who received both regimens in first/second line had a median OS longer than 15 months whichever the sequence. 32 patients (27%) were older than 70-y. 54% patients received a second-line treatment, 56% in the FFX group and 44% in the GnP group. The median OS for patients older than 70 was 9.5 m versus 12.3 m for patients younger than 70. Progression of the disease was the cause of death in 67.6% of the patients. CONCLUSIONS: In our setting, the use of FFX and GnP for treating mPC is quite similar, but superiority could not be demonstrated for any of the schemes in the first line. OS was determined by basal levels of Ca 19.9 and NLR. Patients receiving both regimens in first/second line whichever the sequence, exhibited the best survival rates. In our series, elderly patients had poorer survival rates.

Heterologous microsatellite primers are informative for paca (Cuniculus paca), a large rodent with economic and ecological importance.

OBJECTIVE: This study was designed to facilitate genetic studies that would allow information on population structure and genetic diversity of natural or captive stocks of paca (Cuniculus paca), a species of ecological and socioeconomic importance, by testing cross-amplification of 20 heterologous microsatellite primer pairs developed for guinea pigs (Cavia porcellus) and capybara (Hydrochoerus hydrochaeris). RESULTS: Those primers that showed the best amplification profile in blood samples were subsequently applied to scats and saliva samples, to evaluate their efficiency. Of the 13 microsatellite pairs that amplified in blood, one-third (32%) were successfully amplified in saliva and scat samples. This initial work demonstrates successful cross-amplification in paca providing a solid and promising foundation for future genetic studies with this species. The ability to quantify genetic diversity using noninvasive samples from free-ranging paca is essential to developing applied management strategies for this large neotropical rodent that is not only a prey favored by wide-ranging carnivores [e.g., jaguar (Panthera onca), puma (Puma concolor)], but is also a species targeted by illegal hunting and wildlife trade.

BriXS, a new X-ray inverse Compton source for medical applications.

MariX is a research infrastructure conceived for multi-disciplinary studies, based on a cutting-edge system of combined electron accelerators at the forefront of the world-wide scenario of X-ray sources. The generation of X-rays over a large photon energy range will be enabled by two unique X-ray sources: a Free Electron Laser and an inverse Compton source, called BriXS (Bright compact X-ray Source). The X-ray beam provided by BriXS is expected to have an average energy tunable in the range 20-180 keV and intensities between 1011 and 1013 photon/s within a relative bandwidth ΔE/E=1-10%. These characteristics, together with a very small source size (~20 µm) and a good transverse coherence, will enable a wide range of applications in the bio-medical field. An additional unique feature of BriXS will be the possibility to make a quick switch of the X-ray energy between two values for dual-energy and K-edge subtraction imaging. In this paper, the expected characteristics of BriXS will be presented, with a particular focus on the features of interest to its possible medical applications.

What Differentiates Poor- and Good-Outcome Psychotherapy? A Statistical-Mechanics-Inspired Approach to Psychotherapy Research, Part Two: Network Analyses.

Statistical mechanics is the field of physics focusing on the prediction of the behavior of a given system by means of statistical properties of ensembles of its microscopic elements. The authors examined the possibility of applying such an approach to psychotherapy research with the aim of investigating (a) the possibility of predicting good and poor outcomes of psychotherapy on the sole basis of the correlation pattern among their descriptors and (b) the analogies and differences between the processes of good- and poor-outcome cases. This work extends the results reported in a previous paper and is based on higher-order statistics stemming from a complex network approach. Four good-outcome and four poor-outcome brief psychotherapies were recorded, and transcripts of the sessions were coded according to Mergenthaler's Therapeutic Cycle Model (TCM), i.e., in terms of abstract language, positive emotional language, and negative emotional language. The relative frequencies of the three vocabularies in each word-block of 150 words were investigated and compared in order to understand similarities and peculiarities between poor-outcome and good-outcome cases. Network analyses were performed by means of a cluster analysis over the sequence of TCM categories. The network analyses revealed that the linguistic patterns of the four good-outcome and four poor-outcome cases were grounded on a very similar dynamic process substantially dependent on the relative frequency of the states in which the transition started and ended ("random-walk-like behavior", adjusted R 2 = 0.729, p < 0.001). Furthermore, the psychotherapy processes revealed statistically significant changes in the relative occurrence of visited states between the beginning and the end of therapy, thus pointing to the non-stationarity of the analyzed processes. The present study showed not only how to quantitatively describe psychotherapy as a network, but also found out the main principles on which its evolution is based. The mind, from a linguistic perspective, seems to work-through psychotherapy sessions by passing from the most adjacent states and the most occurring ones. This finding can represent a fertile ground to rethink pivotal clinical concepts such as the timing of an interpretation or a comment, the clinical issue to address within a given session, and the general task of a psychotherapist: from someone who delivers a given technique toward a consultant promoting the flexibility of the clinical field and, thus, of the patient's mind.

GEANT4 Monte Carlo simulations for virtual clinical trials in breast X-ray imaging: Proof of concept.

Virtual clinical trials (VCT) are in-silico reproductions of medical examinations, which adopt digital models of patients and simulated devices. They are intended to produce clinically equivalent outcome data avoiding long execution times, ethical issues related to radiation induced risks and huge costs related to real clinical trials with a patient population. In this work, we present a platform for VCT in 2D and 3D X-ray breast imaging. The VCT platform uses Monte Carlo simulations based on the Geant4 toolkit and patient breast models derived from a cohort of high resolution dedicated breast CT (BCT) volume data sets. Projection images of the breast and three-dimensional glandular dose maps are generated for a given breast model, by simulating both 2D full-field digital mammography (DM) and 3D BCT examinations. Uncompressed voxelized breast models were derived from segmented patient images. Compressed versions of the digital breast phantoms for DM were generated using a previously published digital compression algorithm. The Monte Carlo simulation framework has the capability of generating and tracking ~105 photons/s using a server equipped with 16-cores and 3.0 GHz clock speed. The VCT platform will provide a framework for scanner design optimization, comparison between different scanner designs and between different modalities or protocols on computational breast models, without the need for scanning actual patients as in conventional clinical trials.