Accelerating the Development and Transfer of Freeze-Drying Operations for the Manufacturing of Biopharmaceuticals by Model-Based Design of Experiments

In the pharmaceutical industry, freeze-drying (also known as lyophilization) is often used to increase the shelf life of heat-sensitive biopharmaceuticals such as protein-based therapeutic drugs an..

Primary Drying Optimization in Pharmaceutical Freeze-Drying: A Multivial Stochastic Modeling Framework

Primary drying is the most time-consuming and energy-intensive step in pharmaceutical freeze-drying. Minimizing the duration of this stage is of paramount importance to speed up process development..

Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer

Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP\u27s TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity in human PDAC cells (MIA PaCa-2), co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner. TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs

GLP-1 Receptor Agonists and Coronary Arteries: From Mechanisms to Events.

Objective: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) lower plasma glucose through effects on insulin and glucagon secretion and by decelerating gastric emptying. GLP-1 RAs have many beneficial effects beyond glycemic control, including a protective role on the cardiovascular system. However, underlying mechanisms linking GLP-1 RAs with coronary artery disease are complex and not fully elucidated. In this mini-review, we discuss these mechanisms and subsequent clinical events. Data Sources: We searched PubMed and Google Scholar for evidence on GLP-1 RAs and coronary events. We did not apply restrictions on article type. We reviewed publications for clinical relevance. Synopsis of Content: In the first part, we review the current evidence concerning the role of GLP-1 RAs on potential mechanisms underlying the development of coronary events. Specifically, we discuss the role of GLP-1 RAs on atherosclerosis and vasospasms of epicardial coronary arteries, as well as structural/functional changes of coronary microvasculature. In the second part, we summarize the clinical evidence on the impact of GLP-1 RAs in the prevention of acute and chronic coronary syndromes and coronary revascularization. We conclude by discussing existing gaps in the literature and proposing directions for future research

Coarse-grained simulation of transmembrane peptides in the gel phase

We use Dissipative Particle Dynamics simulations, combined with parallel tempering and umbrella sampling, to investigate the potential of mean force between model transmembrane peptides in the various phases of a lipid bilayer, including the low-temperature gel phase. The observed oscillations in the effective interaction between peptides are consistent with the different structures of the surrounding lipid phases

Culture-dependent and sequencing methods revealed the absence of a bacterial community residing in the urine of healthy cats

A growing number of studies suggest that the lower urinary tract of humans and dogs can harbor a urinary microbiota. Nevertheless, a certain concern has developed that the microbiota reported could be due to unaccounted contamination, especially in low-biomass samples. The aim of this study was to investigate the bacterial community which populates the urine of healthy cats using two approaches: a culture-dependent approach which consisted of the expanded quantitative urine culture (EQUC) techniques capable of identifying live bacteria not growing in standard urine cultures, and a culture-independent approach which consisted of 16S ribosomal RNA next generation sequencing (16S rRNA NGS) capable of identifying bacterial DNA and exploring microbial diversity with high resolution. To avoid confounding factors of possible bacterial contamination, the urine was sampled using ultrasound-guided cystocentesis, and several sample controls and negative controls were analyzed. The urine sampled from the 10 cats included in the study showed no bacterial growth in the EQUC procedure. Although several reads were successfully originated using 16S rRNA NGS, a comparable pattern was observed between urine samples and the negative control, and no taxa were statistically accepted as non-contaminant. Taken together, the results obtained allowed stating that no viable bacteria were present in the urine of healthy cats without lower urinary tract disease and urinary tract infections, and that the bacterial DNA detected was of contaminant origin

FetReg: Placental Vessel Segmentation and Registration in Fetoscopy Challenge Dataset

Fetoscopy laser photocoagulation is a widely used procedure for the treatment of Twin-to-Twin Transfusion Syndrome (TTTS), that occur in mono-chorionic multiple pregnancies due to placental vascular anastomoses. This procedure is particularly challenging due to limited field of view, poor manoeuvrability of the fetoscope, poor visibility due to fluid turbidity, variability in light source, and unusual position of the placenta. This may lead to increased procedural time and incomplete ablation, resulting in persistent TTTS. Computer-assisted intervention may help overcome these challenges by expanding the fetoscopic field of view through video mosaicking and providing better visualization of the vessel network. However, the research and development in this domain remain limited due to unavailability of high-quality data to encode the intra- and inter-procedure variability. Through the \textit{Fetoscopic Placental Vessel Segmentation and Registration (FetReg)} challenge, we present a large-scale multi-centre dataset for the development of generalized and robust semantic segmentation and video mosaicking algorithms for the fetal environment with a focus on creating drift-free mosaics from long duration fetoscopy videos. In this paper, we provide an overview of the FetReg dataset, challenge tasks, evaluation metrics and baseline methods for both segmentation and registration. Baseline methods results on the FetReg dataset shows that our dataset poses interesting challenges, offering large opportunity for the creation of novel methods and models through a community effort initiative guided by the FetReg challenge

FetReg: Placental Vessel Segmentation and Registration in Fetoscopy Challenge Dataset

Fetoscopy laser photocoagulation is a widely used procedure for the treatment of Twin-to-Twin Transfusion Syndrome (TTTS), that occur in mono-chorionic multiple pregnancies due to placental vascular anastomoses. This procedure is particularly challenging due to limited field of view, poor manoeuvrability of the fetoscope, poor visibility due to fluid turbidity, variability in light source, and unusual position of the placenta. This may lead to increased procedural time and incomplete ablation, resulting in persistent TTTS. Computer-assisted intervention may help overcome these challenges by expanding the fetoscopic field of view through video mosaicking and providing better visualization of the vessel network. However, the research and development in this domain remain limited due to unavailability of high-quality data to encode the intra- and inter-procedure variability. Through the \textit{Fetoscopic Placental Vessel Segmentation and Registration (FetReg)} challenge, we present a large-scale multi-centre dataset for the development of generalized and robust semantic segmentation and video mosaicking algorithms for the fetal environment with a focus on creating drift-free mosaics from long duration fetoscopy videos. In this paper, we provide an overview of the FetReg dataset, challenge tasks, evaluation metrics and baseline methods for both segmentation and registration. Baseline methods results on the FetReg dataset shows that our dataset poses interesting challenges, offering large opportunity for the creation of novel methods and models through a community effort initiative guided by the FetReg challenge

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

BACKGROUND Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. METHODS We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. RESULTS Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (β = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (β = -0.37; 95%CI = -0.39, -0.35), hepcidin (β = -0.22, 95%CI = -0.24, -0.20), and TSAT (β = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (β = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (β = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (β = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. CONCLUSION Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways