A quantitative systems pharmacology workflow toward optimal design and biomarker stratification of atopic dermatitis clinical trials.

Background: The development of atopic dermatitis (AD) drugs is challenged by many disease phenotypes and trial design options, which are hard to explore experimentally.

Objective: We aimed to optimize AD trial design using simulations.

Methods: We constructed a quantitative systems pharmacology model of AD and standard of care (SoC) treatments and generated a phenotypically diverse virtual population whose parameter distribution was derived from known relationships between AD biomarkers and disease severity and calibrated using disease severity evolution under SoC regimens.

In Silico Clinical Trials: Is It Possible?

Modeling and simulation (M&S), including in silico (clinical) trials, helps accelerate drug research and development and reduce costs and have coined the term "model-informed drug development (MIDD)." Data-driven, inferential approaches are now becoming increasingly complemented by emerging complex physiologically and knowledge-based disease (and drug) models, but differ in setup, bottlenecks, data requirements, and applications (also reminiscent of the different scientific communities they arose from). At the same time, and within the MIDD landscape, regulators and drug developers start to embrace in silico trials as a potential tool to refine, reduce, and ultimately replace clinical trials.

Loss of ATG4B and ATG4A results in two-stage cell cycle defects in pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) exhibits elevated levels of autophagy, which promote tumor progression and treatment resistance. ATG4B is an autophagy-related cysteine protease under consideration as a potential therapeutic target, but it is largely unexplored in PDAC. Here, we investigated the clinical and functional relevance of ATG4B expression in PDAC.

Modeling the disruption of respiratory disease clinical trials by non-pharmaceutical COVID-19 interventions.

Respiratory disease trials are profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19 because they perturb existing regular patterns of all seasonal viral epidemics. To address trial design with such uncertainty, we developed an epidemiological model of respiratory tract infection (RTI) coupled to a mechanistic description of viral RTI episodes. We explored the impact of reduced viral transmission (mimicking NPIs) using a virtual population and in silico trials for the bacterial lysate OM-85 as prophylaxis for RTI.

Chloroquine treatment induces secretion of autophagy-related proteins and inclusion of Atg8-family proteins in distinct extracellular vesicle populations.

Chloroquine (CQ), a lysosomotropic agent, is commonly used to inhibit lysosomal degradation and macroautophagy/autophagy. Here we investigated the cell-extrinsic effects of CQ on secretion. We showed that lysosomal and autophagy inhibition by CQ altered the secretome, and induced the release of Atg8 orthologs and autophagy receptors.

In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy.

Hemophilia is a hereditary disease that remains incurable. Although innovative treatments such as gene therapy or bispecific antibody therapy have been introduced, substantial unmet needs still exist with respect to achieving long-lasting therapeutic effects and treatment options for inhibitor patients. Antithrombin (AT), an endogenous negative regulator of thrombin generation, is a potent genome editing target for sustainable treatment of patients with hemophilia A and B.

deletion is a frequent event in gastric/gastroesophageal junction/esophageal cancer: a cross-sectional analysis of gene status and signal distribution in 1,580 patients.

Background: gene aberrations are found in several human cancers including gastric, ovarian and lung. In a large multinational cohort of patients with gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma we assessed the MET status with respect to amplification and deletion and correlate the results with the phenotypical gene signal distribution pattern.

Methods: Tissue specimens from 1,580 patients were analyzed using a novel fluorescence in situ hybridization (FISH) assay employing a /CEN-7 IQFISH Probe Mix.

Snake cube puzzle and protein folding.

The snake cube puzzle made of a linear array of 27 cubes and its modified and extended versions are used as theoretical models to study the mechanism of folding of proteins into their sequence-specific native three-dimensional structures. Each of the three versions is characterized by the respective set of characteristics attributed to each of its constituent cubes and an array is characterized by its specific sequence of the cube characteristics. The aim of the puzzles is to fold the cube array into a compact 3×3×3 cubic structure.

Validity of the dietary reference intakes for determining energy requirements in older adults.

Background/objectives: The objectives of this study were to evaluate the accuracy of the Dietary Reference Intakes (DRI) for estimating the energy requirements of older adults, and to develop and validate new equations for predicting the energy requirements of this population group.

Materials/methods: The study subjects were 25 men and 23 women with a mean age of 72.2 ± 3.

How to prevent viremia rebound? Evidence from a PRRSv data-supported model of immune response.

Background: Understanding what determines the between-host variability in infection dynamics is a key issue to better control the infection spread. In particular, pathogen clearance is desirable over rebounds for the health of the infected individual and its contact group. In this context, the Porcine Respiratory and Reproductive Syndrome virus (PRRSv) is of particular interest.

A Multicenter Phase II Study of AMG 337 in Patients with -Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other -Amplified Solid Tumors.

Purpose: gene amplification is associated with poor prognosis in gastric/gastroesophageal junction/esophageal (G/GEJ/E) cancers. We determined antitumor activity, safety, and pharmacokinetics of the small-molecule MET inhibitor AMG 337 in -amplified G/GEJ/E adenocarcinoma or other solid tumors. In this phase II, single-arm study, adults with -amplified G/GEJ/E adenocarcinoma (cohort 1) or other -amplified solid tumors (cohort 2) received AMG 337 300 mg/day orally in 28-day cycles.

A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B.

The cysteine protease ATG4B is a key component of the autophagy machinery, acting to proteolytically prime and recycle its substrate MAP1LC3B. The roles of ATG4B in cancer and other diseases appear to be context dependent but are still not well understood. To help further explore ATG4B functions and potential therapeutic applications, we employed a chemical biology approach to identify ATG4B inhibitors.

Dopamine-grafted heparin as an additive to the commercialized carboxymethyl cellulose/styrene-butadiene rubber binder for practical use of SiO/graphite composite anode.

Graphite is used commercially as the active material in lithium ion batteries, frequently as part of a graphite/SiO composite. Graphite is used in conjunction with SiO to overcome the limited energy density of graphite, and to lessen the adverse effects of volume expansion of Si. However, electrodes based on graphite/SiO composites can be made with only 3-5 wt % SiO because of the increased failure of electrodes with higher SiO contents.

Cochlear Mechanisms and Otoacoustic Emission Test Performance.

Objectives: This study aims to determine the impact of controlling cochlear-source mechanism on the accuracy with which auditory status is identified using otoacoustic emissions (OAEs) in two groups of subjects with normal hearing (NH) and subjects with mild to moderate hearing loss.

Design: Data were collected from 212 subjects with NH and with mild to moderate hearing loss who fell into two categories based on a distortion product OAE (DPOAE) screening protocol: the uncertain-identification group (where errors were likely) and the certain-identification group (where errors were unlikely). DPOAE fine-structure patterns were recorded at intervals surrounding f2 = 1, 2 and 4 kHz (f2/f1 ratio = 1.

Why, when and how should exposure be considered at the within-host scale? A modelling contribution to PRRSv infection.

Understanding the impact of pathogen exposure on the within-host dynamics and its outcome in terms of infectiousness is a key issue to better understand and control the infection spread. Most experimental and modelling studies tackling this issue looked at the impact of the exposure dose on the infection probability and pathogen load, very few on the within-host immune response. Our aim was to explore the impact on the within-host response not only of the exposure dose, but also of its duration and peak, for contrasted virulence levels.

Male breast cancer: diagnosis stages, treatment and survival in a country with limited resources (Burkina Faso).

Background: Male breast cancer is a rare and less known disease. Therapeutic modalities affect survival. In Burkina Faso, male breast cancers are diagnosed in everyday practice, but the prognosis at short-, middle-, and long-term remains unknown.

Detection of amplification in gastroesophageal tumor specimens using IQFISH.

Background: The gene mesenchymal epithelial transition factor () is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. is found to be amplified in several human cancers including gastroesophageal cancer.

Methods: Here we report the amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, /CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay].

Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy.

The 2 main degradative pathways that contribute to proteostasis are the ubiquitin-proteasome system and autophagy but how they are molecularly coordinated is not well understood. Here, we demonstrate an essential role for an effector caspase in the activation of compensatory autophagy when proteasomal activity is compromised. Functional loss of Hsp83, the Drosophila ortholog of human HSP90 (heat shock protein 90), resulted in reduced proteasomal activity and elevated levels of the effector caspase Dcp-1.

A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors.

AMG 337, a selective small-molecule MET inhibitor, was evaluated in Asian patients with advanced solid tumors. Eligible patients orally self-administered AMG 337; the initial dose of 150 mg once daily (QD) was escalated to 300 mg QD (modified 3+3+3 design). Treatment continued until disease progression, intolerability, or death.

Identification of breast cancer cell subtypes sensitive to ATG4B inhibition.

Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target.

Torsion of an accessory spleen: a rare case preoperatively diagnosed and cured by single-port surgery.

We report a very rare case of acute abdomen caused by torsion of an accessory spleen that was preoperatively diagnosed and cured by single-port surgery. A 31-year-old woman was admitted to our hospital with severe left abdominal pain. Physical examination revealed a left upper quadrant abdominal tenderness with voluntary guarding.

Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis.

Epithelial ovarian cancer (EOC) invasion and metastasis are complex phenomena that result from the coordinated action of many metastatic regulators and must be overcome to improve clinical outcomes for patients with these cancers. The identification of novel therapeutic targets is critical because of the limited success of current treatment regimens, particularly in advanced-stage ovarian cancers. In this study, we found that tetraspanin 8 (TSPAN8) is overexpressed in about 52% (14/27) of EOC tissues and correlates with poor survival.

Generation of a human antibody that inhibits TSPAN8-mediated invasion of metastatic colorectal cancer cells.

Tetraspanin 8 (TSPAN8) is a tumor-associated antigen implicated in tumor progression and metastasis. However, the validation of TSPAN8 as a potential therapeutic target in metastatic colorectal cancer (mCRC) has not yet been studied. In this study, through several in vitro methodologies, we identified a large extracellular loop of TSPAN8 (TSPAN8-LEL) as a key domain for regulating mCRC invasion.