Generating a Murine PTEN Null Cell Line to Discover the Key Role of p110β-PAK1 in Castration-Resistant Prostate Cancer Invasion.

Unlabelled: Although androgen deprivation treatment often effectively decreases prostate cancer, incurable metastatic castration-resistant prostate cancer (CRPC) eventually occurs. It is important to understand how CRPC metastasis progresses, which is not clearly defined. The loss of PTEN, a phosphatase to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate in the PI3K pathway, occurs in up to 70% to 80% of CRPC.

Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance.

Unlabelled: For a majority of patients with non-small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi.

Contribution and clinical relevance of germline variation to the cancer transcriptome.

Background: Somatic alterations in the cancer genome, some of which are associated with changes in gene expression, have been characterized in multiple studies across diverse cancer types. However, less is known about germline variants that influence tumor biology by shaping the cancer transcriptome.

Methods: We performed expression quantitative trait loci (eQTL) analyses using multi-dimensional data from The Cancer Genome Atlas to explore the role of germline variation in mediating the cancer transcriptome.

Intercostal Lung Hernia Following Deep Inferior Epigastric Perforator Reconstruction.

Acquired lung hernias typically result from trauma or intra-thoracic surgery is defined as the protrusion of lung parenchyma beyond the anatomic boundaries of the thoracic wall. A 40-year-old woman underwent deep inferior epigastric perforator (DIEP) breast reconstruction following her mastectomies. Post-operatively, she returned to the emergency department with severe chest pain, shortness of breath, and localized chest swelling.

Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant.

Background: The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and immediately classified as a variant of concern (VOC), since it shows substantially more mutations in the spike protein than any previous variant, especially in the receptor-binding domain (RBD). We analyzed the binding of the Omicron RBD to the human angiotensin-converting enzyme-2 receptor (ACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta, or Delta RBD variants.

Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer.

Unlabelled: A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression.

A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations.

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC in a plaque-based live SARS-CoV-2 neutralization assay.

Baculovirus-free insect cell expression system for high yield antibody and antigen production.

Antibodies are essential tools for therapy and diagnostics. Yet, production remains expensive as it is mostly done in mammalian expression systems. As most therapeutic IgG require mammalian glycosylation to interact with the human immune system, other expression systems are rarely used for production.

FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability.

Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. While cortical hyperexcitability is a hallmark of FXS, the reported phenotypes and underlying mechanisms, including alterations in synaptic transmission and ion channel properties, are heterogeneous and at times contradictory.

A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts.

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative.

GMP-grade CD34 selection from HLA-homozygous licensed cord blood units and short-term expansion under European ATMP regulations.

Background: Based on a synergistic consortium, the cord blood (CB) bank Düsseldorf was responsible for the selection of HLA-homozygous (HLA-h) donors, contacting/re-consenting the mothers, Good Manufacturing Practice (GMP)-grade CD34 enrichment, followed by short-term expansion of CD34 cells and qualification of the resulting CD34 population as advanced therapy medicinal product (ATMP)-starting material. Among 20 639 licensed Düsseldorf cord blood units (CBUs), 139 potential HLA-h donors were identified with the most frequent 10 German haplotypes. 100% of the donors were contacted, and for 47·5%, consent was obtained.

Fat-Phobic and Non-Fat-Phobic Anorexia Nervosa: A Conjoint Analysis on the Importance of Shape and Weight.

With the introduction of new diagnostic criteria in DSM-5, fear of weight gain no longer represents a sine qua non-criterion for the diagnosis of anorexia nervosa (AN). This is of relevance as a subgroup of individuals with AN denies fear of weight gain as the reason for restrictive eating but still remain at a very low weight. As self-reports are susceptible to bias, other methods are needed to confirm the existence of the subtype in order to provide adapted treatment.

Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery.

There is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice.

Testing the specificity of interpretation biases in women with eating disorder symptoms: An online experimental assessment.

Objective: Cognitive biases, such as memory, attention, and interpretation bias, are thought to play a central role in the development and maintenance of eating disorders (EDs). The aim of the present study was to investigate whether the interpretation bias is ED-specific or can be generalized to comorbid disorder-related threats in women with high levels of ED symptoms.

Method: In an online study, we measured interpretation bias using the modified Sentence Word Association Paradigm (SWAP), comparing women with (n = 39) and without (sub)threshold eating disorders (n = 56).

Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer.

Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs.

UV-Vis Photodissociation Action Spectroscopy on Thermo LTQ-XL ETD and Bruker amaZon Ion Trap Mass Spectrometers: a Practical Guide.

We report automated procedures for multiple tandem mass spectra acquisition allowing UV-Vis photodissociation action spectroscopy measurements of ions and radicals. The procedures were developed for two commercial ion trap mass spectrometers and applied to collision-induced and electron-transfer dissociation tandem mass spectrometry modes of ion generation.

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers.

Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss.

Interferons (IFNs) are cytokines that play a critical role in limiting infectious and malignant diseases . Emerging data suggest that the strength and duration of IFN signaling can differentially impact cancer therapies, including immune checkpoint blockade . Here, we characterize the output of IFN signaling, specifically IFN-stimulated gene (ISG) signatures, in primary tumors from The Cancer Genome Atlas.

Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study.

Background: The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world.

Objective: To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice.

Methods: Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed.

Hydrogen-Rich Cation Radicals of DNA Dinucleotides: Generation and Structure Elucidation by UV-Vis Action Spectroscopy.

Hydrogen-rich DNA dinucleotide cation radicals (dGG + 2H), (dCG + 2H), and (dGC + 2H) represent transient species comprising protonated and hydrogen atom adducted nucleobase rings that serve as models for proton and radical migrations in ionized DNA. These DNA cation radicals were generated in the gas phase by electron-transfer dissociation of dinucleotide dication-crown-ether complexes and characterized by UV-vis photodissociation action spectra, ab initio calculations of structures and relative energies, and time-dependent density functional theory calculations of UV-vis absorption spectra. Theoretical calculations indicate that (dGG + 2H) cation radicals formed by electron transfer underwent an exothermic conformational collapse that was accompanied by guanine ring stacking and facile internucleobase hydrogen atom transfer, forming 3'-guanine C-8-H radicals.

Correction of copy number induced false positives in CRISPR screens.

Cell autonomous cancer dependencies are now routinely identified using CRISPR loss-of-function viability screens. However, a bias exists that makes it difficult to assess the true essentiality of genes located in amplicons, since the entire amplified region can exhibit lethal scores. These false-positive hits can either be discarded from further analysis, which in cancer models can represent a significant number of hits, or methods can be developed to rescue the true-positives within amplified regions.

Fingolimod's Impact on MRI Brain Volume Measures in Multiple Sclerosis: Results from MS-MRIUS.

Background And Purpose: Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD).

Methods: MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months.

No evidence of disease activity in patients receiving fingolimod at private or academic centers in clinical practice: a retrospective analysis of the multiple sclerosis, clinical, and magnetic resonance imaging outcomes in the USA (MS-MRIUS) study.

Objective: The impact of multiple sclerosis (MS) center type on outcomes has not been investigated. This study aimed to evaluate baseline characteristics and clinical and magnetic resonance imaging (MRI) outcomes in patients with MS receiving fingolimod over 16 months' follow-up at private or academic centers in the USA.

Methods: Clinical and MRI data collected in clinical practice from patients initiating fingolimod were stratified by center type and retrospectively analyzed.