Organoid-based precision medicine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the leading causes of cancer-related deaths worldwide. Despite advances in precision oncology in other malignancies, treatment of PDAC still largely relies on conventional chemotherapy. Given the dismal prognosis and heterogeneity in PDAC, there is an urgent need for personalized therapeutic strategies to improve treatment response.

MADDD-seq, a novel massively parallel sequencing tool for simultaneous detection of DNA damage and mutations.

Our genome is exposed to a wide variety of DNA-damaging agents. If left unrepaired, this damage can be converted into mutations that promote carcinogenesis or the development of genetically inherited diseases. As a result, researchers and clinicians require tools that can detect DNA damage and mutations with exceptional sensitivity.

Effects of the glyphosate-based herbicide roundup on C. elegans and S. cerevisiae mortality, reproduction, and transcription fidelity.

Glyphosate-based weed killers such as Roundup have been implicated in detrimental effects on single- and multicellular eukaryotic model organism health and longevity. However, the mode(s) of action for these effects are currently unknown. In this study, we investigate the impact of exposure to Roundup on two model organisms: Saccharomyces cerevisiae and Caenorhabditis elegans and test the hypothesis that exposure to Roundup decreases transcription fidelity.

Identification of RBM46 as a novel APOBEC1 cofactor for C-to-U RNA-editing activity.

Cytidine (C) to Uridine (U) RNA editing is a post-transcription modification that is involved in diverse biological processes. APOBEC1 (A1) catalyzes the conversion of C-to-U in RNA, which is important in regulating cholesterol metabolism through its editing activity on ApoB mRNA. However, A1 requires a cofactor to form an "editosome" for RNA editing activity.

Genetics, Genomics, and Evolution.

The ciliate genus served as one of the first model systems in microbial eukaryotic genetics, contributing much to the early understanding of phenomena as diverse as genome rearrangement, cryptic speciation, cytoplasmic inheritance, and endosymbiosis, as well as more recently to the evolution of mating types, introns, and roles of small RNAs in DNA processing. Substantial progress has recently been made in the area of comparative and population genomics. species combine some of the lowest known mutation rates with some of the largest known effective populations, along with likely very high recombination rates, thereby harboring a population-genetic environment that promotes an exceptionally efficient capacity for selection.

RBPJ Deficiency Sensitizes Pancreatic Acinar Cells to KRAS-Mediated Pancreatic Intraepithelial Neoplasia Initiation.

Background And Aims: Development of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary.

Modeling Recombination Rate as a Quantitative Trait Reveals New Insight into Selection in Humans.

Meiotic recombination is both a fundamental biological process required for proper chromosomal segregation during meiosis and an important genomic parameter that shapes major features of the genomic landscape. However, despite the central importance of this phenotype, we lack a clear understanding of the selective pressures that shape its variation in natural populations, including humans. While there is strong evidence of fitness costs of low rates of recombination, the possible fitness costs of high rates of recombination are less defined.

Dynamics of Gene Loss following Ancient Whole-Genome Duplication in the Cryptic Paramecium Complex.

Whole-genome duplications (WGDs) have shaped the gene repertoire of many eukaryotic lineages. The redundancy created by WGDs typically results in a phase of massive gene loss. However, some WGD-derived paralogs are maintained over long evolutionary periods, and the relative contributions of different selective pressures to their maintenance are still debated.

TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration.

Background: The reactivation of genetic programs from early development is a common mechanism for injury-induced organ regeneration. T-box 3 (TBX3) is a member of the T-box family of transcription factors previously shown to regulate pluripotency and subsequent lineage commitment in a number of tissues, including limb and lung. TBX3 is also involved in lung and heart organogenesis.

Evolutionary conservation of the fidelity of transcription.

Accurate transcription is required for the faithful expression of genetic information. However, relatively little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address these issues, we measured the error rate of transcription in five organisms of increasing complexity and found that the error rate of RNA polymerase II ranges from 2.

The fidelity of transcription in human cells.

To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others.

A Methodological Workflow to Analyze Synthetic Lethality and Drug Synergism in Cancer Cells.

Current concepts in treating cancer usually neglect individual tumor characteristics such as a given mutational make up. Consequently, a "one-size-fits-all" therapeutic concept may commonly fail in terms of efficacy, evolving drug resistance, and side effects. In times of omics, novel elaborated and personalized approaches emerge for efficiently eradicate cancer cells, while sparing healthy cells.

Contribution of Puma to Inflammatory Resolution During Early Pneumococcal Pneumonia.

Apoptosis of cells at the site of infection is a requirement for shutdown of inflammatory signaling, avoiding tissue damage, and preventing progression of sepsis. and mice were challenged with TIGR4 strain pneumococcus and cytokines were quantitated from lungs and blood using a magnetic bead panel analysis. mice exhibited higher lung and blood cytokine levels of several major inflammatory cytokines, including IL-6, G-CSF, RANTES, IL-12, IFN-ϒ, and IP-10.

A Population-Genetic Lens into the Process of Gene Loss Following Whole-Genome Duplication.

Whole-genome duplications (WGDs) have occurred in many eukaryotic lineages. However, the underlying evolutionary forces and molecular mechanisms responsible for the long-term retention of gene duplicates created by WGDs are not well understood. We employ a population-genomic approach to understand the selective forces acting on paralogs and investigate ongoing duplicate-gene loss in multiple species of Paramecium that share an ancient WGD.

Organoids at the PUB: The Porcine Urinary Bladder Serves as a Pancreatic Niche for Advanced Cancer Modeling.

Despite intensive research and progress in personalized medicine, pancreatic ductal adenocarcinoma remains one of the deadliest cancer entities. Pancreatic duct-like organoids (PDLOs) derived from human pluripotent stem cells (PSCs) or pancreatic cancer patient-derived organoids (PDOs) provide unique tools to study early and late stage dysplasia and to foster personalized medicine. However, such advanced systems are neither rapidly nor easily accessible and require an in vivo niche to study tumor formation and interaction with the stroma.

In vitro coordination of Fe-protoheme with amyloid β is non-specific and exhibits multiple equilibria.

In addition to copper and zinc, heme is thought to play a role in Alzheimer's disease and its metabolism is strongly affected during the course of this disease. Amyloid β, the peptide associated with Alzheimer's disease, was shown to bind heme in vitro with potential catalytic activity linked to oxidative stress. To date, there is no direct determination of the structure of this complex.

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.

Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, , , , , and . Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline -mutated PDAC.

The invasive crayfish Cherax quadricarinatus facing chlordecone in Martinique: Bioaccumulation and depuration study.

The redclaw crayfish, Cherax quadricarinatus, was introduced to Martinique Island for aquaculture purposes at the beginning of the 21st century, in an attempt to revitalize the freshwater crustacean aquaculture sector. Mainly due to its high economical value, it was intentionally released in the wild and was caught and sold by fishermen. Martinican rivers are polluted by chlordecone, considered as one of the worst Persistant Organic Pollutants (POP).

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids.

A Prospective Feasibility Trial to Challenge Patient-Derived Pancreatic Cancer Organoids in Predicting Treatment Response.

Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay.

RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC.

Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors.