Chemotherapy-associated oral microbiome changes in breast cancer patients.

Cytotoxic chemotherapy with or without a combination of humanized monoclonal antibodies is regarded as the gold standard of personalized medicine for the treatment of breast cancer patients. Significant medication-related side effects are common accompanying phenomena for these patients, such as oral discomfort, mucositis, or even osteonecrosis of the jaw. In this study, we analyze the saliva samples of 20 breast cancer patients at three time points throughout their chemotherapy: at the baseline prior to treatment initiation (T1), after four-to-six cycles of chemotherapy (T2), and 1 year after the start of the treatment (T3) to investigate and characterize the long-term effects of chemotherapy on the oral microbiome. We aimed to characterize changes in the oral bacterial microbiome based on 16S rRNA gene amplicon analysis during chemotherapeutic treatment, as a potential target to treat common oral side effects occurring during therapy. The chemotherapeutic drugs used in our study for patient treatment were trastuzumab, docetaxel, pertuzumab, epirubicin, and cyclophosphamide. We find a significant increase in the relative abundance of potentially pathogenic taxa like Escherichia/Shigella and non-significant trends in the relative abundance of, for example, Actinomyces ssp. In conclusion, the role of microbiota in the oral side effects of chemotherapeutic treatment needs to be considered and should be analyzed in more detail using larger patient cohorts. Oral side effects in breast cancer patients undergoing chemotherapy are a common burden and should be treated for a better tolerability of the therapy.

Complementary omics strategies to dissect p53 signaling networks under nutrient stress.

Signaling trough p53is a major cellular stress response mechanism and increases upon nutrient stresses such as starvation. Here, we show in a human hepatoma cell line that starvation leads to robust nuclear p53 stabilization. Using BioID, we determine the cytoplasmic p53 interaction network within the immediate-early starvation response and show that p53 is dissociated from several metabolic enzymes and the kinase PAK2 for which direct binding with the p53 DNA-binding domain was confirmed with NMR studies. Furthermore, proteomics after p53 immunoprecipitation (RIME) uncovered the nuclear interactome under prolonged starvation, where we confirmed the novel p53 interactors SORBS1 (insulin receptor signaling) and UGP2 (glycogen synthesis). Finally, transcriptomics after p53 re-expression revealed a distinct starvation-specific transcriptome response and suggested previously unknown nutrient-dependent p53 target genes. Together, our complementary approaches delineate several nodes of the p53 signaling cascade upon starvation, shedding new light on the mechanisms of p53 as nutrient stress sensor. Given the central role of p53 in cancer biology and the beneficial effects of fasting in cancer treatment, the identified interaction partners and networks could pinpoint novel pharmacologic targets to fine-tune p53 activity.

Adipose Triglyceride Lipase Loss Promotes a Metabolic Switch in A549 Non-Small Cell Lung Cancer Cell Spheroids.

Cancer cells undergo complex metabolic adaptations to survive and thrive in challenging environments. This is particularly prominent for solid tumors, where cells in the core of the tumor are under severe hypoxia and nutrient deprivation. However, such conditions are often not recapitulated in the typical 2D in vitro cancer models, where oxygen as well as nutrient exposure is quite uniform. The aim of this study was to investigate the role of a key neutral lipid hydrolase, namely adipose triglyceride lipase (ATGL), in cancer cells that are exposed to more tumor-like conditions. To that end, we cultured lung cancer cells lacking ATGL as multicellular spheroids in 3D and subjected them to comprehensive proteomics analysis and metabolic phenotyping. Proteomics data are available via ProteomeXchange with identifier PXD021105. As a result, we report that loss of ATGL enhanced growth of spheroids and facilitated their adaptation to hypoxia, by increasing the influx of glucose and endorsing a pro-Warburg effect. This was followed by changes in lipid metabolism and an increase in protein production. Interestingly, the observed phenotype was also recapitulated in an even more "in vivo like" setup, when cancer spheroids were grown on chick chorioallantoic membrane, but not when cells were cultured as a 2D monolayer. In addition, we demonstrate that according to the publicly available cancer databases, an inverse relation between ATGL expression and higher glucose dependence can be observed. In conclusion, we provide indications that ATGL is involved in regulation of glucose metabolism of cancer cells when grown in 3D (mimicking solid tumors) and as such could be an important factor of the treatment outcome for some cancer types. Finally, we also ratify the need for alternative cell culture models, as the majority of phenotypes observed in 3D and spheroids grown on chick chorioallantoic membrane were not observed in 2D cell culture.

Irreversible oxidative post-translational modifications in heart disease.

Introduction: Development of specific biomarkers aiding early diagnosis of heart failure is an ongoing challenge. Biomarkers commonly used in clinical routine usually act as readouts of an already existing acute condition rather than disease initiation. Functional decline of cardiac muscle is greatly aggravated by increased oxidative stress and damage of proteins. Oxidative post-translational modifications occur already at early stages of tissue damage and are thus regarded as potential up-coming disease markers. Areas covered: Clinical practice regarding commonly used biomarkers for heart disease is briefly summarized. The types of oxidative post-translational modification in cardiac pathologies are discussed with a special focus on available quantitative techniques and characteristics of individual modifications with regard to their stability and analytical accessibility. As irreversible oxidative modifications trigger protein degradation pathways or cause protein aggregation, both influencing biomarker abundance, a chapter is dedicated to their regulation in the heart.

Distinct differences in self-assembly of aromatic linear dicarboxylic acids.

Self-assembly into two-dimensionally ordered supramolecular structures of three aromatic dicarboxylic acids-2,6-naphthalenedicarboxylic acid (NDA), 4,4'-biphenyldicarboxylic acid (BPDA), and 4,4'-stilbenedicarboxylic acid (SDA)-is studied at the liquid-solid interface by scanning tunneling microscopy. All compounds possess structural similarities, namely, two interconnected aromatic moieties and functionalization through two carboxylic groups in linear configuration. For all molecules, ordered monolayers were observed on a graphite substrate, and the resulting structures can be described as a dense packing of one-dimensionally hydrogen-bonded rows. However, concerning the stability of the adsorbate layers, the average domain size, and the degree of order, distinct differences were noticed. Supported by density functional theory (DFT) calculations, these differences are analyzed and explained as a consequence of molecular structure, adsorption geometry, and adsorption energy.