Intrinsic Molecular Characteristics Research Articles

IMG-10. IMAGING SUBTYPES OF PEDIATRIC LOW-GRADE GLIOMA ARE ASSOCIATED WITH DISTINCT MOLECULAR CHARACTERISTICS

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) have diverse molecular subtypes with distinct prognoses, necessitating personalized treatments. We aimed to determine whether radiomic features of pLGGs co-segregate with molecular subtypes, establishing a proof-of-concept that distinct molecular aberrations could manifest in differentiable imaging features. METHODS Leveraging radiomic, genomic, and transcriptomic data from 201 pLGG patients from the Children’s Brain Tumor Network (CBTN), we identified imaging-based pLGG subtypes through their radiophenotypes. This involved investigating the association of imaging subtypes with 2021 WHO pLGG classifications and profiling transcriptional characteristics distinguishing pLGG clusters. We used principal component analysis and K-Means clustering on 881 radiomic features and incorporated clinical variables (age, sex, tumor location), and derived three imaging subtypes. RESULTS BRAF V600E mutations were mainly found in subtype 3, while BRAF::KIAA1549 fusion in subtype 1. To ascertain transcriptome pathways most closely associated with imaging-based subtypes, we applied a supervised machine learning model with elastic net logistic regression using a one-versus-rest strategy for each imaging cluster, considering the top 100 most variable pathways, identified through gene set enrichment and gene co-expression network analyses, molecular subtype, tumor location, age, sex, and race. The predictive accuracy (area under the receiver operating characteristic curve) of the model was 0.86 | 0.72 for imaging subtype 1, 0.93 | 0.71 for subtype 2, and 0.91 | 0.64 for subtype 3 in the training | testing sets. Notably, each imaging subtype exhibited distinct molecular mechanisms; subtype 1 showed up-regulation of oxidative phosphorylation, PDGFRB, and interleukin 4, 10, and 13 signaling, while subtype 3 was linked to histone acetylation and DNA methylation pathways, relating to BRAF V600E pLGGs. CONCLUSIONS Our radiogenomics study suggests that intrinsic molecular characteristics of tumors drive distinct imaging subgroups of pLGG, providing a basis for future multi-modal investigations that may better define progression and targetability of the disease.

Deregulated miRNA Expression in Triple-Negative Breast Cancer of Ancestral Genomic-Characterized Latina Patients.

Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, high p53 expression, increased cancer recurrence, presence of distant metastasis, and deceased status. This study reinforces the importance of integration analysis of CNAs and miRNAs in TNBC, allowing for the identification of interactions among molecular mechanisms. Additionally, this study emphasizes the significance of considering the patients ancestral background when examining TNBC, as it can influence the relationship between intrinsic tumor molecular characteristics and clinical manifestations of the disease.

Multi-omics analyses based on genes associated with oxidative stress and phospholipid metabolism revealed the intrinsic molecular characteristics of pancreatic cancer

Oxidative stress (OS), which impacts lipid metabolic reprogramming, can affect the biological activities of cancer cells. How oxidative stress and phospholipid metabolism (OSPM) influence the prognosis of pancreatic cancer (PC) needs to be elucidated. The metabolic data of 35 pancreatic tumor samples, 34 para-carcinoma samples, and 31 normal pancreatic tissues were obtained from the previously published literature. Pan-cancer samples were obtained from The Cancer Genome Atlas (TCGA). And the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), ArrayExpress, and the Genotype-Tissue Expression (GTEx) databases were searched for more PC and normal pancreatic samples. The metabolites in PC were compared with normal and para-carcinoma tissues. The characteristics of the key OSPM genes were summarized in pan-cancer. The random survival forest analysis and multivariate Cox regression analysis were utilized to construct an OSPM-related signature. Based on this signature, PC samples were divided into high- and low-risk subgroups. The dysregulations of the tumor immune microenvironment were further investigated. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to investigate the expression of genes in the signature in PC and normal tissues. The protein levels of these genes were further demonstrated. In PC, metabolomic studies revealed the alteration of PM, while transcriptomic studies showed different expressions of OSPM-related genes. Then 930 PC samples were divided into three subtypes with different prognoses, and an OSPM-related signature including eight OSPM-related genes (i.e., SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, ECT2, SLC22A3, and FGD6) was developed. High- and low-risk subgroups divided by the signature showed different prognoses, expression levels of immune checkpoint genes, immune cell infiltration, and tumor microenvironment. The risk score was negatively correlated with the proportion of TIL, pDC, Mast cell, and T cell co-stimulation. The expression levels of genes in the signature were verified in PC and normal samples. The protein levels of SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, and SLC22A3 showed up-regulation in PC samples compared with normal tissues. After integrating metabolomics and transcriptomics data, the alterations in OSPM in PC were investigated, and an OSPM-related signature was developed, which was helpful for the prognostic assessment and individualized treatment for PC.

Crosslinked networks in electron beam irradiated polyethylenes evaluated by proton low-field NMR spectroscopy

Effect of electron beam (EB) irradiation is analyzed in low and high density polyethylenes (LDPE and HDPE, respectively) at different doses. Parameters as important as degree of crystallinity, melting or crystallization temperatures are dependent on the initial PE molecular architecture, which also controls the gel content developed by action of EB irradiation and the EB dose applied. Thus, this gel amount, ascribed to formation of chain crosslinkings, is raised as irradiation dose increases, being larger in the HDPE than in the LDPE. In both, a plateau value is reached at the highest doses. The molecular changes that take place in both PEs during EB irradiation lead to a hindrance in their crystallization capacity, once macrochains are molten, and, accordingly, to a reduction in crystallinity and to formation of thinner crystallites. Variation with temperature of rigid and soft fractions together with their respective relaxation times is followed in the irradiated LDPE and HDPE specimens by pulse mixed magic-sandwich echo nuclear magnetic resonance (MSE-NMR) measurements. The network structure promoted in these PEs is evaluated by using the multiple-quantum nuclear magnetic resonance (MQ-NMR) approach, showing important differences caused by EB irradiation due to their intrinsic molecular characteristics.

Spatial Transcriptomic Analysis Using R-Based Computational Machine Learning Reveals the Genetic Profile of Yang or Yin Deficiency Syndrome in Chinese Medicine Theory.

Objectives Yang and Yin are two main concepts responsible for harmonious balance reflecting health conditions based on Chinese medicine theory. Of note, deficiency of either Yang or Yin is associated with disease susceptibility. In this study, we aim to clarify the molecular feature of Yang and Yin deficiency by reanalyzing a transcriptomic data set retrieved from the GEO database using R-based machine learning analyses, which lays a foundation for medical diagnosis, prevention, and treatment of unbalanced Yang or Yin. Methods Besides conventional methods for target mining, we took the advantage of spatial transcriptomic analysis using R-based machine learning approaches to elucidate molecular profiles of Yin and Yang deficiency by reanalyzing an RNA-Seq data set (GSE87474) in the GEO focusing on peripheral blood mononuclear cells (PBMCs). The add-on functions in R including GEOquery, DESeq2, WGCNA (target identification with a scale-free topological assumption), Scatterplot3d, Tidyverse, and UpsetR were used. For information in the selected GEO data set, PBMCs representing 20,740 expressed genes were collected from subjects with Yang or Yin deficiency (n = 12 each), based on Chinese medicine-related diagnostic criteria. Results The symptomatic gene targets for Yang deficiency (KAT2B, NFKB2, CREBBP, GTF2H3) or Yin deficiency (JUNB, JUND, NGLY1, TNF, RAF1, PPP1R15A) were potentially discovered. CREBBP was identified as a shared key contributive gene regulating either the Yang or Yin deficiency group. The intrinsic molecular characteristics of these specific genes could link with clinical observations of Yang/Yin deficiency, in which Yang deficiency is associated with immune dysfunction tendency and energy deregulation, while Yin deficiency mainly contains oxidative stress, dysfunction of the immune system, and abnormal lipid/protein metabolism. Conclusion Our study provides representative gene targets and modules for supporting clinical traits of Yang or Yin deficiency in Chinese medicine theory, which is beneficial for promoting the modernization of Chinese medicine theory. Besides, R-based machine learning approaches adopted in this study might be further applied for investigating the underlying genetic polymorphisms related to Chinese medicine theory.

Seasonal Changes of Organic Carbon Mixing, Degradation and Deposition in Yangtze River Dominated Margin Related to Intrinsic Molecular and External Environmental Factors

AbstractThe East Asian monsoon is characterized by warm, humid summer and cool, dry winter that results in seasonal changes in fluvial sediment and organic carbon (OC) discharge. Here, we report measurements of elemental, isotopic, and optical compositions of OC in surface waters and sediments that were collected along the lower Yangtze River, Estuary, and East China Sea continuum in March and July 2019. The principal component analysis separates samples into three groups that correspond to fresh water area, mixing area, and seawater area. The terrigenous signal in the mixing area, indicated by water salinity and δ13C, is stronger in July. The applications of binary mixing models based on water salinity, dissolved OC (DOC) concentration and specific terrigenous fluorescence component suggest: (a) net removal of DOC from waters in July, but net addition of DOC into waters in March, attributed to more extensive degradation and larger deposition of OC in summer; and (b) more conservative behaviors of terrigenous OC compared to marine or mixed OC, suggesting an important role of intrinsic molecular characteristics on the persistence of DOC. The estimated monthly OC burial flux in the estuary and continent shelf is 0.48 × 1012 g in July and 0.081 × 1012 g of OC in March, equal to 15.5% and 2.6% of the annual OC discharge by the Yangtze River, respectively. Our study suggests that the burial of OC mainly occurs in the summer monsoon due to the larger sediment load of the Yangtze River, prevailing southeastern wind, and intensified Kuroshio Current.

Biomarkers and Lung Cancer Early Detection: State of the Art.

Simple SummaryLung cancer is the leading cause of cancer death worldwide. Detecting lung malignancies promptly is essential for any anticancer treatment to reduce mortality and morbidity, especially in high-risk individuals. The use of liquid biopsy to detect circulating biomarkers such as RNA, microRNA, DNA, proteins, autoantibodies in the blood, as well as circulating tumor cells (CTCs), can substantially change the way we manage lung cancer patients by improving disease stratification using intrinsic molecular characteristics, identification of therapeutic targets and monitoring molecular residual disease. Here, we made an update on recent developments in liquid biopsy-based biomarkers for lung cancer early diagnosis, and we propose guidelines for an accurate study design, execution, and data interpretation for biomarker development.Lung cancer burden is increasing, with 2 million deaths/year worldwide. Current limitations in early detection impede lung cancer diagnosis when the disease is still localized and thus more curable by surgery or multimodality treatment. Liquid biopsy is emerging as an important tool for lung cancer early detection and for monitoring therapy response. Here, we reviewed recent advances in liquid biopsy for early diagnosis of lung cancer. We summarized DNA- or RNA-based biomarkers, proteins, autoantibodies circulating in the blood, as well as circulating tumor cells (CTCs), and compared the most promising studies in terms of biomarkers prediction performance. While we observed an overall good performance for the proposed biomarkers, we noticed some critical aspects which may complicate the successful translation of these biomarkers into the clinical setting. We, therefore, proposed a roadmap for successful development of lung cancer biomarkers during the discovery, prioritization, and clinical validation phase. The integration of innovative minimally invasive biomarkers in screening programs is highly demanded to augment lung cancer early detection.

A new metal-organic framework of 3,9-diazatetraasterane-1,5,7,11-tetracarboxylic acid-3,6,9,12-tetraphenyl with sodium ion: Synthesis, characterization and DFT calculations

A new three-dimensional metal-organic framework with regular 1D channel, [Na2(DATA)1/2(H2O)2·H2O]n, NaTADA, was synthesized by solvothermal reaction of 3,9-diazatetraasterane-1,5,7,11-tetracarboxylic acid-3,6,9,12-tetraphenyl (DATAH4) with sodium hydroxide, and characterized by X-Ray single-crystal diffraction, thermogravimetric analysis (TGA) and FT-IR spectroscopy. Besides, electronic structures analysis, including molecular frontier orbitals, molecular electrostatic potential surface distribution, were also performed basing on electronic wavefunction obtained at the same calculated level for revealing intrinsic molecular structural characteristics.

Abstract PO-015: Ex-vivo stimulation of chimeric antigen receptor T cell pre-infusion products predicts clinical response in pediatric B cell acute lymphoblastic leukemia

Abstract CAR T cell therapy has shown remarkable efficacy against refractory hematological malignancies, frequently leading to complete remission. However, some patients do not respond to the therapy, and many patients who do show an initial response eventually relapse. The factors determining these diverse patient responses remain to be understood. We sought to assess whether the intrinsic molecular characteristics of CAR T pre-infusion products could be predictive of clinical outcomes, reasoning that differences in T cell cellular states and subtype proportions determine response. To investigate the heterogeneity and temporal dynamics of CD19-targeted CAR T cells at a molecular level and the relationship to clinical variables in pediatric B cell acute lymphoblastic leukemia, we profiled by single-cell RNA-seq patient-derived pre-infusion CAR T cells before and after stimulation ex-vivo by antigen presenting cells. Computational analysis of data from 12 pediatric patients with chemotherapy-resistant or refractory disease revealed distinct populations of T cells associated with clinical response. We found that CAR T cells from patients with a favorable response had an increased potential to transition to an active, cytokine-expressing state upon stimulation with CD19, and that responding patients were particularly associated with a robust mixed CD4/CD8 Type 1 helper-like response. Conversely, we found that patients who do not did not respond to CAR T therapy had a higher proportion of non-cytokine expressing CD8 cytotoxic T cells upon stimulation. These results demonstrate the potential of single-cell gene expression profiling coupled with computational analysis to uncover the molecular factors determining response to immunotherapy. Citation Format: Steven Woodhouse, Zhiliang Bai, Rong Fan, Pablo G. Camara, J. Joseph Melenhorst. Ex-vivo stimulation of chimeric antigen receptor T cell pre-infusion products predicts clinical response in pediatric B cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-015.

Abstract P4-10-32: Commensal gut microbiota influences efficacy of trastuzumab in patients with HER2-positive breast carcinoma

Abstract Although the clinical benefit of trastuzumab for the management of HER2-positive breast carcinomas (BCs) has been largely demonstrated, many women, even those reported to have tumors potentially most sensitive to trastuzumab (e.g., HER2-enriched by PAM50 and with infiltrating immune cells) do not respond to this agent. The relevance of immunity in the cytotoxic mechanism of action of trastuzumab supports the notion that the anti-tumor effect of this monoclonal antibody depends on host immune system activity. Since gut commensal bacteria reportedly contribute to the development and maintenance of the immune system and have immunomodulatory effects, we investigated whether a relationship between gut microbiota composition and the response to trastuzumab exists in patients with HER2-positive BC. Stool samples were collected from 18 patients with primary HER2-positive BCs before the outset of neoadjuvant trastuzumab-based chemotherapy and analyzed by 16S rRNA gene profiling using Illumina Miseq platform. Gut microbiota β-diversity analysis by UniFrac algorithm revealed a heterogeneous microbiota composition mainly due to differences in the relative abundance of Bacteroides, Faecalibacterium and a genus belonging to Ruminococcaceae family. Unsupervised analysis identified two microbiota clusters that significantly discriminated patients according to pathological complete response (pCR) (p=0.0128, by Fisher test). No association between microbiota clusters and PAM50 molecular classification of tumor biopsies, as evaluated by gene expression, was observed. Moreover, HER2-enriched cases were distributed in the two microbiota clusters based on trastuzumab response. Differences in the intestinal microbiota between responsive (R) and non-responsive (NR) patients were assessed by LEfSe analysis: a significant higher and lower abundance of Clostridiales taxonomic order and Bacteroides taxonomic genus, respectively, was foundin R as compared to NR patients. Immune genes expressed in tumor biopsies that were found significantly correlated with these bacteria mainly belong to innate and adaptive immune response and cellular response to tumor necrosis factor pathways. To investigate the causal role of gut microbiota in trastuzumab benefit, FVB mice bearing syngeneic mammary carcinoma overexpressing human HER2 were transplanted with fecal material from R and NR patients after intestinal flora depletion by the use of an antibiotic cocktail. The mouse response to trastuzumab treatment recapitulated the response observed in patients from which stool derived. The obtained results support the contribution of gut microbiota in trastuzumab activity by influencing tumor immune microenvironment, independently of tumor intrinsic molecular characteristics. These data represent the proof-of-concept that manipulating gut microbes in resistant patients could be a new strategy to improve the response to trastuzumab. Supported by AIRC Citation Format: Elda Tagliabue, Martina Di Modica, Giorgio Gargari, Viola Regondi, Arianna Bonizzi, Stefania Arioli, Fabio Corsi, Simone Guglielmetti, Tiziana Triulzi. Commensal gut microbiota influences efficacy of trastuzumab in patients with HER2-positive breast carcinoma [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-32.

Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast.

The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells' expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non-small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified.

Abstract 55: Intrinsic molecular characteristics of bone marrow-disseminated tumor cells

Abstract Dormant or slow-cycling disseminated tumor cells (DTC) in bone marrow (BM) are known to persist in patients with various types of cancer including head and neck squamous cell carcinoma (HNSCC). BM-DTC has been thought to have possible metastatic stem cell traits although functional and clonal analysis of BM-DTC remain elusive. Recently, we reported that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis was crucial for drug resistance dependent on a slow-cycling state in BM-DTC but not in lung metastatic cells. This study aimed to elucidate intrinsic molecular characteristics in BM-DTC. We used the human HNSCC cell line HEp3-originated sublines [i.e. parental line (P-HEp3), BM-DTC-derived (BM-HEp3), and lung metastases-derived sublines (Lu-HEp3)]. Our transcriptome analyses for these sublines revealed that slow-cycling and drug-resistant BM-HEp3 cells had unique gene expression signatures. In addition, our investigation for phosphorylation of 39 kinases associated with tumor progression showed enhanced activation of only Src in BM-HEp3 compared with P- and Lu-HEp3. Importantly, Src inhibition by dasatinib in these sublines led to a remarkable reduction in cell viability only in BM-HEp3. These data suggest that intrinsic molecular characteristics of BM-DTC are distinct from primary and lung metastatic tumor cells. Src activation may be important for survival of dormant or slow-cycling BM-DTC. Further studies should contribute to better understanding of biology of minimal residual disease in BM and metastatic initiation. Citation Format: Manabu Maeshiro, Satoru Shinriki, Takuya Nakamura, Hirofumi Jono, Hideki Nakayama, Yukio Ando, Hirotaka Matsui. Intrinsic molecular characteristics of bone marrow-disseminated tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 55.

Translating Mechanism-Based Strategies to Break the Obesity−Cancer Link: A Narrative Review

Prevalence of obesity, an established risk factor for many cancers, has increased dramatically over the past 50 years in the United States and across the globe. Relative to normoweight cancer patients, obese cancer patients often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity−cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression and, thus, there are multiple opportunities for primary prevention and treatment of obesity-related cancers. Obesity-associated alterations, including systemic metabolism, adipose inflammation, growth factor signaling, and angiogenesis, are emerging as primary drivers of obesity-associated cancer development and progression. These obesity-associated host factors interact with the intrinsic molecular characteristics of cancer cells, facilitating several of the hallmarks of cancer. Each is considered in the context of potential preventive and therapeutic strategies to reduce the burden of obesity-related cancers. In addition, this review focuses on emerging mechanisms behind the obesity−cancer link, as well as relevant dietary interventions, including calorie restriction, intermittent fasting, low-fat diet, and ketogenic diet, that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-related cancers.

Molecular Frame Reconstruction Using Time-Domain Photoionization Interferometry.

Photoionization of molecular species is, essentially, a multipath interferometer with both experimentally controllable and intrinsic molecular characteristics. In this work, XUV photoionization of impulsively aligned molecular targets (N_{2}) is used to provide a time-domain route to "complete" photoionization experiments, in which the rotational wave packet controls the geometric part of the photoionization interferometer. The data obtained is sufficient to determine the magnitudes and phases of the ionization matrix elements for all observed channels, and to reconstruct molecular frame interferograms from lab frame measurements. In principle, this methodology provides a time-domain route to complete photoionization experiments and the molecular frame, which is generally applicable to any molecule (no prerequisites), for all energies and ionization channels.

The molecular mechanisms of obesity paradox.

Clinical observations suggest a complex relationship between human obesity and cardiovascular disease. Whilst abdominal (visceral) adiposity leads to deleterious metabolic disturbances, subcutaneous fat accumulation has a benign effect on cardiometabolic risk. Notably, an accumulating body of evidence paradoxically links increased body mass index with a better prognosis in patients with established cardiovascular disease, a finding that has been termed the 'obesity paradox'. Whilst this is now acknowledged to be an epidemiological finding, a metabolically healthy obese group associated with low cardiovascular risk has also been identified. The current concept of adipose tissue (AT) biology suggests that AT expansion is feasible without accompanying adipocyte dysfunction. A metabolically healthy obese phenotype can be promoted by exercise, but is also linked with intrinsic AT molecular characteristics such as efficient fat storage and lipid droplet formation, high adipogenesis capacity, low extracellular matrix fibrosis, angiogenesis potential, adipocyte browning and low macrophages infiltration/activation. Such features are associated with a secretomic profile of human AT which is protective for the cardiovascular system. In the present review, we summarize the existing knowledge on the molecular mechanisms underlying the 'obesity paradox' and whether fatness can be healthy too.

Differential surface density and modulatory effects of presynaptic GABAB receptors in hippocampal cholecystokinin and parvalbumin basket cells

The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in their intrinsic physiological, anatomical and molecular characteristics, but also in their presynaptic modulation of their synaptic output. Most GABAergic terminals are known to contain GABAB receptors (GABABR), but their role in presynaptic inhibition and surface expression have not been comparatively characterized in the two BC types. To address this, we performed whole-cell recordings from CCK and PV BCs and postsynaptic pyramidal cells (PCs), as well as freeze-fracture replica-based quantitative immunogold electron microscopy of their synapses in the rat hippocampal CA1 area. Our results demonstrate that while both CCK and PV BCs contain functional presynaptic GABABRs, their modulatory effects and relative abundance are markedly different at these two synapses: GABA release is dramatically inhibited by the agonist baclofen at CCK BC synapses, whereas a moderate reduction in inhibitory transmission is observed at PV BC synapses. Furthermore, GABABR activation has divergent effects on synaptic dynamics: paired-pulse depression (PPD) is enhanced at CCK BC synapses, but abolished at PV BC synapses. Consistent with the quantitative differences in presynaptic inhibition, virtually all CCK BC terminals were found to contain GABABRs at high densities, but only 40% of PV BC axon terminals contain GABABRs at detectable levels. These findings add to an increasing list of differences between these two interneuron types, with implications for their network functions.

Molecular mechanisms of interfacial slip for polymer melts under shear flow

Interfacial slip plays a crucial role in a variety of fluid dynamics problems occurring in practical polymer processing, lubrication, adhesion, nanocomposites, etc. Despite many research efforts, a fundamental understanding of the underlying molecular mechanisms and dynamics is still lacking. Here, we present the intrinsic molecular characteristics of the slip phenomena by using atomistic nonequilibrium molecular dynamics simulations of polyethylene melts under shear flow. Our results identify three distinctive characteristic regimes with regard to the degree of slip and reveal the underlying molecular mechanisms for each regime: (i) the z-to-x chain rotation mechanism in the vorticity plane in the weak flow regime, which effectively diminishes the wall friction against chain movement along the flow direction, (ii) the repetitive chain detachment-attachment (out-of-plane wagging) and disentanglement mechanism in the intermediate regime, and (iii) irregular (chaotic) chain rotation and tumbling mechanisms ...

Expression profiling-based clustering of healthy subjects recapitulates classifications defined by clinical observation in Chinese medicine

Differences between healthy subjects and associated disease risks are of substantial interest in clinical medicine. Based on clinical presentations, Traditional Chinese Medicine (TCM) classifies healthy people into nine constitutions: Balanced, Qi, Yang or Yin deficiency, Phlegm-dampness, Damp-heat, Blood stasis, Qi stagnation, and Inherited special constitutions. In particular, Yang and Yin deficiency constitutions exhibit cold and heat aversion, respectively. However, the intrinsic molecular characteristics of unbalanced phenotypes remain unclear. To determine whether gene expression-based clustering can recapitulate TCM-based classification, peripheral blood mononuclear cells (PBMCs) were collected from Chinese Han individuals with Yang/Yin deficiency (n = 12 each) and Balanced (n = 8) constitutions, and global gene expression profiles were determined using the Affymetrix HG-U133A Plus 2.0 array. Notably, we found that gene expression-based classifications reflected distinct TCM-based subtypes. Consistent with the clinical observation that subjects with Yang deficiency tend toward obesity, series-clustering analysis detected several key lipid metabolic genes (diacylglycerol acyltransferase (DGAT2), acyl-CoA synthetase (ACSL1), and ATP-binding cassette subfamily A member 1 (ABCA1)) to be down- and up-regulated in Yin and Yang deficiency constitutions, respectively. Our findings suggest that Yin/Yang deficiency and Balanced constitutions are unique entities in their mRNA expression profiles. Moreover, the distinct physical and clinical characteristics of each unbalanced constitution can be explained, in part, by specific gene expression signatures.

Single molecule binding dynamics measured with atomic force microscopy

We present a new method to analyse simultaneous Topography and RECognition Atomic Force Microscopy data such that it becomes possible to measure single molecule binding rates of surface bound proteins. We have validated this method on a model system comprising a S-layer surface modified with Strep-tagII for binding sites and strep-tactin bound to an Atomic Force Microscope tip through a flexible Poly-Ethylene-Glycol linker. At larger distances, the binding rate is limited by the linker, which limits the diffusion of the strep-tactin molecule, but at lateral distances below 3 nm, the binding rate is solely determined by the intrinsic molecular characteristics and the surface geometry and chemistry of the system. In this regime, Kon as determined from single molecule TREC data is in agreement with Kon determined using traditional biochemical methods.

An overview on new anticancer molecular targets in human testicular germ cell tumors

Testicular germ cell tumors (TGCTs) are the most frequent solid malignant tumors in men 20–40 years of age and the most frequent cause of death from solid tumors in this age group. TGCTs can be subdivided into seminoma and non-seminoma germ cell tumors (NSGCTs), including embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma. Seminomas and NSGCTs do not only present distinctive clinical features, but they also show significant differences as far as therapy and prognosis are concerned. The different therapeutic outcome might be explained by inherent properties of the cells from which testicular neoplasia originates. The unique treatment sensitivity of TGCTs is unexplained so far, but it is likely to be related to intrinsic molecular characteristics of the primordial germ cells/gonocytes, from which these tumors originate. Many discovered biomarkers including OCT3/4, SOX2, SOX17, HMGA1, Nek2, GPR30, Aurora-B, estrogen receptor β, and others have given further advantages to discriminate between histological subgroups and could represent useful novel molecular targets for antineoplastic strategies.