bluuebunny/crossref_metadata_2025 huggingface dataset:
Predict ovarian cancer by pairing serum miRNAs: Construct of single sample classifiers
Authors: Hong Guini , Luo Fengyuan , Chen Zhihong , Ma Liyuan , Lin Guiyang , Wu Tong , Li Na , Cai Hao , Hu Tao , Zhong Haijian , Guo You , Li Hongdong
Published: August 2022

Objective

The accuracy of CA125 or clinical examination in ovarian cancer (OVC) screening is still facing challenges. Serum miRNAs have been considered as promising biomarkers for clinical applications. Here, we propose a single sample classifier (SSC) method based on within-sample relative expression orderings (REOs) of serum miRNAs for OVC diagnosis.

Methods

Based on the stable REOs within 4,965 non-cancer serum samples, we developed the SSC for OVC in the training cohort (GSE106817: OVC = 200, non-cancer = 2,000) by focusing on highly reversed REOs within OVC. The best diagnosis is achieved using a combination of reversed miRNA pairs, considering the largest evaluation index and the lowest number of miRNA pairs possessed according to the voting rule. The SSC was then validated in internal data (GSE106817: OVC = 120, non-cancer = 759) and external data (GSE113486: OVC = 40, non-cancer = 100).

Results

The obtained 13-miRPairs classifier showed high diagnostic accuracy on distinguishing OVC from non-cancer controls in the training set (sensitivity = 98.00%, specificity = 99.60%), which was reproducible in internal data (sensitivity = 98.33%, specificity = 99.21%) and external data (sensitivity = 97.50%, specificity = 100%). Compared with the published models, it stood out in terms of correct positive predictive value (PPV) and negative predictive value (NPV) (PPV = 96.08% and NPV=95.16% in training set, and both above 99% in validation set). In addition, 13-miRPairs demonstrated a classification accuracy of over 97.5% for stage I OVC samples. By integrating other non-OVC serum samples as a control, the obtained 17-miRPairs classifier could distinguish OVC from other cancers (AUC>92% in training and validation set).

Conclusion

The REO-based SSCs performed well in predicting OVC (including early samples) and distinguishing OVC from other cancer types, proving that REOs of serum miRNAs represent a robust and non-invasive biomarker.
Effect of SARS-CoV-2 infection on asthma patients
Authors: Li Xin-yu , Wang Jing-bing , An Hong-bang , Wen Ming-zhe , You Jian-xiong , Yang Xi-tao
Published: August 2022

Background

SARS-CoV-2 causes coronavirus disease 2019 (COVID-19), a new coronavirus pneumonia, and containing such an international pandemic catastrophe remains exceedingly difficult. Asthma is a severe chronic inflammatory airway disease that is becoming more common around the world. However, the link between asthma and COVID-19 remains unknown. Through bioinformatics analysis, this study attempted to understand the molecular pathways and discover potential medicines for treating COVID-19 and asthma.

Methods

To investigate the relationship between SARS-CoV-2 and asthma patients, a transcriptome analysis was used to discover shared pathways and molecular signatures in asthma and COVID-19. Here, two RNA-seq data (GSE147507 and GSE74986) from the Gene Expression Omnibus were used to detect differentially expressed genes (DEGs) in asthma and COVID-19 patients to find the shared pathways and the potential drug candidates.

Results

There were 66 DEGs in all that were classified as common DEGs. Using a protein-protein interaction (PPI) network created using various bioinformatics techniques, five hub genes were found. We found that asthma has some shared links with the progression of COVID-19. Additionally, protein-drug interactions with common DEGs were also identified in the datasets.

Conclusion

We investigated possible links between COVID-19 and asthma using bioinformatics databases, which might be useful in treating COVID-19 patients. More studies on populations affected by these diseases are needed to elucidate the molecular mechanism behind their association.
Identification of Novel Therapeutic Candidates Against SARS-CoV-2 Infections: An Application of RNA Sequencing Toward mRNA Based Nanotherapeutics
Authors: Khalid Zunera , Huan Ma , Sohail Raza Muhammad , Abbas Misbah , Naz Zara , Kombe Kombe Arnaud John , Zeng Weihong , He Hongliang , Jin Tengchuan
Published: August 2022

Due to fast transmission and various circulating SARS-CoV-2 variants, a significant increase of coronavirus 2019 infection cases with acute respiratory symptoms has prompted worries about the efficiency of current vaccines. The possible evasion from vaccine immunity urged scientists to identify novel therapeutic targets for developing improved vaccines to manage worldwide COVID-19 infections. Our study sequenced pooled peripheral blood mononuclear cells transcriptomes of SARS-CoV-2 patients with moderate and critical clinical outcomes to identify novel potential host receptors and biomarkers that can assist in developing new translational nanomedicines and vaccine therapies. The dysregulated signatures were associated with humoral immune responses in moderate and critical patients, including B-cell activation, cell cycle perturbations, plasmablast antibody processing, adaptive immune responses, cytokinesis, and interleukin signaling pathway. The comparative and longitudinal analysis of moderate and critically infected groups elucidated diversity in regulatory pathways and biological processes. Several immunoglobin genes (IGLV9-49, IGHV7-4, IGHV3-64, IGHV1-24, IGKV1D-12, and IGKV2-29), ribosomal proteins (RPL29, RPL4P2, RPL5, and RPL14), inflammatory response related cytokines including Tumor Necrosis Factor (TNF, TNFRSF17, and TNFRSF13B), C-C motif chemokine ligands (CCL3, CCL25, CCL4L2, CCL22, and CCL4), C-X-C motif chemokine ligands (CXCL2, CXCL10, and CXCL11) and genes related to cell cycle process and DNA proliferation (MYBL2, CDC20, KIFC1, and UHCL1) were significantly upregulated among SARS-CoV-2 infected patients. 60S Ribosomal protein L29 (RPL29) was a highly expressed gene among all COVID-19 infected groups. Our study suggested that identifying differentially expressed genes (DEGs) based on disease severity and onset can be a powerful approach for identifying potential therapeutic targets to develop effective drug delivery systems against SARS-CoV-2 infections. As a result, potential therapeutic targets, such as the RPL29 protein, can be tested in vivo and in vitro to develop future mRNA-based translational nanomedicines and therapies to combat SARS-CoV-2 infections.
Deciphering Resistome in Patients With Chronic Obstructive Pulmonary Diseases and Clostridioides difficile Infections
Authors: Cho Youna , Kim Jieun , Pai Hyunjoo , Rho Mina
Published: August 2022

Antibiotics alter the gut microbiome and cause dysbiosis leading to antibiotic-resistant organisms. Different patterns of antibiotic administration cause a difference in bacterial composition and resistome in the human gut. We comprehensively investigated the association between the distribution of antibiotic resistance genes (ARGs), bacterial composition, and antibiotic treatments in patients with chronic obstructive pulmonary diseases (COPD) and Clostridioides difficile infections (CDI) who had chronic or acute intermittent use of antibiotics and compared them with healthy individuals. We analyzed the gut microbiomes of 61 healthy individuals, 16 patients with COPD, and 26 patients with CDI. The COPD patients were antibiotic-free before stool collection for a median of 40 days (Q1: 9.5; Q3: 60 days), while the CDI patients were antibiotic-free for 0 days (Q1: 0; Q3: 0.3). The intra-group beta diversity measured by the median Bray-Curtis index was the lowest for the healthy individuals (0.55), followed by the COPD (0.69) and CDI groups (0.72). The inter-group beta diversity was the highest among the healthy and CDI groups (median index = 0.89). The abundance of ARGs measured by the number of reads per kilobase per million reads (RPKM) was 684.2; 1,215.2; and 2,025.1 for the healthy, COPD, and CDI groups. It was negatively correlated with the alpha diversity of bacterial composition. For the prevalent ARG classes, healthy individuals had the lowest diversity and abundance of aminoglycoside, β-lactam, and macrolide-lincosamide-streptogramin (MLS) resistance genes, followed by the COPD and CDI groups. The abundances of Enterococcus and Escherichia species were positively correlated with ARG abundance and the days of antibiotic treatment, while Bifidobacterium and Ruminococcus showed negative correlations for the same. In addition, we analyzed the mobilome patterns of aminoglycoside and β-lactam resistance gene carriers using metagenomic sequencing data. In conclusion, the ARGs were significantly enhanced in the CDI and COPD groups than in healthy individuals. In particular, aminoglycoside and β-lactam resistance genes were more abundant in the CDI and COPD groups, but the dominant mobile genetic elements that enable the transfer of such genes showed similar prevalence patterns among the groups.
Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study
Authors: Xu Jiahui , Sun Zhaoqing , Zhang Rui , Li Ruixue , Yu Zhecong , Zhang Qianlong , Ma Yanan , Xing Fuguo , Zheng Liqiang
Published: August 2022

Background

Although animal studies show that spermidine (SPD) affects cognitive function, the relevant evidence among humans is limited. We aim to examine the association between serum SPD levels and cognitive performance.

Materials and Methods

We conducted a cross-sectional and longitudinal study including a baseline and one follow-up survey. The baseline survey was conducted from June 2019 to August 2019, while the follow-up survey was conducted from June 2021 to August 2021. We analyzed 3,774 adult participants aged >35 years, who had no history of dementia.

Results

The mean (SD) age of the participants was 57.4 (9.8) years. Relative to the first tertile, the multivariate-adjusted ORs (95% CIs) of mild cognitive impairment (MCI) for the second and third tertile groups were 0.78 (0.65, 0.93) and 0.80 (0.67, 0.96), respectively. Restricted cubic spline models show that there is a non-linear association between SPD and MCI. In line with cross-sectional findings, the longitudinal study showed that a high SPD concentration may indicate a lower risk of MCI [ORs (95% CIs) for the third tertile of 0.62 (0.39, 0.99)].

Conclusion

Our findings suggest that SPD is favorable for cognitive function. Monitoring the SPD levels may help reduce the incidence of MCI, hence decreasing the burden of MCI.
Spikes and High Frequency Oscillations in Lateral Neocortical Temporal Lobe Epilepsy: Can They Predict the Success Chance of Hippocampus-Sparing Resections?
Authors: Maccabeo Alessandra , van 't Klooster Maryse A. , Schaft Eline , Demuru Matteo , Zweiphenning Willemiek , Gosselaar Peter , Gebbink Tineke , Otte Wim M. , Zijlmans Maeike
Published: August 2022

Purpose

We investigated the distribution of spikes and HFOs recorded during intraoperative electrocorticography (ioECoG) and tried to elaborate a predictive model for postsurgical outcomes of patients with lateral neocortical temporal lobe epilepsy (TLE) whose mesiotemporal structures are left in situ.

Methods

We selected patients with temporal lateral neocortical epilepsy focus who underwent ioECoG-tailored resections without amygdalo–hippocampectomies. We visually marked spikes, ripples (80–250 Hz), and fast ripples (FRs; 250–500 Hz) on neocortical and mesiotemporal channels before and after resections. We looked for differences in event rates and resection ratios between good (Engel 1A) and poor outcome groups and performed logistic regression analysis to identify outcome predictors.

Results

Fourteen out of 24 included patients had a good outcome. The poor-outcome patients showed higher rates of ripples on neocortical channels distant from the resection in pre- and post-ioECoG than people with good outcomes (ppre = 0.04, ppost = 0.05). Post-ioECoG FRs were found only in poor-outcome patients (N = 3). A prediction model based on regression analysis showed low rates of mesiotemporal post-ioECoG ripples (ORmesio = 0.13, pmesio = 0.04) and older age at epilepsy onset (OR = 1.76, p = 0.04) to be predictors of good seizure outcome.

Conclusion

HFOs in ioECoG may help to inform the neurosurgeon of the hippocampus-sparing resection success chance in patients with lateral neocortical TLE.
The enigma of infra-slow fluctuations in the human EEG
Authors: Kropotov Juri D.
Published: August 2022

Spontaneous Infra-Slow Fluctuations (ISFs) of the human EEG (EEG-ISFs) were discovered 60 years ago when appropriate amplifiers for their recordings were designed. To avoid skin-related artifacts the recording of EEG-ISFs required puncturing the skin under the electrode. In the beginning of the 21st century the interest in EEG-ISFs was renewed with the appearance of commercially available DC-coupled amplified and by observation of ISFs of the blood oxygen level–dependent (BOLD) functional magnetic resonance imaging signal at a similar frequency. The independent components of irregular EEG-ISFs were shown to correlate with BOLD signals which in turn were driven by changes in arousal level measured by galvanic skin response (GSR), pupil size and HRV. There is no consensus regarding the temporal organization of EEG-ISFs: some studies emphasize the absence of peaks on EEG-ISFs spectra, some studies report prominent oscillations with frequency around 0.1 or 0.02 Hz, while some emphasize multiple discrete infraslow oscillations. No studies used parameters of EEG-ISFs as neuromarkers to discriminate psychiatric patients from healthy controls. Finally, a set of working hypotheses is suggested that must be tested in future research to solve the enigma of EEG-ISFs.
Development of a composite diffusion tensor imaging score correlating with short-term neurological status in neonatal hypoxic–ischemic encephalopathy
Authors: Onda Kengo , Catenaccio Eva , Chotiyanonta Jill , Chavez-Valdez Raul , Meoded Avner , Soares Bruno P. , Tekes Aylin , Spahic Harisa , Miller Sarah C. , Parker Sarah-Jane , Parkinson Charlamaine , Vaidya Dhananjay M. , Graham Ernest M. , Stafstrom Carl E. , Everett Allen D. , Northington Frances J. , Oishi Kenichi
Published: August 2022

Hypoxic–ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10−16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10−04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10−13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.
Brainstem activation of GABAB receptors in the nucleus tractus solitarius increases gastric motility
Authors: Bellusci Lorenza , Kim Elizabeth , Garcia DuBar Selena , Gillis Richard A. , Vicini Stefano , Sahibzada Niaz
Published: August 2022

Background and aim

Local GABAergic signaling in the dorsal vagal complex (DVC) is essential to control gastric function. While the inhibitory GABAA receptor action on motility in the DVC is well-documented, the role of the GABAB receptor on gastric function is less well-established. Microinjection of baclofen, a selective GABAB receptor agonist, in the dorsal motor nucleus of the vagus (DMV) increases gastric tone and motility, while the effect on motility in the nucleus tractus solitarius (NTS) needs to be investigated. Previous in vitro studies showed that GABAB receptors exert a local inhibitory effect in unidentified NTS neurons. Since the NTS and DMV nuclei have differential control of gastric motility, we compared GABAB receptor activation in the NTS to that reported in the DMV. We microinjected baclofen unilaterally in the NTS while monitoring intragastric pressure and compared its action to optogenetic activation of somatostatin (SST) neurons in transgenic sst-Cre::channelrhodopsin-2 (ChR2) mice. We also performed patch-clamp recordings from SST and DMV neurons in brainstem slices from these mice.

Methods

In vivo drug injections and optogenetic stimulation were performed in fasted urethane/α-chloralose anesthetized male mice. Gastric tone and motility were monitored by an intragastric balloon inserted in the antrum and inflated with warm water to provide a baseline intragastric pressure (IGP). Coronal brainstem slices were obtained from the sst-Cre::ChR2 mice for interrogation with optogenetics and pharmacology using electrophysiology.

Results

The unilateral microinjection of baclofen into the NTS caused a robust increase in gastric tone and motility that was not affected by ipsilateral vagotomy. Optogenetic activation of SST neurons that followed baclofen effectively suppresses the gastric motility in vivo. In brain slices, baclofen suppressed spontaneous and light-activated inhibitory postsynaptic currents in SST and gastrointestinal-projection DMV neurons and produced outward currents.

Conclusion

Our results show that GABAB receptors in the NTS strongly increase gastric tone and motility. Optogenetic stimulation in vivo and in vitro suggests that these receptors activated by baclofen suppress the glutamatergic sensory vagal afferents in the NTS and also inhibit the interneurons and the inhibitory neurons that project to the DMV, which, in turn, increase motility via a cholinergic excitatory pathway to the stomach.
Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves
Authors: Chernov Andrei V. , Shubayev Veronica I.
Published: August 2022

The convergence of transcriptional and epigenetic changes in the peripheral nervous system (PNS) reshapes the spatiotemporal gene expression landscape in response to nerve transection. The control of these molecular programs exhibits sexually dimorphic characteristics that remain not sufficiently characterized. In the present study, we recorded genome-wide and sex-dependent early-phase transcriptional changes in regenerating (proximal) sciatic nerve 24 h after axotomy. Male nerves exhibited more extensive transcriptional changes with male-dominant upregulation of cytoskeletal binding and structural protein genes. Regulation of mRNAs encoding ion and ionotropic neurotransmitter channels displayed prominent sexual dimorphism consistent with sex-specific mRNA axonal transport in an early-phase regenerative response. Protein kinases and axonal transport genes showed sexually dimorphic regulation. Genes encoding components of synaptic vesicles were at high baseline expression in females and showed post-injury induction selectively in males. Predictive bioinformatic analyses established patterns of sexually dimorphic regulation of neurotrophic and immune genes, including activation of glial cell line-derived neurotrophic factor Gfra1 receptor and immune checkpoint cyclin D1 (Ccnd1) potentially linked to X-chromosome encoded tissue inhibitor of matrix metallo proteinases 1 (Timp1). Regulatory networks involving Olig1, Pou3f3/Oct6, Myrf, and Myt1l transcription factors were linked to sex-dependent reprogramming in regenerating nerves. Differential expression patterns of non-coding RNAs motivate a model of sexually dimorphic nerve regenerative responses to injury determined by epigenetic factors. Combined with our findings in the corresponding dorsal root ganglia (DRG), unique early-phase sex-specific molecular triggers could enrich the mechanistic understanding of peripheral neuropathies.
A putative causality of vitamin D in common diseases: A mendelian randomization study
Authors: Liu Hui , Shen Xudan , Yu Tunan , Wang Yifan , Cai Sheng , Jiang Xia , Cai Xiujun
Published: August 2022

Backgrounds

Vitamin D is considered as a nutrient protecting individuals against an array of diseases based on observational studies. Such a protective effect, however, has not been demonstrated by randomized controlled trials. This study aims to explore a putative causal role of vitamin D in common diseases through a two-sample Mendelian randomization (MR) framework.

Methods

Circulating vitamin D was predicted by 41 genetic variants discovered in European populations. Common diseases were verified through two ways, using information from Japanese patients of Biobank Japan and using information from European patients of FinnGen project. We additionally validated the results by replacing vitamin D-associated instrumental variables (IVs) of European population with that of an independent Japanese population and of an independent Indian population. Inverse-variance weighted method was used as the primary analytical approach while a series of MR methods including MR-Egger regression, weighted median, maximum likelihood, MR-PRESSO and multivariate MR were adopted to guarantee MR model assumptions and to detect horizontal pleiotropy.

Results

Genetically predicted vitamin D was significantly associated with an increased risk of Graves' disease (OR = 1.71, 95%CI: 1.25–2.33, P = 0.001) and cataract (OR = 1.14, 95%CI: 1.03–1.28, P = 0.016); while with a decreased risk of esophageal cancer (OR = 0.66, 95%CI: 0.46–0.93, P = 0.019). This significant causal link between vitamin D and cataract was validated replacing IVs identified in the European population with those from Japanese population. No notable associations of vitamin D with other diseases were observed.

Conclusions

Our findings indicate a potential causal role of vitamin D in common diseases, which needs further validation.
iRGD-modified exosomes-delivered BCL6 siRNA inhibit the progression of diffuse large B-cell lymphoma
Authors: Liu Qinhua , Dai Guanrong , Wu Yi , Zhang Mingxia , Yang Mingya , Wang Xiaonan , Song Mingyue , Li Xiaodan , Xia Ruixiang , Wu Zhengsheng
Published: August 2022

Clinical applications of siRNA therapeutics have been limited by the immunogenicity of the siRNA and low efficiency of siRNA delivery to target cells. Recently, evidence have shown that exosomes, endogenous nano-vesicles, can deliver siRNA to the tumor tissues in mice. Here, to reduce immunogenicity, we selected immature dendritic cells (DCs) to produce exosomes. In addition, tumor targeting was achieved by engineering the DCs to express exosomal membrane protein (Lamp2b), fused to av integrin-specific iRGD peptide (CRGDKGPDC). Next, iRGD targeted exosomes (iRGD-Exo) were isolated from the transfected DCs, and then the isolated exosomes were loaded with BCL6 siRNA by electroporation. Our results found that integrin (αvβ3) receptors were highly expressed on OCI-Ly8 cells. In addition, iRGD-Exo showed high targeting ability with avβ3 integrins positive OCI-Ly8 cells. Significantly, iRGD-Exo loaded with BCL6 siRNA suppressed DLBCL cell proliferation in vitro. Furthermore, intravenously injected iRGD-Exo delivered BCL6 siRNA to tumor tissues, resulting in inhibition of tumor growth in DLBCL. Meanwhile, exosomes mediated BCL6 siRNA delivery did not exhibit appreciable toxicity in mice. Collectively, our study demonstrates a therapeutic potential of exosomes as a promising vehicle for RNAi delivery to treat DLBCL.
Hot flushes and sweating, sleep problems, joint and muscular discomfort, and physical and mental exhaustion in breast cancer survivors during the first 24 months of tamoxifen therapy: a prospective observational study
Authors: Sung Sumi , Min Yul Ha , Park Seul Ki , Lee Sae Byul
Published: August 2022

Purpose

This study aimed to explore symptom trajectories over 24 months for hot flushes and sweating, sleep problems, joint and muscular discomfort, and physical and mental exhaustion experienced by premenopausal women diagnosed with tamoxifen-treated breast cancer.

Methods

A total of 104 patients participated in the study. The menopausal symptoms were examined using the Menopausal Rating Scale at baseline, 3–6, 12, and 18–24 months after initiating tamoxifen. The changes over four time points were analyzed using repeated measures analysis of variance. The chi-square test was used to examine the differences between “no symptom-to-mild” and “moderate-to-extremely severe” 3–6 months after initiating tamoxifen according to the patients’ chemotherapy treatment experiences.

Results

All menopausal symptoms occurred in > 70% of patients with breast cancer and persisted until 24 months. More than 50% of patients experienced four menopausal symptoms, with at least two at a serious severity level after initiating tamoxifen. Hot flushes and sweating occurred in the highest number of patients, recording high scores. Sleep problems and physical and mental exhaustion exhibited relatively high scores, even before tamoxifen initiation. There were significant changes over four time points in all symptoms. Young patients aged < 40 years experienced more severe sleep problems, and patients who had previously received chemotherapy experienced more severe joint and muscular discomfort.

Conclusions

This study’s findings may assist in alerting healthcare providers to menopausal symptoms that develop during tamoxifen therapy and the need for early and active intervention to minimize symptom occurrence and distress.
Interplay Between Chemotherapy-Activated Cancer Associated Fibroblasts and Cancer Initiating Cells Expressing CD44v6 Promotes Colon Cancer Resistance
Authors: Ghatak Shibnath , Hascall Vincent C. , Karamanos Nikos , Markwald Roger R. , Misra Suniti
Published: August 2022

Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs
TElomeric repeat-containing RNA (TERRA): Physiological functions and relevance in cancer
Authors: Kroupa Michal , Tomasova Kristyna , Kavec Miriam , Skrobanek Pavel , Buchler Tomas , Kumar Rajiv , Vodickova Ludmila , Vodicka Pavel
Published: August 2022

Telomeres are complex protective structures located at the ends of linear eukaryotic chromosomes. Their purpose is to prevent genomic instability. Research progress in telomere biology during the past decades has identified a network of telomeric transcripts of which the best-studied is TElomeric Repeat-containing RNA (TERRA). TERRA was shown to be important not only for the preservation of telomere homeostasis and genomic stability but also for the expression of hundreds of genes across the human genome. These findings added a new level of complexity to telomere biology. Herein we provide insights on the telomere transcriptome, its relevance for proper telomere function, and its implications in human pathology. We also discuss possible clinical opportunities of exosomal telomere transcripts detection as a biomarker in cancer precision medicine.
Complex metabolic interactions between ovary, plasma, urine, and hair in ovarian cancer
Authors: Zhong Xiaocui , Ran Rui , Gao Shanhu , Shi Manlin , Shi Xian , Long Fei , Zhou Yanqiu , Yang Yang , Tang Xianglan , Lin Anping , He Wuyang , Yu Tinghe , Han Ting-Li
Published: August 2022

Ovarian cancer (OC) is the third most common malignant tumor of women accompanied by alteration of systemic metabolism, yet the underlying interactions between the local OC tissue and other system biofluids remain unclear. In this study, we recruited 17 OC patients, 16 benign ovarian tumor (BOT) patients, and 14 control patients to collect biological samples including ovary plasma, urine, and hair from the same patient. The metabolic features of samples were characterized using a global and targeted metabolic profiling strategy based on Gas chromatography-mass spectrometry (GC-MS). Principal component analysis (PCA) revealed that the metabolites display obvious differences in ovary tissue, plasma, and urine between OC and non-malignant groups but not in hair samples. The metabolic alterations in OC tissue included elevated glycolysis (lactic acid) and TCA cycle intermediates (malic acid, fumaric acid) were related to energy metabolism. Furthermore, the increased levels of glutathione and polyunsaturated fatty acids (linoleic acid) together with decreased levels of saturated fatty acid (palmitic acid) were observed, which might be associated with the anti-oxidative stress capability of cancer. Furthermore, how metabolite profile changes across differential biospecimens were compared in OC patients. Plasma and urine showed a lower concentration of amino acids (alanine, aspartic acid, glutamic acid, proline, leucine, and cysteine) than the malignant ovary. Plasma exhibited the highest concentrations of fatty acids (stearic acid, EPA, and arachidonic acid), while TCA cycle intermediates (succinic acid, citric acid, and malic acid) were most concentrated in the urine. In addition, five plasma metabolites and three urine metabolites showed the best specificity and sensitivity in differentiating the OC group from the control or BOT groups (AUC > 0.90) using machine learning modeling. Overall, this study provided further insight into different specimen metabolic characteristics between OC and non-malignant disease and identified the metabolic fluctuation across ovary and biofluids.
Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor–resistant pancreatic ductal adenocarcinoma
Authors: Malvi Parmanand , Rawat Vipin , Gupta Romi , Wajapeyee Narendra
Published: August 2022

Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
Construction of an immune-related gene signature for the prognosis and diagnosis of glioblastoma multiforme
Authors: Yu Ziye , Yang Huan , Song Kun , Fu Pengfei , Shen Jingjing , Xu Ming , Xu Hongzhi
Published: August 2022

Background

Increasing evidence has suggested that inflammation is related to tumorigenesis and tumor progression. However, the roles of immune-related genes in the occurrence, development, and prognosis of glioblastoma multiforme (GBM) remain to be studied.

Methods

The GBM-related RNA sequencing (RNA-seq), survival, and clinical data were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Immune-related genes were obtained from the Molecular Signatures Database (MSigDB). Differently expressed immune-related genes (DE-IRGs) between GBM and normal samples were identified. Prognostic genes associated with GBM were selected by Kaplan–Meier survival analysis, Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox regression analysis, and multivariate Cox analysis. An immune-related gene signature was developed and validated in TCGA and CGGA databases separately. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore biological functions of the signature. The correlation between immune cell infiltration and the signature was analyzed by single-sample gene set enrichment analysis (ssGSEA), and the diagnostic value was investigated. The gene set enrichment analysis (GSEA) was performed to explore the potential function of the signature genes in GBM, and the protein–protein interaction (PPI) network was constructed.

Results

Three DE-IRGs [Pentraxin 3 (PTX3),TNFSF9, and bone morphogenetic protein 2 (BMP2)] were used to construct an immune-related gene signature. Receiver operating characteristic (ROC) curves and Cox analyses confirmed that the 3-gene-based prognostic signature was a good independent prognostic factor for GBM patients. We found that the signature was mainly involved in immune-related biological processes and pathways, and multiple immune cells were disordered between the high- and low-risk groups. GSEA suggested thatPTX3andTNFSF9were mainly correlated with interleukin (IL)-17 signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and Toll-like receptor signaling pathway, and the PPI network indicated that they could interact directly or indirectly with inflammatory pathway proteins. Quantitative real-time PCR (qRT-PCR) indicated that the three genes were significantly different between target tissues.

Conclusion

The signature with three immune-related genes might be an independent prognostic factor for GBM patients and could be associated with the immune cell infiltration of GBM patients.
Comprehensive analysis of the potential cuproptosis-related biomarker LIAS that regulates prognosis and immunotherapy of pan-cancers
Authors: Cai Yuan , He Qingchun , Liu Wei , Liang Qiuju , Peng Bi , Li Jianbo , Zhang Wenqin , Kang Fanhua , Hong Qianhui , Yan Yuanliang , Peng Jinwu , Xu Zhijie , Bai Ning
Published: August 2022

Lipoic acid synthetase (LIAS) has been demonstrated to play a crucial role in the progression of cancer. Exploring the underlying mechanisms and biological functions of LIAS could have potential therapeutic guidance for cancer treatment. Our study has explored the expression levels and prognostic values of LIAS in pan-cancer through several bioinformatics platforms, including TIMER2.0, Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), and Human Protein Atlas (HPA). We found that a high LIAS expression was related to the good prognosis in patients with kidney renal clear cell carcinoma (KIRC), rectum adenocarcinoma (READ), breast cancer, and ovarian cancer. Inversely, a high LIAS expression showed unfavorable prognosis in lung cancer patients. In addition, the genetic alteration, methylation levels, and immune analysis of LIAS in pan-cancer have been evaluated. To elucidate the underlying molecular mechanism of LIAS, we conduct the single-cell sequencing to implicate that LIAS expression was related to hypoxia, angiogenesis, and DNA repair. Thus, these comprehensive pan-cancer analyses have conveyed that LIAS could be potentially significant in the progression of various cancers. Moreover, the LIAS expression could predict the efficacy of immunotherapy in cancer patients.
Impact of maternal gestational weight gain in twin pregnancies on early childhood obesity risk: A longitudinal birth cohort study
Authors: Li Sisi , Qiu Yuhan , Yuan Xi , Zhang Qin , Kilby Mark D. , Saffery Richard , Baker Philip N. , Wen Li , Tong Chao , Qi Hongbo
Published: August 2022

Objectives

To investigate the impact of gestational weight gain (GWG) on the body mass index-for-age z score (BAZ) and obesity risk among twin offspring.

Methods

This study included 263 women who were pregnant with twins and their offspring. Maternal GWG was measured in each trimester, and infant weight and length were measured at 6, 12, and 24 months.

Results

Total GWG was positively correlated with offspring birthweight and BAZ at 6, 12 and 24 months [adjusted β 0.013 (95% CI: 0.008–0.019), 0.028 (95% CI: 0.005–0.050), 0.033 (95% CI: 0.010–0.056) and 0.025 (95% CI: 0.004–0.047), respectively]. Excessive total GWG was related to an increased relative risk (RR) of large for gestational age (LGA) and overweight at 6 and 12 months. Only the second trimester gestational weight gain rate (GWGR) was positively correlated with birthweight (adjusted β 0.380, 95% CI: 0.256–0.504), and RRs of 6.818 (95% CI: 1.568–29.642) and 2.852 (95% CI: 1.466–5.548) were found for LGA and overweight at 12 months, respectively.

Conclusions

Total GWG and the second trimester GWGR were correlated with BAZ and overweight/obesity risk in twin offspring; the impact was obvious in the first year of life and gradually disappeared over time.

Clinical trial registration

ChiCTR-OOC-16008203, Registered on 1 April 2016 at the Chinese Clinical Trial Registry.
Protective effect of Astragaloside IV on chronic intermittent hypoxia-induced vascular endothelial dysfunction through the calpain-1/SIRT1/AMPK signaling pathway
Authors: Zhao Fang , Meng Yan , Wang Yue , Fan Siqi , Liu Yu , Zhang Xiangfeng , Ran Chenyang , Wang Hongxin , Lu Meili
Published: August 2022

Vascular endothelial dysfunction (VED) is linked with the pathogenesis of obstructive sleep apnea (OSA) comorbidities, such as cardiovascular disease. Astragaloside IV (As-IV) has exhibited significant improvement for endothelial dysfunction. Nonetheless, the protective mechanism is not clear. Therefore, the present study investigated the potential mechanism of As-IV on VED. Calpain-1 knockout and wild-type C57BL/6 mice exposed to chronic intermittent hypoxia (CIH) were established and treated with As-IV (40, 80 mg/kg) for 4 weeks. Human coronary artery endothelial cells (HCAECs) subjected to CIH exposure were pretreated with As-IV, MDL-28170 (calpain-1 inhibitor) and SRT1720 (SIRT1 activator) for 48 h in vitro. The endothelial function, inflammation, oxidative stress and mitochondrial function were measured to evaluate VED. Our data revealed that As-IV treatment ameliorated CIH-induced endothelial-dependent vasomotion and augmented nitric oxide (NO) production. As-IV administration suppressed the secretion of inflammation, oxidative stress and mitochondrial dysfunction. As-IV treatment reduced the expression of calpain-1 and restored the downregulated expression of SIRT1 and Thr172 AMPK and Ser1177 eNOS phosphorylation. The effects of calpain-1 knockout and SRT1720 were similar to the effect of As-IV on VED. These findings demonstrated that As-IV ameliorated VED induced by chronic intermittent hypoxia via the calpain-1/SIRT1/AMPK signaling pathway.
Fucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets
Authors: Mumu Mumtaza , Das Ayan , Emran Talha Bin , Mitra Saikat , Islam Fahadul , Roy Arpita , Karim Md. Mobarak , Das Rajib , Park Moon Nyeo , Chandran Deepak , Sharma Rohit , Khandaker Mayeen Uddin , Idris Abubakr M. , Kim Bonglee
Published: August 2022

Fucoxanthin (FX) is a special carotenoid having an allenic bond in its structure. FX is extracted from a variety of algae and edible seaweeds. It has been proved to contain numerous health benefits and preventive effects against diseases like diabetes, obesity, liver cirrhosis, malignant cancer, etc. Thus, FX can be used as a potent source of both pharmacological and nutritional ingredient to prevent infectious diseases. In this review, we gathered the information regarding the current findings on antimicrobial, antioxidant, anti-inflammatory, skin protective, anti-obesity, antidiabetic, hepatoprotective, and other properties of FX including its bioavailability and stability characteristics. This review aims to assist further biochemical studies in order to develop further pharmaceutical assets and nutritional products in combination with FX and its various metabolites.
Biochemical Changes in Two Barley Genotypes Inoculated With a Beneficial Fungus Trichoderma harzianum Rifai T-22 Grown in Saline Soil
Authors: Gupta Sneha Vinay Kumar , Smith Penelope M. C. , Natera Siria H. A. , Roessner Ute
Published: August 2022

One of the most important environmental factors impacting crop plant productivity is soil salinity. Fungal endophytes have been characterised as biocontrol agents that help in plant productivity and induce resistance responses to several abiotic stresses, including salinity. In the salt-tolerant cereal crop barley (Hordeum vulgare L.), there is limited information about the metabolites and lipids that change in response to inoculation with fungal endophytes in saline conditions. In this study, gas chromatography coupled to mass spectrometry (GC–MS) and LC–electrospray ionisation (ESI)–quadrupole–quadrupole time of flight (QqTOF)-MS were used to determine the metabolite and lipid changes in two fungal inoculated barley genotypes with differing tolerance levels to saline conditions. The more salt-tolerant cultivar was Vlamingh and less salt tolerant was Gairdner. Trichoderma harzianum strain T-22 was used to treat these plants grown in soil under control and saline (200 mM NaCl) conditions. For both genotypes, fungus-colonised plants exposed to NaCl had greater root and shoot biomass, and better chlorophyll content than non-colonised plants, with colonised-Vlamingh performing better than uninoculated control plants. The metabolome dataset using GC–MS consisted of a total of 93 metabolites of which 74 were identified in roots of both barley genotypes as organic acids, sugars, sugar acids, sugar alcohols, amino acids, amines, and a small number of fatty acids. LC-QqTOF-MS analysis resulted in the detection of 186 lipid molecular species, classified into three major lipid classes—glycerophospholipids, glycerolipids, and sphingolipids, from roots of both genotypes. In Cultivar Vlamingh both metabolites and lipids increased with fungus and salt treatment while in Gairdner they decreased. The results from this study suggest that the metabolic pathways by which the fungus imparts salt tolerance is different for the different genotypes.