Associations of 10 dietary habits with breast cancer: a Mendelian randomization study.

Introduction: Epidemiological studies have revealed a link between dietary habits and the breast cancer risk. The causality of the association between food consumption and breast cancer requires further investigation. Methods: Using Mendelian randomization, we assessed the causal effects of 10 dietary habits on the risks of breast cancer and its subtypes (estrogen receptor [ER] + and ER- breast cancer). We obtained dietary pattern data in 2018 (number of single-nucleotide polymorphisms [SNPs] = 9,851,867) and breast cancer data in 2017 (number of SNPs = 10,680,257) from IEU OpenGWAS. Rigorous sensitivity analyses were conducted to ensure that the study results were credible and robust. Results: We identified that genetic predisposition to higher dried fruit intake was linked to a reduced risk of overall breast cancer (inverse variance-weighted [IVW] odds ratio [OR] = 0.55; 95% confidence interval [CI]: 0.43-0.70; p = 1.75 × 10-6), ER+ breast cancer (IVW OR = 0.62; 95% CI: 0.47-0.82; p = 8.96 × 10-4) and ER- breast cancer (IVW OR = 0.48; 95% CI: 0.34-0.68; p = 3.18 × 10-5), whereas genetic predisposition to more oily fish intake was linked to a lower risk of ER+ breast cancer (IVW OR = 0.73; 95% CI: 0.53-0.99; p = 0.04). Discussion: Our findings suggest that a genetic predisposition for dried fruit and oily fish consumption may be protective against breast cancer; however, further investigation is required.

Causal pathways linking polycystic ovary syndrome to distinct breast cancer subtypes through mediator factors: a multivariable mendelian randomization analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovarian cysts, high androgen levels, and irregular menstruation. The causality between PCOS and breast cancer (BC) has been widely discussed as they share a significant intersection in clinical manifestations. Previous epidemiological studies have not provided consistent conclusions in association between PCOS and BC, while mendelian randomization (MR) analyses have confirmed the causality between PCOS and estrogen receptor-positive breast cancer (ER + BC), but among a series of clinical manifestations resulting from PCOS, which related traits mediate the causal effect remains unknown. In this study, we conducted multivariable mendelian randomization (MVMR) analysis to explore the potential mediator variables in the mechanism linking PCOS to distinct subtypes of BC, and calculated the mediating effects proportion. We analyzed 13 PCOS-related traits and found that age at menopause may mediate PCOS-induced ER + BC (with -4.82% proportion) with a weak protective effect through the repair of DNA double-strand breaks by homologous recombination. This study helps to better comprehend the shared mechanisms contributing to the development of both PCOS and BC, and to screen high-risk populations for BC and take appropriate preventive measures.

Cationic lipid-assisted nanoparticles for simultaneous delivery of CD47 siRNA and R848 to promote antitumor immune responses.

Introduction: Triple-negative breast cancer (TNBC) usually has a poor prognosis. Although the immunotherapy of TNBC has achieved great progress, only a few patients can benefit from the current treatment. CD47 is widely expressed on the surface of TNBC cells and may become an immune checkpoint for TNBC treatment. Nevertheless, increasingly more attention has been paid to systemic side effects since the ubiquitous expression of CD47 on normal cells. The toll-like receptor (TLR) agonist resiquimod (R848) can activate dendritic cells (DCs) and promote the maturation of immune cells in the tumor microenvironment, which further enhances the tumor inhibition ability of the immune system and synergizes with CD47 small interfering RNA (siRNA) for TNBC therapy. However, ideal delivery platforms such as nanocarriers are still needed because its weakness of hydrophobicity. Methods: In order to improve efficacy and reduce toxicity, R848 and siCD47 were entrapped in amphiphilic PEG-PLGA nanoparticles by double emulsification and stable nanoparticles NP/R848/siCD47 were generated to investigate their anti-tumor effects in a TNBC tumor-bearing mouse model. Results: Here, we show that PEG-PLGA nanoparticles are effective nanocarriers that can safely and effectively deliver siCD47 and R848 to tumor tissue, as demonstrated by retarded tumor growth. Mechanistically, downregulation of CD47 expression and activation of DCs took part in promoting the immune response of cytotoxic T cells (CTLs). Meanwhile, a decrease of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) indicated the modulating of the tumor immune microenvironment. Discussion: To our best knowledge, our study pioneered co-delivery system for hydrophilic siCD47 and hydrophobic R848. It can maximize break tumor immune escape caused by CD47 and simultaneously enhance antigen presentation by activating DCs for effector T cell killing while regulating the tumor microenvironment as expected. Not only does it conform to the reports of previous basic research, but also it can break the bottleneck of their clinical application hopefully. Collectively, our findings could lay the foundation for future therapeutic strategies of TNBC.

Domain and cell type-specific immunolocalisation of voltage-gated potassium channels in the mouse striatum.

Diverse classes of voltage-gated potassium channels (Kv) are integral to the variety of electrical activity patterns that distinguish different classes of neurons in the brain. A feature of their heterogenous expression patterns is the highly precise manner in which specific cell types target their location within functionally specialised sub-cellular domains. Although Kv expression profiles in cortical brain regions are widely reported, their immunolocalisation in sub-cortical areas such as the striatum, and in associated diseases such as Parkinson's disease (PD), remain less well described. Therefore, the broad aims of this study were to provide a high resolution immunolocalisation analysis of various Kv subtypes within the mouse striatum and assess their potential plasticity in a model of PD. Immunohistochemistry and confocal microscopy revealed that immunoreactivity for Kv1.1, 1.2 and 1.4 overlapped to varying degrees with excitatory and inhibitory axonal marker proteins suggesting these Kv subtypes are targeted to axons innervating striatal medium spiny neurons (MSNs). Immunoreactivity for Kv1.3 strongly overlapped with signal for mitochondrial marker proteins in MSN somata and dendrites. Kv1.5 immunoreactivity was expressed in parvalbumin-immunopositive neurons whereas Kv1.6 was located in cells immunopositive for microglia. Signal for Kv2.1 was concentrated on the somatic and proximal dendritic plasma membrane of MSNs, whilst immunoreactivity for Kv4.2 was targeted to their distal dendritic regions. Finally, striatal Kv2.1 expression, at both the mRNA and protein levels, was decreased in alpha-synuclein overexpressing mice, yet increased in alpha-synuclein knockout mice, compared to wild-type counterparts. The data indicate a variety of Kv expression patterns that are distinctive to the striatum and susceptible to pathology that mirrors PD. Furthermore, these findings advance our understanding of the molecular diversity of various striatal cell types, and potentially have implications for the homeostatic changes of MSN excitability during associated medical conditions such as PD.

Association Between Dopaminergic Medications and the Evolution of REM Sleep Behavior Disorder in Parkinson's Disease.

REM sleep behavior disorder (RBD) is closely associated with Parkinson's disease (PD), however, the influence of dopaminergic replacement therapy (DRT) on the clinical course of RBD in PD remains less understood. The objective of our study is to investigate how DRTs modify the evolution of RBD in a longitudinal cohort study of initially de novo PD patients. Four hundred and five drug-naive patients with early-stage PD were included. RBD symptoms were assessed using the 10-item RBD Screening Questionnaire (RBDSQ) at baseline and during the 5-year follow-up. A generalized estimating equation was used to examine predictors of the evolution of RBD symptoms. For patients without baseline pRBD, patients on levodopa treatment showed a greater increase in RBDSQ scores than those not on levodopa treatment, and the increase in RBDSQ scores was significantly correlated with the levodopa-LEDD. Moreover, the changes in RBDSQ scores at a given post-baseline visit were significantly associated with the use of levodopa (OR = 1.875, p = 0.008) and the combined use of levodopa and DA (OR = 2.188, p = 0.012), as well as the levodopa-LEDD (OR = 1.001, p = 0.005) at that visit. The use of DA alone or the DA-LEDD was not a significant predictor of changes in RBDSQ scores. Similarly, a conversion from pRBD negative to pRBD positive was significantly associated with levodopa-LEDD (OR = 1.001, p = 0.014) but not DA-LEDD. Together, these finding implicated that the use of levodopa may act as a contributing factor to the increasing prevalence of RBD after the onset of PD, suggesting different mechanisms underlying prodromal RBD and late-onset RBD.

Obstructive sleep apnea is associated with cognitive impairment in minor ischemic stroke.

OBJECTIVES: Obstructive sleep apnea (OSA) is commonly seen in stroke patients, and its relationship with cognitive impairment remains poorly understood. This study aimed to explore the roles of OSA in cognition impairment in patients with minor ischemic stroke. METHODS: Patients with minor ischemic stroke were consecutively enrolled from January 2020 to May 2021. Every patient underwent polysomnography (PSG) to assess for OSA. Based on the apnea hypopnea index (AHI), patients were grouped into the no OSA (AHI < 5), mild OSA (5 ≤ AHI < 15), and moderate-to-severe OSA (MS OSA, AHI ≥ 15) groups. Neuropsychological assessments were performed to evaluate cognitive function, and the correlations between cognitive function and OSA were investigated. RESULTS: Of 94 patients, 35 had no OSA, 32 had mild OSA, and 27 had moderate-to-severe OSA. Compared to the no or mild OSA groups, the moderate-to-severe OSA group performed worse on the Chinese version of the Auditory Verbal Learning Test (CAVLT)-Recognition (p < 0.001), Digital Span Test (DST)-Backward (p < 0.001), Montreal Cognitive Assessment (MoCA) (p < 0.001), and Stroop Color and Word Test (SCWT)-Interference (p < 0.001). The severity of cognitive impairment was assessed using the MoCA, which was negatively related to the AHI (p = 0.041) and lowest SpO2 (p = 0.048). CONCLUSIONS: The findings suggest that OSA has significant effects on cognition impairment in patients with minor ischemic stroke and that hypoxemia may be a potential pathophysiological mechanism of OSA-induced cognitive impairment.

Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability.

AIMS: Amyloid ß-oligomers (AßO) are potent modulators of Alzheimer's pathology, yet their impact on one of the earliest brain regions to exhibit signs of the condition, the locus coeruleus (LC), remains to be determined. Of particular importance is whether AßO impact the spontaneous excitability of LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all compromised in Alzheimer's patients. Therefore, the aim of the study was to determine the expression profile of AßO in the LC of Alzheimer's patients and to probe their potential impact on the molecular and functional correlates of LC excitability, using a mouse model of increased Aß production (APP-PSEN1). METHODS AND RESULTS: Immunohistochemistry and confocal microscopy, using AßO-specific antibodies, confirmed LC AßO expression both intraneuronally and extracellularly in both Alzheimer's and APP-PSEN1 samples. Patch clamp electrophysiology recordings revealed that APP-PSEN1 LC neuronal hyperexcitability accompanied this AßO expression profile, arising from a diminished inhibitory effect of GABA due to impaired expression and function of the GABA-A receptor (GABAA R) α3 subunit. This altered LC α3-GABAA R expression profile overlapped with AßO expression in samples from both APP-PSEN1 mice and Alzheimer's patients. Finally, strychnine-sensitive glycine receptors (GlyRs) remained resilient to Aß-induced changes and their activation reversed LC hyperexcitability. CONCLUSIONS: The data suggest a close association between AßO and α3-GABAA Rs in the LC of Alzheimer's patients, and their potential to dysregulate LC activity, thereby contributing to the spectrum of pathology of the LC-NA system in this condition.

The Prediction of Infectious Diseases: A Bibliometric Analysis.

OBJECTIVE: The outbreak of infectious diseases has a negative influence on public health and the economy. The prediction of infectious diseases can effectively control large-scale outbreaks and reduce transmission of epidemics in rapid response to serious public health events. Therefore, experts and scholars are increasingly concerned with the prediction of infectious diseases. However, a knowledge mapping analysis of literature regarding the prediction of infectious diseases using rigorous bibliometric tools, which are supposed to offer further knowledge structure and distribution, has been conducted infrequently. Therefore, we implement a bibliometric analysis about the prediction of infectious diseases to objectively analyze the current status and research hotspots, in order to provide a reference for related researchers. METHODS: We viewed "infectious disease*" and "prediction" or "forecasting" as search theme in the core collection of Web of Science from inception to 1 May 2020. We used two effective bibliometric tools, i.e., CiteSpace (Drexel University, Philadelphia, PA, USA) and VOSviewer (Leiden University, Leiden, The Netherlands) to objectively analyze the data of the prediction of infectious disease domain based on related publications, which can be downloaded from the core collection of Web of Science. Then, the leading publications of the prediction of infectious diseases were identified to detect the historical progress based on collaboration analysis, co-citation analysis, and co-occurrence analysis. RESULTS: 1880 documents that met the inclusion criteria were extracted from Web of Science in this study. The number of documents exhibited a growing trend, which can be expressed an increasing number of experts and scholars paying attention to the field year by year. These publications were published in 427 different journals with 11 different document types, and the most frequently studied types were articles 1618 (83%). In addition, as the most productive country, the United States has provided a lot of scientific research achievements in the field of infectious diseases. CONCLUSION: Our study provides a systematic and objective view of the field, which can be useful for readers to evaluate the characteristics of publications involving the prediction of infectious diseases and for policymakers to take timely scientific responses.

A miR-210-3p regulon that controls the Warburg effect by modulating HIF-1α and p53 activity in triple-negative breast cancer.

Reprogrammed energy metabolism, especially the Warburg effect (aerobic glycolysis), is an emerging hallmark of cancer. Different from other breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits high metabolic remodeling, increased aggressiveness and lack of targeted therapies. MicroRNAs (miRNA) are essential to TNBC malignant phenotypes. However, little is known about the contribution of miRNA to aerobic glycolysis in TNBC. Through an integrated analysis and functional verification, we reported that several miRNAs significantly correlates to the Warburg effect in TNBC, including miR-210-3p, miR-105-5p, and miR-767-5p. Ectopic expression of miR-210-3p enhanced glucose uptake, lactate production, extracellular acidification rate, colony formation ability, and reduced serum starvation-induced cell apoptosis. Moreover, GPD1L and CYGB were identified as two functional mediators of miR-210-3p in TNBC. Mechanistically, miR-210-3p targeted GPD1L to maintain HIF-1α stabilization and suppressed p53 activity via CYGB. Ultimately, miR-210-3p facilitated aerobic glycolysis through modulating the downstream glycolytic genes of HIF-1α and p53. Taken together, our results decipher miRNAs that regulate aerobic glycolysis and uncover that miR-210-3p specifically contributes to the Warburg effect in TNBC.

Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels.

TREK-1 channel activity is a critical regulator of neuronal, cardiac, and smooth muscle physiology and pathology. The antidepressant peptide, spadin, has been proposed to be a TREK-1-specific blocker. Here we sought to examine the mechanism of action underlying spadin inhibition of TREK-1 channels. Heterologous expression in Xenopus laevis oocytes and electrophysiological analysis using two-electrode voltage clamp in standard bath solutions was used to characterize the pharmacological profile of wild-type and mutant murine TREK-1 and TREK-2 channels using previously established human K2P activators; arachidonic acid (AA), cis-4,7,10,13,16,19-docosahexaenoic acid (DHA), BL-1249, and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and inhibitors; spadin and barium (Ba2+). Mouse TREK-1 and TREK-2 channel currents were both significantly increased by AA, BL-1249, and CDC, similar to their human homologs. Under basal conditions, both TREK-1 and TREK-2 currents were insensitive to application of spadin, but could be blocked by Ba2+. Spadin did not significantly inhibit either TREK-1 or TREK-2 currents either chemically activated by AA, BL-1249, or CDC, or structurally activated via a gating mutation. However, pre-exposure to spadin significantly perturbed the subsequent activation of TREK-1 currents by AA, but not TREK-2. Furthermore, spadin was unable to prevent activation of TREK-1 by BL-1249, CDC, or the related bioactive lipid, DHA. Spadin specifically antagonizes the activation of TREK-1 channels by AA, likely via an allosteric mechanism. Lack of intrinsic activity may explain the absence of clinical side effects during antidepressant therapy.

Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer.

BACKGROUND: Hypoxia is an important environmental factor and has been correlated with tumor progression, treatment resistance and poor prognosis in many solid tumors, including triple-negative breast cancer (TNBC). Emerging evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in tumor biology. However, little is known about the link between hypoxia and lncRNAs in TNBC. METHODS: TNBC molecular profiles from The Cancer Genome Atlas (TCGA) were leveraged to identify hypoxia-related molecular alterations. Loss-of-function studies were performed to determine the regulatory role of MIR210HG in tumor glycolysis. The potential functions and mechanisms of hypoxia-MIR210HG axis were explored using qPCR, Western blotting, luciferase reporter assay, and polysome profiling. RESULTS: We found that MIR210HG is a hypoxia-induced lncRNA in TNBC. Loss-of-function studies revealed that MIR210HG promoted the Warburg effect as demonstrated by glucose uptake, lactate production and expression of glycolytic components. Mechanistically, MIR210HG potentiated the metabolic transcription factor hypoxia-inducible factor 1α (HIF-1α) translation via directly binding to the 5'-UTR of HIF-1α mRNA, leading to increased HIF-1a protein level, thereby upregulating expression of glycolytic enzymes. MIR210HG knockdown in TNBC cells reduced their glycolytic metabolism and abolished their tumorigenic potential, indicating the glycolysis-dependent oncogenic activity of MIR210HG in TNBC. Moreover, MIR210HG was highly expressed in breast cancer and predicted poor clinical outcome. CONCLUSION: Our results decipher a positive feedback loop between hypoxia and MIR210HG that drive the Warburg effect and suggest that MIR210HG may be a good prognostic marker and therapeutic target for TNBC patients.

TREK-1 Channel Expression in Smooth Muscle as a Target for Regulating Murine Intestinal Contractility: Therapeutic Implications for Motility Disorders.

Gastrointestinal (GI) motility disorders such as irritable bowel syndrome (IBS) can occur when coordinated smooth muscle contractility is disrupted. Potassium (K+) channels regulate GI smooth muscle tone and are key to GI tract relaxation, but their molecular and functional phenotypes are poorly described. Here we define the expression and functional roles of mechano-gated K2P channels in mouse ileum and colon. Expression and distribution of the K2P channel family were investigated using quantitative RT-PCR (qPCR), immunohistochemistry and confocal microscopy. The contribution of mechano-gated K2P channels to mouse intestinal muscle tension was studied pharmacologically using organ bath. Multiple K2P gene transcripts were detected in mouse ileum and colon whole tissue preparations. Immunohistochemistry confirmed TREK-1 expression was smooth muscle specific in both ileum and colon, whereas TREK-2 and TRAAK channels were detected in enteric neurons but not smooth muscle. In organ bath, mechano-gated K2P channel activators (Riluzole, BL-1249, flufenamic acid, and cinnamyl 1-3,4-dihydroxy-alpha-cyanocinnamate) induced relaxation of KCl and CCh pre-contracted ileum and colon tissues and reduced the amplitude of spontaneous contractions. These data reveal the specific expression of mechano-gated K2P channels in mouse ileum and colon tissues and highlight TREK-1, a smooth muscle specific K2P channel in GI tract, as a potential therapeutic target for combating motility pathologies arising from hyper-contractility.