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Abstract Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive type of breast cancer, yet its defining genomic, molecular, and immunological features remain largely unknown. In this study, we performed the largest and most comprehensive genomic and transcriptomic analyses of prospectively collected TN-IBC patient samples from a phase II clinical trial (ClinicalTrials.gov, NCT02876107, registered on August 22, 2016) and compared them to similarly analyzed stage III TN-non-IBC patient samples (ClinicalTrials.gov, NCT02276443, registered on October 21, 2014). We found that TN-IBC tumors have distinctive genomic, molecular, and immunological characteristics, including a lower tumor mutation load than TN-non-IBC, and an association of immunosuppressive tumor-infiltrating immune components with an unfavorable response to neoadjuvant chemotherapy. To our knowledge, this is the only study in which TN-IBC and TN-non-IBC samples were collected prospectively. Our analysis improves the understanding of the molecular landscape of the most aggressive subtype of breast cancer. Further studies are needed to discover novel prognostic biomarkers and druggable targets for TN-IBC.

Abstract Reactive oxygen species (ROS)‐induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)‐mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS‐mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8‐oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8‐oxo‐7,8‐dihydroguanine (8‐oxoG), recruiting NF‐κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E‐cadherin‐loaded EVs, which depletes intracellular E‐cadherin, thereby inducing epithelial‐mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8‐oxoG/OGG1/SYT7 axis‐driven EVs release in oxidative stress‐induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

Abstract The catalytic valorisation of biomass to afford synthetically useful small molecules is essential for sustainable biorefinery processes. Herein, we present a mild cascaded electrochemical protocol for converting furoic acid, a common biomass-derived feedstock, into a versatile platform chemical, gamma-butyrolactone. In the platinum(+)|nickel(−) electrode paired undivided cell, furoic acid is electrochemically oxidised with 84.2% selectivity to 2(5H)-furanone, the olefin of which is then hydrogenated to yield gamma-butyrolactone with 98.5% selectivity. The final gamma-butyrolactone yield is 69.1% with 38.3% Faradaic efficiency and 80.1% carbon balance when the reaction is performed with 100 mM furoic acid at 80 °C at +2.0 VAg/AgCl. Mechanistic investigation revealed the critical temperature and electrolyte pH conditions that maximise the production and protection of the key intermediate, furan radical, promoting its transition to 2(5H)-furanone rather than self-polymerising. The reaction is scalable, as 2.1 g of 98.1% pure gamma-butyrolactone is isolated through a simple solvent extraction.

Abstract Aim Atrial fibrillation (AF) is a progressive disease from paroxysmal to persistent, and persistent AF (PerAF) had worse prognosis. AF has potential link with inflammation, but it is not clear whether PerAF or paroxysmal AF (ParAF) is more closely related to inflammation. On the basis of inhibiting myocardial physiological uptake, 18F-fluorodeoxyglucosepositron emission tomography/computed tomography (18F-FDG PET/CT) is an established imaging modality to detect cardiac inflammation. We aimed to decipher the association between AF and atrial inflammatory activity by 18F-FDG PET/CT. Methods Thirty-five PerAF patients were compared to age and sex matched ParAF group with baseline 18F-FDG PET/CT scans prior to radiofrequency catheter ablation (RFCA) in the prospective case-control study. High-fat and low-carbohydrate diet and prolonged fast (HFLC+Fast) was applied to all AF patients before PET/CT. Then 22 AF patients with positive right atrial (RA) wall FDG uptake (HFLC+Fast) were randomly selected and underwent HFLC+Fast+heparin the next day. The CHA2DS2-VASc score was calculated to evaluate the risk of stroke. Clinical data, ECG, echocardiography, and atrial 18F-FDG uptake were compared. Results PerAF patients had significantly higher probability of RA wall positive FDG uptake and higher SUVmax than ParAF group [91.4% VS. 28.6%, P

Chimeric antigen receptor T cells (CAR T) targeting CD7 for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed promising efficacy and safety in some clinical trials. However, most of them were bridged with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We described successful treatment with preventive donor-derived anti-CD7 CAR-T therapy in a case of refractory T lymphoblastic lymphoma following allo-HSCT, who could not receive autologous anti-CD7 CAR-T products due to the low-quality of T lymphocytes. To date, the patient’s complete remission has persisted for 20 months after HSCT.

Abstract Background G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3’s functions and clinical utility in GAC progression and metastases are unknown. Methods We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined. Results GRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1 + cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells’ malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE. Conclusions GRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC.

Abstract Background The conventional belief that glucocorticosteroid (GC) acts through a single brand glucocorticoid receptor (GR)α protein has changed dramatically with the discovery of multiple GR isoforms. We aimed to evaluate whether multiple GR protein isoforms are expressed in chronic rhinosinusitis with nasal polyps (CRSwNP) and whether GR protein isoform expression profiles differ between different endotypes of CRSwNP. Methods Thirty-eight patients with CRSwNP and ten healthy volunteers were included. The protein expression of multiple GR isoforms in nasal polyps (NPs) tissue and control mucosae was examined by western blot analysis with different GR antibodies. Results Five bands, including three bands for known proteins (GRα-A/B, GRα-C, and GRα-D) and two bands for unidentified proteins at 67 kilodaltons (kDa) and 60 kDa, were identified with both total GR antibody (PA1-511A) and GRα-specific antibody (PA1-516). GRα-D intensity, which was abundant in nasal mucosa, was significantly increased in the CRSwNP group and was especially elevated in the noneosinophilic CRSwNP (NE-CRSwNP) group (PA1-511A: P

PurposeTo establish a fast and accurate detection method for interspecies contaminations in the patient-derived xenograft (PDX) models and cell lines, and to elucidate possible mechanisms if interspecies oncogenic transformation is detected.MethodsA fast and highly sensitive intronic qPCR method detecting Gapdh intronic genomic copies was developed to quantify if cells were human or murine or a mixture. By this method, we documented that murine stromal cells were abundant in the PDXs; we also authenticated our cell lines to be human or murine.ResultsIn one mouse model, GA0825-PDX transformed murine stromal cells into a malignant tumorigenic murine P0825 cell line. We traced the timeline of this transformation and discovered three subpopulations descended from the same GA0825-PDX model: epithelium-like human H0825, fibroblast-like murine M0825, and main passaged murine P0825 displayed differences in tumorigenic capability in vivo. P0825 was the most aggressive and H0825 was weakly tumorigenic. Immunofluorescence (IF) staining revealed that P0825 cells highly expressed several oncogenic and cancer stem cell markers. Whole exosome sequencing (WES) analysis revealed that TP53 mutation in the human ascites IP116-generated GA0825-PDX may have played a role in the human-to-murine oncogenic transformation.ConclusionThis intronic qPCR is able to quantify human/mouse genomic copies with high sensitivity and within a time frame of a few hours. We are the first to use intronic genomic qPCR for authentication and quantification of biosamples. Human ascites transformed murine stroma into malignancy in a PDX model.

Summary: Chronic pain is one of the most significant medical problems throughout the world. Recent evidence has confirmed the hippocampus as an active modulator of pain chronicity, but the underlying mechanisms remain unclear. Using in vivo electrophysiology, we identify a neural ensemble in the ventral hippocampal CA1 (vCA1) that shows inhibitory responses to noxious but not innocuous stimuli. Following peripheral inflammation, this ensemble becomes responsive to innocuous stimuli, representing hypersensitivity. Mimicking the inhibition of vCA1 neurons using chemogenetics induces chronic pain-like behaviors in naive mice, whereas activating vCA1 neurons in mice with peripheral inflammation results in a reduction of pain-related behaviors. Pathway-specific manipulation of vCA1 projections to basolateral amygdala (BLA) and infralimbic cortex (IL) shows that these pathways are differentially involved in pain modulation at different temporal stages of chronic inflammatory pain. These results confirm a crucial role of the vCA1 and its circuits in modulating the development of chronic pain.

Background: Clinical studies on the effectiveness of omalizumab in patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are scarce in China. Moreover, identifying potential biomarkers predicting its efficacy remains a great challenge. Methods: In this prospective trial, all enrolled patients underwent endoscopic examination, computed tomography, blood tests, etc, and they completed a 22-item sino-nasal outcome test (SNOT-22), visual analogue scale (VAS), and asthma control test (ACT) evaluation, at baseline and after 24-week omalizumab therapy. Results: Twenty-two patients were finally recruited. Their VAS scores were significantly better including nasal congestion, anterior rhinorrhea, postnasal drip, and loss of smell (P 20. The median change in the Lund-MacKay score (LMS) was 6. Both the Lund-Kennedy score (LKS) and nasal polyp score showed significant improvement (P

BackgroundAtrial fibrillation (AF) is a common arrhythmia, and its most severe and dreaded complication is stroke. The CHA2DS2-VASc score is currently recommended for stroke risk assessment in AF. We aimed to explore the relationship between atrial FDG uptake and stroke and whether atrial FDG uptake could provide incremental value above the CHA2DS2-VAS score to predict stroke in AF by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT).Materials and MethodsFrom September 2017 to December 2020, we retrospectively enrolled 230 patients (115 with AF and 115 without AF as the non-AF group, matched for the date of PET/CT examination and the basic characteristics of the patient) who underwent 18F-FDG PET/CT due to tumor screening or preoperative staging after prolonged fasting and followed up for at least 12 months from the date of PET/CT examination; the endpoint event is the occurrence of stroke. We visually and quantitatively analyzed 18F-FDG uptake in the right and left atria (RA/LA), right and left atrial appendage (RAA/LAA), right and left ventricle (RV/LV), and collected clinical features. In addition, according to the endpoint event (stroke), the enrolled population was divided into the stroke group and non-stroke group, and relevant clinical features and atrial FDG uptake indicators of the two groups were analyzed. Univariate and multivariate Cox regression analyzes were used to analyze the risk factors of stroke events. The Kaplan–Meier survival curve of atrial FDG uptake was drawn, and the log-rank method was used to compare the differences in the survival curves of the two groups. Receiver operating characteristic (ROC) curves were used to examine the discriminatory power of atrial FDG uptake in predicting stroke and determine whether the addition of atrial FDG uptake improves predictive value beyond the CHA2DS2-VASc score for stroke.ResultsIn the AF group, more than half of patients had RA FDG uptake and one-fifth had LA FDG uptake, while one patient had RA FDG uptake and two patients had LA FDG uptake in the non-AF group. In quantitative analysis, the maximum standardized uptake value (SUVmax) of the RA and LA in the AF group was significantly higher than that of the non-AF group (all P < 0.001). We followed up the patients for 28 ± 10 months, and finally, 31 patients had stroke. In the stroke group, atrial fibrillation, RA SUVmax, RAA SUVmax, LAA SUVmax, age ≥ 75 years, and left atrial dilation were significantly higher than those of the non-stroke group (all P < 0.05). Multivariate Cox regression analysis showed that high RA SUVmax (RA SUVmax ≥ 2.62) was an independent risk factor for stroke (HR = 4.264, 95% CI 1.368–13.293, P = 0.012). By using the log-rank test, patients with high RA SUVmax had a significantly higher incidence of stroke compared with patients with low RA SUVmax (P < 0.001). Addition of high RA SUVmax to the CHA2DS2-VASc score could predict stroke more effectively, with a larger AUC 0.790 (P < 0.001).ConclusionThis study found a significant correlation between atrial FDG uptake and AF, especially in RA. Meanwhile, RA FDG uptake is an independent risk factor for stroke, and patients with high RA SUVmax have a significantly higher risk of stroke. Moreover, RA FDG uptake improves prediction of stroke above the CHA2DS2-VASc score in patients with AF.

The objective of this article is to explore the clinical efficacy of acupuncture therapy of Traditional Chinese Medicine (TCM) combined with Astragalus injection in the treatment of children with diarrhea-predominant irritable bowel syndrome (IBS), and its effects on 5-hydroxytryptamine (5-HT), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) in peripheral blood. A total of 116 children with diarrhea-predominant IBS admitted to our hospital from January 2017 to January 2018 were randomly divided into two groups. The control group was treated with Astragalus injection, while the research group was treated with acupuncture therapy of TCM combined with Astragalus injection. The therapeutic effects, the concentrations of CGRP, NPY, and 5-HT in peripheral blood were compared between the two groups. The therapeutic efficacy of the study group was better than that of the control group ( P

In this study, we investigated whether miR-125a participated in the resistance of the leukemia cell lines to the chemotherapeutic agent daunorubicin. Higher expression of miR-125a is correlated with lower treatment response and shorter overall survival in acute leukemia patients. Overexpression of miR-125a induced drug resistance in HL-60, K562, and THP-1cell lines through reducing apoptosis. We also showed that miR-125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRK2 and Puma which were proved to be direct targets of miR-125a. This study may provide novel therapeutic targets for therapy and improve predictions of therapeutic responses in leukemia to daunorubicin.

The role of marrow microenvironment in the pathogenesis of myelodysplastic syndrome (MDS) remains controversial. Therefore, we studied the influence of bone marrow-derived mesenchymal stromal cells (BMSCs) from patients with different risk types of MDS on the survival of the MDS cell lines SKM-1 and MUTZ-1. We first demonstrated that the expression of Sonic hedgehog (Shh), smoothened (Smo), and glioma-associated oncogene homolog 1 (Gli1) was increased in MDS patients n=23; the increase in expression was positively correlated with the presence of high-risk factors. The Shh signaling inhibitor, cyclopamine, inhibited high-risk MDS BMSC-induced survival of SKM-1 and MUTZ-1 cells, suggesting a role for Shh signaling in MDS cell survival. Furthermore, cyclopamine-mediated inhibition of Shh signaling in SKM-1 and MUTZ-1 cells resulted in decreased DNMT1 expression and cell survival; however, exogenous Shh peptide had the opposite effect, suggesting that Shh signaling could regulate the expression of DNMT1, thereby modulating cell survival in MDS. In addition, the apoptosis of SKM-1 and MUTZ-1 cell increased significantly when cultured with cyclopamine and a demethylation agent, 5-Aza-2′-deoxycytidine. These findings suggest that Shh signaling from BMSCs is important in the pathogenesis of MDS and could play a role in disease progression by modulating methylation.

Vascular endothelial growth factor receptor-1 (VEGFR-1 or Flt-1), a tyrosine kinase receptor, is highly expressed in breast cancer tissues, but near absent in normal breast tissue. While VEGFR-1 expression is associated with poor prognosis of women with breast cancer, it is not clear whether it is involved in the aggressiveness of breast cancer. Thus, the present study examined whether VEGFR-1 activation is associated with the invasiveness of breast cancer. We reported that VEGFR-1 was detected in 60.6% of invasive breast carcinoma tissue sections. In addition, VEGFR-1 expression positively correlated with lymph node-positive tumor status, low expression level of membranous E-cadherin, and high expression levels of N-cadherin and Snail. We found that PlGF-mediated VEGFR-1 activation promoted migration and invasion in MCF-7 (luminal) cells and led to morphologic and molecular changes of epithelial-mesenchymal transition (EMT). This was blocked by the down-regulation of VEGFR-1. Conversely, down-regulation of VEGFR-1 in MDA-MB-231 (post-EMT) cells resulted in morphologic and molecular changes similar to mesenchymal-epithelial transition (MET), and exogenous PlGF could not reverse these changes. Moreover, VEGFR-1 activation led to an increase in nuclear translocation of Snail. Finally, MDA-MB-231 cells expressing shRNA against VEGFR-1 significantly decreased the tumor growth and metastasis capacity in a xenograft model. Histological examination of VEGFR-1/shRNA-expressing tumor xenografts showed up-regulation of E-cadherin and down-regulation of N-cadherin and Snail. These findings suggest that VEGFR-1 may promote breast cancer progression and metastasis, and therapies that target VEGFR-1 may be beneficial in the treatment of breast cancer patients.

The electrochemical selective oxidative transformation of lignin feedstocks into valuable oxygenated aromatics is essential to establish a sustainable biorefinery. In this study, we used a rhombohedral ZnIn2S4 (R-ZIS) electrocatalyst to realise the efficient anodic cleavage of C-O bonds in benzyl phenyl ether (BPE), an a-O-4 lignin model compound, to a series of industrially relevant oxygenated mono-aromatics. The reaction occurred at +2 VAg/AgCl, 65 °C, and atmospheric pressure. In optimised conditions, the reaction achieved over 99% conversion rate with a Faraday efficiency of 51.6% at 91.3% conversion of BPE, that is greater than most known electrocatalytic oxidative cleavage examples. The ZnIn2S4 electrocatalyst was deposited on a carbon cloth support, and its structural properties and surface morphology were extensively investigated. Systematic potential controlled electrolysis coupled with 18O isotopic labelling confirmed that C-O scission occurred exclusively between the benzylic carbon and phenolic oxygen. Furthermore, substrate competition studies were conducted to compare the electrocatalytic performance of the R-ZIS catalyst with that of its structural analogue, hexagonal ZnIn2S4, in terms of BPE and monoaromatics conversion. The experimental results were supported by density functional theory calculations. The substrate scoping study revealed the suitability of the R-ZIS induced electrocatalytic system for a variety of substituted a-O-4/ß-O-4 model dimers. Overall, this work demonstrates an efficient anodic process that can enable the atom-efficient valorisation of lignin to produce oxygenated aromatics. The proposed approach can complement the numerous existing reductive lignin cleavage methods. [ABSTRACT FROM AUTHOR]