Study on the bioactive ingredients and mechanism of Huangqi against diabetic retinopathy based on network pharmacology and experimental verification.

BACKGROUND: Diabetic retinopathy (DR) is one of the most well-known microvascular complications of diabetes mellitus. As a traditional Chinese medicine, Huangqi (HQ), has been used for treating DR for a long time. However, its anti-DR active ingredients and mechanism are still unknown. Therefore, we designed this study to explore the active components and mechanism of HQ against DR via network pharmacology analysis. METHODS: The ingredients of HQ, and potential targets of HQ and DR were obtained from public databases. We used the protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment, and Gene Ontology (GO) analysis to identify core targets and pathways of HQ against DR. Finally, molecular docking and vitro experiments were applied to validate our results. RESULTS: A total of 34 potential targets of HQ against DR were obtained. Based on PPI network, VEGFA, PTGS2, Interleukin-6 (IL-6), and CCL2 were considered as core targets. GO analysis involved 692 biological processes, 21 cellular components, and 35 molecular functions. KEGG enrichment analysis manifested that the anti-DR effect of HQ was mainly mediated via the AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that kaempferol had higher affinity with CCL2, IL-6, VEGFA, and PTGS2. The vitro experiments showed that the mRNA expressions of CCL2, IL-6, VEGFA, and PTGS2 in ARPE-19 cells were differentially decreased after kaempferol treatment. CONCLUSION: This study preliminarily unveiled that the therapeutic efficacy of HQ against DR might be attributed to the reduced expression of CCL2, IL-6, VEGFA, and PTGS2.

Acupuncture alleviates inflammatory pain by activating CXCL1/CXCR2 signaling in the primary somatosensory cortex in adjuvant induced arthritis rats. / S1脑区CXCL1/CXCR2å‚ä¸Žé’ˆåˆºæ”¹å–„ä½å‰‚æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ç—›çš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To observe whether acupuncture up-regulates chemokine CXC ligand 1 (CXCL1) in the brain to play an analgesic role through CXCL1/chemokine CXC receptor 2 (CXCR2) signaling in adjuvant induced arthritis (AIA) rats, so as to reveal its neuro-immunological mechanism underlying improvement of AIA. METHODS: BALB/c mice with relatively stable thermal pain reaction were subjected to planta injection of complete Freund adjuvant (CFA) for establishing AIA model, followed by dividing the AIA mice into simple AF750 (fluorochrome) and AF750+CXCL1 groups (n=2 in each group). AF750 labeled CXCL1 recombinant protein was then injected into the mouse's tail vein to induce elevation of CXCL1 level in blood for simulating the effect of acupuncture stimulation which has been demonstrated by our past study. In vivo small animal imaging technology was used to observe the AF750 and AF750+CXCL1-labelled target regions. After thermal pain screening, the Wistar rats with stable pain reaction were subjected to AIA modeling by injecting CFA into the rat's right planta, then were randomized into model and manual acupuncture groups (n=12 in each group). Other 12 rats that received planta injection of saline were used as the control group. Manual acupuncture (uniform reinforcing and reducing manipulations) was applied to bilateral "Zusanli" (ST36) for 4×2 min, with an interval of 5 min between every 2 min, once daily for 7 days. The thermal pain threshold was assessed by detecting the paw withdrawal latency (PWL) using a thermal pain detector. The contents of CXCL1 in the primary somatosensory cortex (S1), medial prefrontal cortex, nucleus accumbens, amygdala, periaqueductal gray and rostroventromedial medulla regions were assayed by using ELISA, and the expression levels of CXCL1, CXCR2 and mu-opioid receptor (MOR) mRNA in the S1 region were detected using real time-quantitative polymerase chain reaction. The immune-fluorescence positive cellular rate of CXCL1 and CXCR2 in S1 region was observed after immunofluorescence stain. The immunofluorescence double-stain of CXCR2 and astrocyte marker glial fibrillary acidic protein (GFAP) or neuron marker NeuN or MOR was used to determine whether there is a co-expression between them. RESULTS: In AIA mice, results of in vivo experiments showed no obvious enrichment signal of AF750 or AF750+CXCL1 in any organ of the body, while in vitro experiments showed that there was a stronger fluorescence signal of CXCL1 recombinant protein in the brain. In rats, compared with the control group, the PWL from day 0 to day 7 was significantly decreased (P<0.01) and the expression of CXCR2 mRNA in the S1 region significantly increased in the model group (P<0.05), while in comparison with the model group, the PWL from day 2 to day 7, CXCL1 content, CXCR2 mRNA expression and CXCR2 content, and MOR mRNA expression in the S1 region were significantly increased in the manual acupuncture group (P<0.05, P<0.01). Immunofluorescence stain showed that CXCR2 co-stained with NeuN and MOR in the S1 region, indicating that CXCR2 exists in neurons and MOR-positive neurons but not in GFAP positive astrocytes. CONCLUSIONS: Acupuncture can increase the content of CXCL1 in S1 region, up-regulate CXCR2 on neurons in the S1 region and improve MOR expression in S1 region of AIA rats, which may contribute to its effect in alleviating inflammatory pain.

Clinical features, prognostic stratification, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma: a multi-institutional real-world study.

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs.

Multi-Kernel Graph Attention Deep Autoencoder for MiRNA-Disease Association Prediction.

Accumulating evidence indicates that microRNAs (miRNAs) can control and coordinate various biological processes. Consequently, abnormal expressions of miRNAs have been linked to various complex diseases. Recognizable proof of miRNA-disease associations (MDAs) will contribute to the diagnosis and treatment of human diseases. Nevertheless, traditional experimental verification of MDAs is laborious and limited to small-scale. Therefore, it is necessary to develop reliable and effective computational methods to predict novel MDAs. In this work, a multi-kernel graph attention deep autoencoder (MGADAE) method is proposed to predict potential MDAs. In detail, MGADAE first employs the multiple kernel learning (MKL) algorithm to construct an integrated miRNA similarity and disease similarity, providing more biological information for further feature learning. Second, MGADAE combines the known MDAs, disease similarity, and miRNA similarity into a heterogeneous network, then learns the representations of miRNAs and diseases through graph convolution operation. After that, an attention mechanism is introduced into MGADAE to integrate the representations from multiple graph convolutional network (GCN) layers. Lastly, the integrated representations of miRNAs and diseases are input into the bilinear decoder to obtain the final predicted association scores. Corresponding experiments prove that the proposed method outperforms existing advanced approaches in MDA prediction. Furthermore, case studies related to two human cancers provide further confirmation of the reliability of MGADAE in practice.

Patent ductus arteriosus shunting direction and diameter predict inpatient outcomes in newborns with congenital diaphragmatic hernia.

Objective: To evaluate whether the patent ductus arteriosus (PDA) can serve as a predictive factor for inpatient outcomes in congenital diaphragmatic hernia (CDH) patients. Methods: A retrospective cohort study was conducted on 59 CDH patients at the Capital Institute of Pediatrics from January 2020 to August 2022. Echocardiography was performed at least three times: within 2-3 h after birth, pre-operatively, and post-operatively of CDH surgery. Based on the direction of the PDA shunt in the first echocardiogram, patients were classified into three groups: left-to-right shunting or closed PDA (L-R), bi-directional shunting, and right-to-left shunting (R-L). Results: The mortality rate was 15.3% (9/59), with all non-survivors having R-L shunting and group mortality of 39.1% (9/23). The direction of the PDA shunt was significantly associated with the duration of ventilation and length of hospital stay (p < 0.05). Decreased PDA diameter or pre-operative shunting direction change towards L-R or bi-directional shunting were associated with higher survival rates, while increased PDA diameter or continuous R-L shunting were associated with higher mortality rates. Pre-operative PDA shunt direction, PDA size after birth and before surgery, gestational age of diagnosis, and shortening fraction before surgery were significantly correlated with patient outcomes. The direction of the preoperative PDA shunt was the most relevant factor among these relationships (p = 0.009, OR 20.6, CI 2.2∼196.1). Conclusion: Our findings highlight the importance of monitoring changes in PDA shunt directionality and diameter in the early stage after birth, as these parameters may serve as valuable predictors of patient outcomes.

Comparison Between the Efficacy of Spinal Cord Stimulation and of Endovascular Revascularization in the Treatment of Diabetic Foot Ulcers: A Retrospective Observational Study.

OBJECTIVE: We aimed to compare the effects of spinal cord stimulation (SCS) with those of endovascular revascularization on the treatment of diabetic foot ulcers. MATERIALS AND METHODS: A total of 104 patients with diabetic foot ulcers who met the inclusion criteria were retrospectively analyzed and classified to the SCS treatment group (n = 46) and endovascular revascularization treatment group (n = 46). The quality-of-life scores (Quality of Life Scale for Patients with Liver Cancer v2.0), visual pain analog scale score, lower limb skin temperature, lower limb arterial ultrasound results, and lower extremity electromyography results were analyzed to compare the efficacy of the two treatments for diabetic foot ulcers in the two groups before surgery and six months after surgery. RESULTS: A total of 92 patients (men: 73.9%, mean age: 66.51 ± 11.67 years) completed the six-month postoperative follow-up period. The patients in the SCS treatment group had a higher quality-of-life score (25.54% vs 13.77%, p < 0.05), a larger reduction in pain scores (69.18% vs 37.21%, p < 0.05), and a larger reduction in foot temperature (18.56% vs 7.24%, p < 0.05) than those of the endovascular revascularization treatment group at six months after surgery. The degree of vasodilation in the lower limbs on color Doppler arterial ultrasound and the nerve conduction velocity were higher in the SCS treatment group than in the endovascular revascularization treatment group at six months after surgery (p < 0.05). CONCLUSION: SCS was more effective than endovascular revascularization in improving quality of life, relieving pain, improving lower limb skin temperature, increasing lower limb blood flow, and improving nerve conduction in patients with diabetic foot ulcers at six months after surgery.

Intensive therapy can improve long-term survival in newly diagnosed, advanced-stage extranodal NK/T-cell lymphoma: A multi-institutional, real-world study.

The study investigated the treatment and prognosis of advanced-stage extranodal natural killer/T-cell lymphoma (ENKTL). With a median follow-up of 75.03 months, the median overall survival (mOS) for the 195 newly diagnosed stage III/IV ENKTL patients was 19.43 months, and estimated 1-, 2-, 3- and 5-year OS were 59.5%, 46.3%, 41.8% and 35.1%, respectively. Chemotherapy (CT) + radiotherapy (RT) compared to CT alone (P = .007), and hematopoietic stem cell transplantation (HSCT) compared to non-HSCT (P < .001), both improved OS. For patients ≤60 years and ineligible for HSCT, other therapies with complete remission led to comparable OS (P = .141). Nine patients ever treated with chidamide achieved a median progression-free survival (mPFS) and mOS of 53.63 (range, 3.47-92.33) and 54.80 (range, 5.50-95.70) months, and four with chidamide maintenance therapy (MT) achieved a mPFS and mOS of 55.83 (range, 53.27-92.33) and 60.65 (range, 53.70-95.70) months, possibly providing an alternative option for non-HSCT patients. Non-anthracycline (ANT)- compared to ANT-, asparaginase (Aspa)- compared to non-Aspa- and gemcitabine (Gem)- compared to non-Gem-based regimens, prolonged PFS (P = .031; P = .005; P = .009) and OS (P = .010; P = .086; P = .003), respectively. Multivariate analysis demonstrated that Gem-based regimens improved PFS (HR = 0.691, P = .061) and OS (HR = 0.624, P = .037). Gem + Aspa combinations slightly improved PFS and OS compared to regimens containing Gem or Aspa alone (P > 0.05). First-line "intensive therapy," including CT (particularly Gem + Aspa regimens), RT, HSCT and alternative chidamide MT, was proposed and could improve long-term survival for advanced-stage ENKTLs. Ongoing prospective clinical studies may shed further light on the value of chidamide MT.

Identification of acid phosphatase (ShACP) from the freshwater crab Sinopotamon henanense and its expression pattern changes in response to cadmium.

Acid phosphatase(ACP) is an important immune enzyme in crustacean humoral immunity. At present, the research on ACP mainly focuses on the biochemical properties of the enzyme, while few studies on gene expression. In this study, ShACP was cloned and the effect of cadmium stress on the expression and function of ShACP in the freshwater crab Sinopotamon henanense was studied. Analysis of the ShACP sequence and tissue distribution results showed that the cDNA sequence of ShACP was 1629 bp, including 48 bp 5' untranslated region, 1209 bp open reading frame region, and 372 bp 3' untranslated region, encoding 402 amino acids. ShACP contained multiple phosphorylation sites and mainly played a role in the hemolymph. Under low-concentration cadmium stress, the body improved immunity by enhancing the expression of ShACP, while high-concentration cadmium stress inhibited the expression of ShACP. ShACP can promote the phagocytosis of hemocytes, while cadmium stress reduced the phagocytosis of hemocytes. This study provides a theoretical basis for further research on the immune system of crabs and is of great significance for the study of crustacean immune responses under heavy metal stress.

Clinical Effect Analysis of Spinal Cord Electrical Stimulator Implantation for Diabetic Foot.

OBJECTIVE: To investigate the clinical effect of spinal cord electrical stimulator implantation in the treatment of a diabetic foot (DF). MATERIALS AND METHODS: We recruited 19 patients with DF who were admitted to Shengjing Hospital of China Medical University between January 2018 and May 2020. All the patients were treated with spinal cord electrical stimulator implantation. Skin temperature, degree of pain, quality of life (QOL) score, limb (toe) preservation, and nerve conduction velocity of the patients were compared pre- and postoperatively. RESULTS: The diameter and peak velocity of multisegment arteries in the lower limbs had significantly increased post surgery. Foot skin temperature significantly increased in patients with good effect. The postoperative visual analog scale score of the patients was significantly lower than that noted preoperatively (p < 0.05). The conduction velocities of the lower limb sensory nerves (eg, superficial peroneal nerve and sural nerve) and motor nerves (eg, common peroneal nerve and tibial nerve) had improved post surgery. Moreover, patients' QOL score had significantly improved postoperatively (p < 0.05). The limb (toe) salvage rate was 94.74%. CONCLUSION: The implantation of a spinal cord electrical stimulator for treating DF can effectively relieve pain and other associated symptoms. Additionally, this device can promote nerve function recovery and lower limb blood supply and reduce the risk of toe amputation; therefore, it is clinically effective and should be considered in the treatment of DF.

MiR-485-5p Suppress the Malignant Characteristics of the Lung Adenocarcinoma via Targeting NADPH Quinone Oxidoreductase-1 to Inhibit the PI3K/Akt.

Lung adenocarcinoma (LUAD), a prevalent form of non-small cell lung cancer (NSCLC), has a high incidence and mortality rate. However, its molecular regulatory mechanisms have yet to be fully understood. The purpose of this study was to look into how NADPH quinone oxidoreductase-1 (NQO1) and it miR-485-5p and affected LUAD cells. The levels of miR-485-5p and NQO1 expression in LUAD cells and tissues were determined by means of quantitative reverse transcription polymerase chain reaction. The viability, proliferation, migration, and apoptosis of LUAD cells were assessed using cell counting Kit-8, 5-bromo-2'-deoxyuridine, transwell, and caspase-3 assays, respectively. Western blot experiments were used to examine the relative protein expression of matrix metallopeptidase 2 and matrix metallopeptidase 9, as well as the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) in LUAD cells. Luciferase and RNA pull-down experiments were also conducted for the verification of miR-485-5p's underlying relationship with NQO1. In our study, we found that LUAD cells and tissues had miR-485-5p downregulation and NQO1 upregulation. The experimental outcomes indicated that miR-485-5p overexpression in LUAD cells reduced their malignant behaviors, suppressed PI3K and Akt phosphorylation, and facilitated apoptosis. The results also revealed that NQO1 was a direct miR-485-5p target, and that NQO1 could reverse miR-485-5p's inhibitory effect on the malignant phenotype of LUAD cells. Furthermore, it was also observed that through targeting NQO1, miR-485-5p could suppress LUAD cell migration and proliferation, further blocking the phosphorylation of PI3K and Akt and inducing apoptosis among LUAD cells. In conclusion, the miR-485-5/NQO1 axis regulates LUAD progression through the PI3K/Akt pathway.

Polyketides with anti-inflammatory activity isolated from Rhodiola tibetica endophytic fungus Penicillium sp. HJT-A-10.

Seven undescribed polyketide compounds (1-4, 9-11) and six known polyketide compounds (5-8,12, 13) were isolated from Rhodiola tibetica endophytic Penicillium sp. HJT-A-10. The structural of seven undescribed polyketides metabolites were established on the basis of spectroscopic methods. The results of anti-inflammatory activity showed that compounds 1-8，10-13 had significant inhibitory effects on LPS-induced NO production in RAW 264.7 cells.

Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression.

Dual-specificity mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1/CL-100) has been documented to promote breast cancer cell survival and chemoresistance. MKP-1 is an unstable protein that is ubiquitinated and degraded via the ubiquitin-proteasome system. However, it is not clear how MKP-1 protein stability is regulated in breast cancer. In this study, we performed a genome-wide siRNA library screen of deubiquitinases (DUBs) and identified STAMBPL1 as an MKP-1 DUB in breast cancer cells. STAMBPL1 interacts with MKP-1 and stabilizes MKP-1 via deubiquitination. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin in vitro and in vivo, and ectopic overexpression of MKP-1 partially rescues STAMBPL1 depletion-induced cisplatin sensitivity. Furthermore, STAMBPL1 and MKP-1 depletion increased breast cancer sensitivity to cisplatin by increasing the phosphorylation and activation of c-Jun N-terminal protein kinase (JNK). Collectively, our findings not only identify STAMBPL1 as an MKP-1 DUB but also reveal a critical mechanism that regulates MKP-1 expression in breast cancer. Our findings indicate that the STAMBPL1/MKP-1 axis represents a potential therapeutic target in breast cancer.

The Effect of Geometry and TGF-ß Signaling on Tumor Cell Migration from Free-Standing Microtissues.

Recapitulation of 3D multicellular tissues in vitro is of great interest to the field of tumor biology to study the integrated effect of local biochemical and biophysical signals on tumor cell migration and invasion. However, most microengineered tissues and spheroids are unable to recapitulate in vitro the complexities of 3D geometries found in vivo. Here, lithographically defined degradable alginate microniches are presented to produce free-standing tumor microtissues, with precisely controlled geometry, high viability, and allowing for high cell proliferation. The role of microtissue geometry and TGF-ß signaling in tumor cell migration is further investigated. TGF-ß is found to induce the expression of p-myosin II, vimentin, and YAP/TAZ nuclear localization at the periphery of the microtissue, where enhanced nuclear stiffness and orientation are also observed. Upon embedding in a collagen matrix, microtissues treated with TGF-ß maintain their geometric integrity, possibly due to the higher cell tension observed around the periphery. In contrast, cells in microtissues not treated with TGF-ß are highly mobile and invade the surrounding matrix rapidly, with the initial migration strongly dependent on the local geometry. The microtissues presented here are promising model systems for studying the influence of biophysical properties and soluble factors on tumor cell migration.

Impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in patients with Ebstein anomaly and tricuspid valve dysplasia.

OBJECTIVES: To evaluate the impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in severe Ebstein anomaly and tricuspid valve dysplasia. METHODS: Thirty-four fetuses with Ebstein anomaly/tricuspid valve dysplasia were referred from 2013 to 2019 for fetal echocardiography and clinical management. Nineteen fetuses with Ebstein anomaly/tricuspid valve dysplasia and 30 controls underwent cardiovascular magnetic resonance to quantify the fetal blood flow and to calculate cerebral oxygen delivery (cDO2) and consumption (cVO2). The 3D steady-state free precession acquisition was used to measure fetal brain volume. Surgical outcome, brain MRI, and neurodevelopmental follow-up were reviewed. RESULTS: Twenty-six fetuses were live born (76%) and survival (65%) at a mean follow-up of 4 years. Nine fetuses had a brain MRI before discharge, and all had clinically silent injuries and volume loss. At 18 months, five single-ventricle patients had a neurodevelopmental delay in cognition and language (mean percentile: 11th), with gross-motor skills more affected than fine-motor skills (mean percentiles: 4th and 34th). Fetuses with Ebstein anomaly/tricuspid valve dysplasia had smaller brains, lower combined ventricular output, ascending aorta, superior caval vien and umbilical vein flows, lower oxygen saturation in ascending aorta and superior caval vien, lower cDO2 and cVO2 (p < 0.05). Superior caval vien/combined ventricular output and descending aorta/combined ventricular output ratios were lower in fetuses with circular shunt (p < 0.05). Fetuses requiring the Starnes procedure tended to have smaller brains, lower combined ventricular output, superior caval vien, descending aorta, and umbilical vein flows. CONCLUSIONS: All patients with Ebstein anomaly/tricuspid valve dysplasia are at high risk of neurodevelopmental delay and warrant follow-up. Fetal cardiovascular magnetic resonance revealed impaired brain growth with diminished cerebral blood flow and cDO2, the extenting dependent on the severity of the haemodynamic compromise.

Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis.

Aberrant variations in angiogenesis have been observed in tumor tissues with abnormal stiffness of extracellular matrix (ECM). However, it remains largely unclear how ECM stiffness influences tumor angiogenesis. Numerous studies have reported that vascular endothelial growth factor-A (VEGF-A) released from tumor cells plays crucial roles in angiogenesis. Hence, we demonstrated the role of ECM stiffness in VEGF-A release from neuroblastoma (NB) cells and the underlying mechanisms. Based on 17 NB clinical samples, a negative correlation was observed between the length of blood vessels and stiffness of NB tissues. In vitro, an ECM stiffness of 30 kPa repressed the secretion of VEGF165 from NB cells which subsequently inhibited the tube formation of human umbilical vein endothelial cells (HUVECs). Knocked down VEGF165 in NB cells or blocked VEGF165 with neutralizing antibodies both repressed the tube formation of HUVECs. Specifically, 30 kPa ECM stiffness repressed the expression and nuclear accumulation of Yes-associated protein (YAP) to regulate the expression of Serine/Arginine Splicing Factor 1 (SRSF1) via Runt-related transcription factor 2 (RUNX2), which may then subsequently induce the expression and secretion of VEGF165 in NB tumor cells. Through implantation of 3D col-Tgels with different stiffness into nude mice, the inhibitory effect of 30 kPa on NB angiogenesis was confirmed in vivo. Furthermore, we found that the inhibitory effect of 30 kPa stiffness on NB angiogenesis was reversed by YAP overexpression, suggesting the important role of YAP in NB angiogenesis regulated by ECM stiffness. Overall, our work not only showed a regulatory effect of ECM stiffness on NB angiogenesis, but also revealed a new signaling axis, YAP-RUNX2-SRSF1, that mediates angiogenesis by regulating the expression and secretion of VEGF165 from NB cells. ECM stiffness and the potential molecules revealed in the present study may be new therapeutic targets for NB angiogenesis.

Bradykinin-Potentiating Peptide-Paclitaxel Conjugate Directed at Ectopically Expressed Angiotensin-Converting Enzyme in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide-drug conjugate (PDC)─bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugate─synthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.

Asymptomatic gastric adenomyoma and heterotopic pancreas in a patient with pancreatic cancer: A case report and review of the literature.

BACKGROUND: Gastric adenomyoma (GA) is a rare submucosal benign neoplasm that occurs mostly in the gastric antrum and is often misdiagnosed. No standard treatment has been established for this disease in cases of malignancy. CASE SUMMARY: A 75-year-old woman with a 10-year history of hypertension was admitted to the Emergency Department of our hospital complaining of paroxysmal exacerbation of acute abdominal pain for 1 d with no apparent cause. Enhanced computed tomography and magnetic resonance imaging indicated a mass in the caudal pancreas, cholecystitis, and cholecystic polypus. Gastrointestinal endoscopy showed a mass arising from the gastric antrum. Due to the imaging findings, pancreatic cancer (PC), gastric lesion, cholecystitis, and cholecystic polypus were our primary consideration. Radical pancreatectomy, splenectomy, and cholecystectomy were performed successfully, and the gastric tumor was locally resected. Postoperative paraffin specimens confirmed the diagnosis of caudal PC, GA, and heterotopic pancreas (HP). Unfortunately, the patient died 13 mo later due to PC metastases to the liver, lung, and adrenal glands. CONCLUSION: GA is a rare benign disease, especially when occurring with HP. It may stem from the same origin as HP. This is the first case report to date of a patient suffering from the simultaneous occurrence of GA, HP, and PC. GA is a lesion that can mimic other benign or malignant gastrointestinal diseases; thus, a definitive diagnosis depends on postoperative pathological biopsy. Although GA and HP are both benign lesions, they should be resected because there is a chance of malignancy. Additional research should be conducted to better understand these submucosal lesions.