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Over the last few decades, our understanding of the molecular mechanisms underlying tumor angiogenesis has advanced at a significant pace and the clinical translation of these mechanisms has benefited millions of patients. However, limited efficacy and the rapid expansion of drug resistance remain unresolved issues. Recent studies in both preclinical and clinical settings have revealed that circRNAs, as a novel identified non-coding RNA can mediate intercellular communication and regulate the microenvironment within tumors after being selectively packaged, secreted, and transmitted via exosomes. This review aims to provide a comprehensive understanding of how exosomal circRNAs orchestrate inducers and inhibitors of angiogenesis, including their functions, molecular mechanisms, and potential roles as diagnostic biomarkers and therapeutic targets. Finally, we discuss the technological advances in exosome functionalization and exosome-mimetic nanovesicles intending to improve the clinical translation of exosomal circRNAs.

Kidney disease is usually "silent" at the early stage but can lead to severe kidney failure later on. The development of bioimaging probes with rapid distribution and long-term retention in the kidney is significant for the precise diagnosis of renal diseases. Here, a strategy for the peptide-mediated delivery and long-term accumulation (>48 h) of second near-infrared window (NIR-II) fluorophores into the kidney is demonstrated. It is shown that both the hepatic-cleared organic molecules and fast renal-cleared ultrasmall nanoparticles can be retained in the kidney after conjugation to the peptide with high polarity. Moreover, a ROS-responsive activatable bilateral NIR-II sensor was designed based on the kidney targeting peptide, which enables both in vivo long-term kidney monitoring and in vitro urine analysis. The capability of the peptide-based sensor to detect early kidney injury and report on kidney dysfunctional progression is particularly crucial for chemotherapy regimen optimization and timely renoprotective intervention during medication.

LncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). This study determined that LINC01235 expression has greater fold changes by analyzing TCGA RNA-Seq data. The qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. In vitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in the EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins. In conclusion, LINC01235 can promote GC cell metastasis via EMT and function as a prognostic biomarker.

Although conventional oxygen therapy (COT) is widely used, hypoxemia frequently occurs in gastrointestinal endoscopy with conscious sedation and can lead to life-threatening consequences. High flow nasal oxygen (HFNO) has been applied to improve oxygenation in clinical entities. However, its efficacy to prevent hypoxemia in gastrointestinal endoscopy with conscious sedation has not been evaluated.We searched databases to identify randomized controlled trials that compared the efficacy of HFNO with COT in gastrointestinal endoscopy with conscious sedation. The primary outcome was hypoxemia. Meta-analyses with trial sequential analysis were performed using a random-effects model.Eight trials with 3212 patients were included. Compared with COT, HFNO significantly reduced the risk of hypoxemia (eight trials; 3212 patients; risk ratio 0.30; 95% confidence interval [CI] 0.13-0.70). Trial sequential analysis showed that the cumulative Z curve did not cross the monitoring or futility boundaries, nor reach the required information size line, indicating that more trials are needed to reach a definitive conclusion. Subgroup analyses indicated the superiority of HFNO over COT with respect to hypoxemia in patients at low risk and high risk. HFNO further improved the lowest oxygen saturation (four trials; 459 patients; mean difference 2.30, 95% CI 0.84-3.77).Compared with COT, HFNO can reduce the risk of hypoxemia and improve the lowest oxygen saturation in gastrointestinal endoscopy with conscious sedation. However, the results should be interpreted with caution due to substantial heterogeneity and limited evidence. Further studies are needed to verify the preliminary findings.

The burdens and trends of gastric cancer are poorly understood, especially in high-prevalence countries. Based on the Global Burden of Disease Study 2019, we analyzed the incidence, death, and possible risk factors of gastric cancer in five Asian countries, in relation to year, age, sex, and sociodemographic index. The annual percentage change was calculated to estimate the trends in age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR). The highest ASIR per 100,000 person-years in 2019 was in Mongolia [44 (95% uncertainty interval (UI), 34 to 55)], while the lowest was in the Democratic People’s Republic of Korea (DPRK) [23 (95% UI, 19 to 29)]. The highest ASDR per 100,000 person-years was in Mongolia [46 (95% UI, 37 to 57)], while the lowest was in Japan [14 (95% UI, 12 to 15)]. Despite the increase in the absolute number of cases and deaths from 1990 to 2019, the ASIRs and ASDRs in all five countries decreased with time and improved sociodemographic index but increased with age. Smoking and a high-sodium diet were two possible risk factors for gastric cancer. In 2019, the proportion of age-standardized disability-adjusted life-years attributable to smoking was highest in Japan [23% (95% UI, 19 to 28%)], and the proportions attributable to a high-sodium diet were highest in China [8.8% (95% UI, 0.21 to 33%)], DPRK, and the Republic of Korea. There are substantial variations in the incidence and death of gastric cancer in the five studied Asian countries. This study may be crucial in helping policymakers to make better decisions and allocate appropriate resources.

Log Odds of Positive Lymph Nodes (LODDS) have a better predictive ability than N stage for colon cancer. However, the prognostic value of developing a novel prognostic classification by combining T stage and LODDS (TLODDS) for colon cancer remains unknown. Therefore, in the present study, we aimed to develop a TLODDS classification for colon cancer, and assess whether or not the novel TLODDS classification could improve survival stratification by comparing its discrimination, model-fitting, and net benefits, with the American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) classification.45,558 Western colon cancers were identified in the Surveillance, Epidemiology, and End Results database as a training set. A novel LODDS stage was established and patients with similar survival rates were grouped by combining T and LODDS stages to develop a novel TLODDS classification. The TLODDS classification was further assessed in a Chinese validation set of 3,515 colon cancers and an application set of 3,053 rectal cancers.We developed a novel TLODDS classification that incorporated 7 stages: stage I (T1LODDS1), IIA (T2LODDS1, T1LODDS2, T1LODDS3), IIB (T2LODDS2-3, T3LODDS1, T1LODDS4), IIC (T3LODDS2, T2LODDS4, T4aLODDS1), IIIA (T3LODDS3, T1-2LODDS5, T4bLODDS1, T4aLODDS2), IIIB (T3LODDS4-5, T4aLODDS3-4, T4bLODDS2) and IIIC (T4bLODDS3-5, T4aLODDS5). In the training set, it showed significantly better discrimination (area under the receiver operating characteristic (ROC) curve, 0.691 vs. 0.664, P 0.001), better model-fitting (Akaike information criteria, 265,644 vs. 267,410), and superior net benefits, than the latest AJCC TNM classification. The predictive performance of the TLODDS classification was further validated in colon cancers and was successfully applied in rectal cancers with regards to both overall and disease-free survival.The TLODDS classification has better discriminatory ability, model-fitting, and net benefits than the existing TNM classification, and represents an alternative to the current TNM classifications for colon and rectal cancers.

BackgroundHypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia.MethodsWe screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis.ResultsWe developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits.ConclusionsThe hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.

Emerging evidence has exhibited an obvious decreased expression of miR-106a-5p in the ectopic endometrial tissue of endometriosis (EMS) patients. Thus far, the pathophysiological function of miR-106a-5p in EMS is unknown. A previous study showed an increased FOXC1 expression in the ectopic endometrial tissue of patients with EMS. Moreover, we found that there was a binding site of miR-106a-5p on the 3ʹUTR of FOXC1 through bioinformatics predictions. Hence, we speculated that miR-106a-5p might affect the development of EMS via targeting FOXC1. We first showed a decreased level of miR-106a-5p and an increased level of FOXC1 mRNA in ectopic endometrial tissues compared with normal tissues. Functionally, we transfected ectopic endometrial stromal cells (ESCs) with miR-106a-5p mimics or NC mimics and indicated an inhibitory role of miR-106a-5p on ESC proliferation, invasion, and migration. Mechanistically, FOXC1 was found to be a target gene of miR-106a-5p. To confirm whether miR-106a-5p exerted an inhibitory activity in ESCs via targeting FOXC1, miR-106a-5p mimic was co-transfected into ESCs with the FOXC1-plasmid or vector. We found that FOXC1 overexpression evidently reversed the results caused by a miR-106a-5p mimic in ESCs. Additionally, our results demonstrated that miR-106a-5p mimic inhibited the expression of p-Akt and p-PI3K. Collectively, these results revealed that miR-106a-5p inhibited the proliferative, migratory, and invasive ability of ESCs via directly binding to FOXC1, likely through the suppression of the PI3K and its downstream signaling pathway, which offered a potential and novel therapeutic strategy for EMS treatment., Graphical abstract

Ground-coupled heat pump (GCHP) is used to recovery shallow geothermal energy, a widely distributed green energy source. Due to the imbalance between heat rejection and extraction, heat buildup underground is commonly associated with the long-term operation of GCHPs, which undermine system performance. Heat buildup intrinsically results the irreversibilities (entropy production) in subsurface heat sink, in which thermodynamic and transport properties are largely influenced by hydrogeologic properties, especially the existence of fractures and groundwater. This study investigates the influence of water flow in fractures on the thermodynamic performance of a single borehole heat exchanger (BHX) and heat buildup in the underground heat exchange zone (UHXZ). Potential influence factors were screened out, and new terms were proposed to quantify the scale of fractures and available heat and cold in the heat sink. Governing equations were established to calculate the impacts of vertical and horizontal fractures on the heat exchange rate in BHX as well as on the heat flow across the UHXZ. The analysis results show that water flow in fractures can significantly enhance heat transfer, reduce required number of boreholes, mitigate heat buildup and reduce irreversibilities underground. The results also suggest that the role of fracture scales and water velocity in GCHP operation should be carefully evaluated. Therefore, detailed hydrogeological survey is necessary. The study results provide a guide on more accurately evaluating the risk of heat buildup and how to take advantage of hydrogeological characters to improve the performance of GCHPs.

Background The American Joint Committee on Cancer (AJCC) 8th tumor-node-metastasis (TNM) classification for colorectal cancer (CRC) has limited ability to predict prognosis. Methods We included 45 379 eligible stage I-III CRC patients from the Surveillance, Epidemiology, and End Results Program. Patients were randomly assigned individually to a training (n = 31 772) or an internal validation cohort (n = 13 607). External validation was performed in 10 902 additional patients. Patients were divided according to T and N stage permutations. Survival analyses were conducted by a Cox proportional hazard model and Kaplan-Meier analysis, with T1N0 as the reference. Area under receiver operating characteristic curve and Akaike information criteria were applied for prognostic discrimination and model fitting, respectively. Clinical benefits were further assessed by decision curve analyses. Results We created a modified TNM (mTNM) classification: stages I (T1-2N0-1a); IIA (T1N1b, T2N1b, T3N0); IIB (T1-2N2a-2b, T3N1a-1b, T4aN0); IIC (T3N2a, T4aN1a-2a, T4bN0); IIIA (T3N2b, T4bN1a); IIIB (T4aN2b, T4bN1b); and IIIC (T4bN2a-2b). In the internal validation cohort, compared with the AJCC 8th TNM classification, the mTNM classification showed superior prognostic discrimination (area under receiver operating characteristic curve = 0.675 vs 0.667, respectively; 2-sided P Conclusions The mTNM classification provides better prognostic discrimination than AJCC 8th TNM classification, with good applicability in various populations and settings, to help better stratify stage I-III CRC patients into prognostic groups.

To investigate the correlation between number of retrieved lymph nodes (rLNs) and prognosis and further ascertain the optimal number of rLNs with a beneficial survival impact in patients with pN0 colon cancer.The Surveillance, Epidemiology, and End Results (SEER) database was searched for pN0 colon cancer cases. X-Tile software and Kaplan-Meier survival analysis were applied to determine the optimal number of rLNs based on the minimal probability (P) value and the largest χA total of 6269 pN0 colon cancer patients who underwent surgical therapy were finally included for analysis. Harvest of at least 18 lymph nodes was determined as the optimal rLN number. This cut-off rLN value ( 18 versus ≥ 18) was identified as an independent prognostic factor (P 0.001) of overall survival via multivariate analysis. Similar findings were obtained in patients with retrieval of at least 12 lymph nodes (18 rLNs ≥ 12 versus rLNs ≥ 18) stratified into several groups.The number of rLNs was identified as an independent prognostic factor for pN0 colon cancer. Retrieval of at least 18 lymph nodes was associated with favorable prognosis in patients with pN0 colon cancer, and should, therefore, be regarded as an alternative cut-off value for survival analysis.

As carcinogenic and ubiquitous pollutants, an in-depth understanding of the long-term environmental behaviors of polycyclic aromatic hydrocarbons (PAHs) and their driving forces is crucial for reducing human health risks. Based on long-term monitoring data from 2001 to 2016, this study systematically investigated the temporal and seasonal trends, periodic oscillation, source apportionment, and human health risks of PAHs in eight rivers in the Free State of Saxony, Germany. The results showed that the annual average ∑16PAHs (sum of 16 PAH concentrations) ranged from 28.2 ng L−1 to 202 ng L−1. Using the Mann–Kendall test, a trend of decreasing PAH concentrations was determined (slope range: −0.103 to −0.0159). Wavelet analysis indicated that the most significant periodic oscillation of PAHs was 10–30 months, with more pollution in winter. Source apportionment analysis suggested that vehicular emissions and coal combustion contributed the most to PAH concentrations (20.6–40.3% and 21.7–41.4%, respectively) and related health risks (54.1–80.1% and 5.61–37.9%, respectively). Furthermore, the risks (oral lifetime: 4.24×10−7–1.34×10−6; dermal lifetime: 2.86×10−5–9.05×10−5) were determined to be low. The data revealed that the substitution of petroleum and coal with cleaner energy would facilitate the mitigation of PAHs.

A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for cancer therapy. To ensure that the chemotherapeutic drug and photothermal agent can be simultaneously delivered to the tumor site to exert their synergistic effects, a safe and efficient delivery system is needed. Herein, we fabricated doxorubicin hydrochloride (DOX)- and indocyanine green (ICG)-loaded microneedle (MN) patches (PVP@DOX/MSN@ICG) using a two-step casting process. Mesoporous silica nanoparticles (MSNs) were used to improve the ICG stability and avoid reducing its PTT efficiency in vivo. The MN patches exhibited a good skin penetration ability, and the tips of the MN patches were dissolved by the interstitial fluid to release DOX and ICG at the tumor sites. Under 808 nm laser irradiation within 2 min, the local temperature in the tumor quickly reached 48 °C at a low power of 0.34 W cm-2. A combination of chemotherapy and PTT for PVP@DOX/MSN@ICG MN patches may maximally induce human osteosarcoma MG-63 cells in vitro. Moreover, the in vivo results showed that PVP@DOX/MSN@ICG MN patches had the best antitumor effects because of synergistic chemotherapy and PTT. Therefore, the composite-dissolving MN patch is a promising strategy for enhancing the antitumor effect of chemotherapy alone and shows the potential for the synergistic therapy of superficial tumors.

Evidence has shown that miRNAs can be regulated by multiple mechanisms and can participate in tumorigenesis and progression through binding to 3′-UTRs of target mRNAs. The present study identified differentially expressed miRNAs, mRNAs, and TFs by analyzing miRNA-Seq and mRNA-Seq data to construct a TFs/miRNAs/mRNAs regulation network for GC. We found five miRNAs (miR-18a-5p, miR-21-5p, miR-96-5p, miR-182-5p, and miR-196b-5p) that were significantly overexpressed in GC tissues. Clinical analyses indicated that higher miR-21-5p expression was associated with T3 + T4 and stage III + IV. The expression of miR-96-5p, miR-182-5p, and miR-196b-5p were positively correlated with the patients' ages. The five miRNAs had diagnostic efficacy in distinguishing GC from normal tissues. The gene interaction network showed that the five miRNAs were transcriptionally regulated by 11 TFs and negatively regulated 53 mRNA expressions through binding to the 3′-UTRs. Biological pathway analysis suggested that these TFs and target genes were involved in the p53 pathway, epithelial-to-mesenchymal transition, ErbB receptor, mTOR, VEGF, and VEGFR signaling networks. KEGG pathway analysis indicated that these genes were enriched in some cancer-associated pathways, including in GC. The five miRNAs may act as potential diagnostic markers and the TFs/miRNAs/mRNAs network could suggest a regulation mechanism of miRNAs.

Three new minor oleanane triterpenoid saponins, cylindrosides B (1), C (2), and D (3), were isolated from the seed of Cylindrokelupha dalatensis using chromatographic method. Their structures were established on the basis of the chemical and spectroscopic evidences. They displayed significant antitumor activity in vitro against HL60 cancer cell lines and IC50 values were 7.15 ± 0.63, 10.07 ± 0.97, and 4.74 ± 0.57 μM, respectively, by MTT method.

In the clinic, bone defects resulting from infections, trauma, surgical resection and genetic malformations remain a significant challenge. In the field of bone tissue engineering, three-dimensional (3D) scaffolds are promising for the treatment of bone defects. In this study, calcium sulfate hydrate (CSH)/mesoporous bioactive glass (MBG) scaffolds were successfully fabricated using a 3D printing technique, which had a regular and uniform square macroporous structure, high porosity and excellent apatite mineralization ability. Human bone marrow-derived mesenchymal stem cells (hBMSCs) were cultured on scaffolds to evaluate hBMSC attachment, proliferation and osteogenesis-related gene expression. Critical-sized rat calvarial defects were applied to investigate the effect of CSH/MBG scaffolds on bone regeneration in vivo. The in vitro results showed that CSH/MBG scaffolds stimulated the adhesion, proliferation, alkaline phosphatase (ALP) activity and osteogenesis-related gene expression of hBMSCs. In vivo results showed that CSH/MBG scaffolds could significantly enhance new bone formation in calvarial defects compared to CSH scaffolds. Thus 3D printed CSH/MBG scaffolds would be promising candidates for promoting bone regeneration.

To discuss the characteristics of lumbar disc herniation (LDH) with symptom aggravated caused by spinal manipulative therapy (SMT).Detailed clinical profiles of a total number of 10 LDH patients with symptoms aggravated after SMT were reviewed including 5 males and 5 females with age from 46 to 68 years old, 7 patients of them were more than 50 years old. The clinical data of 10 patients were analyzed involving age, gender, clinical symptoms, signs, imaging findings, surgical treatment and prognosis. Laminectomy and discectomy were performed, and follow-up was carried out in all patients.The duration of symptoms in all the patients before SMT was 4 to 15 years. After the therapy, an acute exacerbation of back and radicular pain was observed within 24 hours. MRI showed intervertebral disc herniation, 7 patients were observed in L4-L5. The time internal between the exacerbation of presentation and surgery was 23.1 days. No perioperative complications occurred. All the patients were relieved of radicular pain a few days after surgery. During postoperative follow-up, all patients regained the ability to walk; Eight patients reported a complete resolution of presentation and the rest two patients were significantly improved.SMT should be prohibited in some LDH patients to prevent neurological damages, in whom there are 5 possible risk factors.

To study the levels of inhibin (INH) and epidermal growth factor (EGF) in maternal plasma and umbilical cord plasma of patients with hypertensive disorder complicating pregnancy, and to explore their influence on the disease and fetal growth.Enzyme linked immunosorbent assay (ELISA) was used to detect maternal and umbilical cord plasma INH and EGF levels in 65 patients with hypertensive disorder complicating pregnancy (test groups) and 21 normal pregnant women (control group).Plasma level of INH in test groups (499 +/- 52) ng/L was significantly higher than that (421 +/- 36) ng/L in control group (P0.01); however, the umbilical cord plasma level of INH had no significant difference (P0.05). Plasma level of EGF in test groups (408 +/- 60) ng/L was significantly lower than that (463 +/- 87) ng/L in control group (P0.05), also there was significant difference in umbilical cord plasma level of two groups (232 +/- 99) ng/L vs (380 +/- 97) ng/L (P0.01). The level of EGF in umbilical cord blood was positively correlated with newborn's body weight and placental weight.Plasma levels of INH and EGF in pregnancy women are related with hypertensive disorder complicating pregnancy. EGF level of umbilical cord blood affects the growth of fetus and placenta.

To detect the expression of IgG receptors (FcgammaR) on cytokine-stimulated human umbilical vein endothelial cells (HUVECs).By using ELISA, immunocytochemical staining, immunofluorescent staining and RT-PCR, the expression and subtypes of FcgammaR were detected.Non-stimulated HUVECs expressed very low level of FcgammaRIIa. FcgammaRIIa mRNA was dramatically up-regulated upon 24 hour stimulation with tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma(IFN-gamma). ELISA results indicated that the expression of FcgammaRIIa increased 16 folds after stimulation with TNF-alpha and IFN-gamma for 3 days (P0.01). Immunofluorescent staining showed that FcgammaRIIa was expressed on the surface of the stimulated HUVECs.TNF-alpha and IFN-gamma could increase FcgammaRIIa expression on HUVECs. The enhanced expression of FcgammaRIIa may mediate the deposition of immune complexes to blood vessels under vasculitic conditions.

A measurement system of X-ray fluorescence excited by 109Cd was set up for the in vivo measurement of bone lead. In the system, a HPGe detector (phi 10 mm x 7 mm) was used to detect the characteristic K X-rays of lead in tibia excited by gamma rays of 88.0 keV from 109Cd. By the normalization of lead X-rays to the coherent scatter, the content of bone lead was calculated from the calibration curves of the ratio (X-ray intensity: coherent intensity) against the lead concentration in tibia phantoms. The normalization technique rendered the measurement accuracy independent of tissue overlay thickness, bone shape, size, mass, and subject motion. Calibration curves obtained from a set of tibia phantoms with lead-doped plaster of Paris were linear. The results of pilot measurements showed that the contents of bone lead in the occupationally exposed workers were higher than those in the control group.

To review and summarize literature regarding stimulatory and inhibitory signaling pathways from different types of Fc gamma receptors (FcgammaRs).Articles were obtained from Medline from January 1991 to April 2002.Over 100 English language papers and reviews published over the last 11 years were selected.Stimulatory Fcgamma receptors include FcgammaRI, FcgammaRIIA, FcgammaRIIC, and FcgammaRIII A. They transduce signals through the immunoreceptor tyrosine-based activation motif (ITAM) in subunits or in the cytoplasmic domain. Inhibitory Fcgamma receptors, such as FcgammaRIIB, are single chain receptors, transducing signals through an immunoreceptor tyrosine-based inhibitory motif (ITIM) in cytoplasmic domains. Stimulatory signals include protein phosphorylation, increase in intracellular free calcium, the production of 1,4,5-triphosphate inositol (IP(3)) and diacylglycerol (DAG) mainly through the Src-family kinases, phosphoinositide 3-kinase (PI3-K) and phospholipase C (PLC). Inhibitory signaling has been implicated in the repression of the above activities as well as inhibition of B cell responses through Src homology 2-containing inositol phosphatase (SHIP).