Analysis of delayed initial radioactive iodine therapy and clinical outcomes in papillary thyroid cancer: a two-center retrospective study.

BACKGROUND: It remains unclear whether the time interval between total thyroidectomy and radioactive iodine (RAI) therapy influences clinical outcomes in papillary thyroid carcinoma (PTC). This study aims to evaluate the impact of the timing to initiate RAI therapy on the response in PTC patients. METHODS: We retrospectively included 405 patients who underwent total thyroidectomy and subsequent RAI therapy at two tertiary hospitals in southwest China. Patients were categorized into two groups based on the interval between thyroidectomy and initial RAI therapy, that is, an early group (interval ≤90 days, n = 317) and a delayed group (interval >90 days, n = 88). Responses to RAI therapy were classified as excellent, indeterminate, biochemical incomplete, or structural incomplete. Univariate and multivariate analyses were conducted to identify factors associated with a nonexcellent response. RESULTS: Excellent responses were observed in 77.3% of the early group and 83.0% of the delayed group (P = 0.252). No significant impact of RAI therapy timing was also observed across all American Thyroid Association risk classification categories. These findings persisted when patients were analyzed separately according to RAI dose (intermediate-dose group: 3.7 GBq [n = 332]; high-activity group: ≥5.5 GBq [n = 73]), further subdivided by the timing of RAI therapy. Multivariate analysis identified lymph node dissection, RAI dose, and stimulated thyroglobulin as independent risk factors for excellent response (P < 0.05). CONCLUSION: The timing of initial RAI therapy following surgery did not significantly affect outcomes in patients with PTC.

Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain.

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

In Silico-Predicted Dynamic Oxlipidomics MS/MS Library: High-Throughput Discovery and Characterization of Unknown Oxidized Lipids.

Nontargeted lipidomics using liquid chromatography-tandem mass spectrometry can detect thousands of molecules in biological samples. However, the annotation of unknown oxidized lipids is limited to the structures present in libraries, restricting the analysis and interpretation of experimental data. Here, we describe Doxlipid, a computational tool for oxidized lipid annotation that predicts a dynamic MS/MS library for every experiment. Doxlipid integrates three key simulation algorithms to predict libraries and covers 32 subclasses of oxidized lipids from the three main classes. In the evaluation, Doxlipid achieves very high prediction and characterization performance and outperforms the current oxidized lipid annotation methods. Doxlipid, combined with a molecular network, further annotates unknown chemical analogs in the same reaction or pathway. We demonstrate the broad utility of Doxlipid by analyzing oxidized lipids in ferroptosis hepatocellular carcinoma, tissue samples, and other biological samples, substantially advancing the discovery of biological pathways at the trace oxidized lipid level.

Excess Mortality for Femoral Intertrochanteric Fracture Patients Aged 50 Years and Older Treated Surgically and Conservatively in Tianjin, China: A Cohort Study.

OBJECTIVE: Intertrochanteric fracture is one type of hip fracture, which is the most serious consequence of osteoporosis. Along with the growing elderly population, intertrochanteric fracture is expected to rise increasingly. The aim of this study was to assess excess mortality after intertrochanteric fractures and to identify the predictors of long-term mortality by therapy among patients aged 50 years and older in Tianjin. METHODS: This is a retrospective cohort study on mortality for 3029 patients aged 50 years and older in Tianjin experiencing an intertrochanteric fracture between December 26, 2014 and December 31, 2018. Data were from Tianjin Hospital Hip Fracture (THHF) cohort. Follow-up period was until March 31, 2022. Mortality, excess mortality, and comorbidities were analyzed and stratified by therapy and gender. Time dependent Cox models were performed to estimate the effects of the variables. RESULTS: Absolute mortality for all the patients was 5.90% at 3 months, 12.55% at 12 months, 19.92% at 24 months and 27.28% at 36 months. Absolute mortality for surgical group was 1.57% at 3 months, 4.77% at 12 months, 8.49% at 24 months and 12.07% at 36 months, significantly lower than conservative group: 10.50% at 3 months, 20.73% at 12 months, 31.96% at 24 months and 43.04% at 36 months. We found a substantially lower mortality (hazard ratio [HR] 0.34, 95% confidence internal, [CI]: 0.23-0.52, p = 0.000) among patients undergoing surgical therapy than those undergoing conservative therapy, even when controlled for gender, age, the length of hospital stay, and all the comorbidities. Female patients (HR 0.68, 95% CI: 0.58-0.79, p = 0.000) were less likely to die than male patients after an intertrochanteric fracture. Patients treated by the two methods were both found to have excess mortality rates compared to the general population, although in different levels. The excess mortality rates for patients in the conservative therapy group were 14.46% in males and 17.93% in females, while in the surgical therapy group, 2.78% in females and 4.37% in males. The comorbidities moderate or severe renal disease (HR 2.19, 95% CI: 1.61-2.98, p = 0.000), metastatic solid tumor (HR 6.35, 95% CI: 1.56-25.85, p = 0.010), hypoproteinemia (HR 1.22, 95% CI: 1.01-1.47, p = 0.034), and older age (HR 1.89, 95% CI: 1.73-2.08, p = 0.000) were also risk factors on mortality. A worse-case analysis for the primary outcome were performed as sensitivity analysis and it was consistent with the original conclusion. CONCLUSION: Intertrochanteric factures for people aged 50 years older were found to have excess mortality compared to the general population in Tianjin city, and preventing the fractures in the hip for elderly people was imperative. After controlling tfor comorbidities and age, female gender and surgical therapy were protective factors for the death after fractures, which could provide strong evidence for patients and surgeons to make decisions.

A Short-Time Real-World Study of Two Perfluoropropane Tamponade Methods in Pars Plana Vitrectomy for Retinal Detachment.

INTRODUCTION: This real-world study evaluated the efficacy, safety, and operative parameters of two perfluoropropane (C3F8) tamponade methods combined with pars plana vitrectomy (PPV) for retinal detachment (RD). METHODS: A retrospective study of 132 patients (132 eyes) with RD (pure C3F8 in 38 eyes, mixed C3F8 in 94 eyes). All eyes underwent PPV with C3F8 tamponade and were followed up for at least 3 months. Retinal reattachment rate, time of gas configuration and injection, C3F8 dosage, intraocular pressure (IOP), best corrected visual acuity, postoperative ocular inflammation, and patients' complaints were evaluated. RESULTS: The single-surgery retinal reattachment rates of the pure C3F8 group and mixed C3F8 group were 97.4% and 96.8%, respectively, with no significant difference (p = 1.00). The final retinal reattachment rates of the two groups were 100% and 97.2%, respectively, with no significant difference (p = 1.00). The gas configuration time, gas injection time, and C3F8 dosage were significantly less in the pure C3F8 group (all p < 0.001). Time, but not group, was the influencing factor of postoperative IOP changes in the two groups (p < 0.001, p = 0.547, respectively). Compared with the baseline, the IOP estimates of the pure C3F8 group showed a significant increase immediately after surgery (p < 0.001), and the mixed C3F8 group showed a significant increase immediately and 1-2 days after surgery (all p < 0.05). There was no statistical difference in ocular inflammation (p = 0.339) and patients' complaints of discomfort (p = 0.175) between the two groups. CONCLUSION: Both the two methods of C3F8 tamponade combined with PPV in RD patients showed good efficacy and safety, but the clinical operation of pure C3F8 tamponade was more convenient and eco-friendly.

Programming conformational cooperativity to regulate allosteric protein-oligonucleotide signal transduction.

Conformational cooperativity is a universal molecular effect mechanism and plays a critical role in signaling pathways. However, it remains a challenge to develop artificial molecular networks regulated by conformational cooperativity, due to the difficulties in programming and controlling multiple structural interactions. Herein, we develop a cooperative strategy by programming multiple conformational signals, rather than chemical signals, to regulate protein-oligonucleotide signal transduction, taking advantage of the programmability of allosteric DNA constructs. We generate a cooperative regulation mechanism, by which increasing the loop lengths at two different structural modules induced the opposite effects manifesting as down- and up-regulation. We implement allosteric logic operations by using two different proteins. Further, in cell culture we demonstrate the feasibility of this strategy to cooperatively regulate gene expression of PLK1 to inhibit tumor cell proliferation, responding to orthogonal protein-signal stimulation. This programmable conformational cooperativity paradigm has potential applications in the related fields.

Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization.

Neuropathic pain (NP) is a common pain disease that seriously affects the quality of life and physical and mental health of patients. Daphnetin is extracted from the Daphne giraldii Nitsche and has the structure of 7,8-dihydroxy coumarin. As a natural product, daphnetin displays a wide range of pharmacological activities, such as analgesia and anti-inflammatory activities, but whether it is able to improve NP through anti-inflammatory effects is unknown. Therefore, this paper intends to investigate the mechanism of daphnetin in improving NP rats affected by the intrathecal injection of tumor necrosis factor-α (TNF-α) from the perspective of anti-inflammation. Our results showed that daphnetin significantly improved hyperalgesia in NP rats. Daphnetin inhibited the activation and polarization of glial cells and neurons in the spinal cord of NP rats and reduced the expression of mRNA and protein of inflammatory factors and chemokine pairs in the spinal cord. Daphnetin inhibited the polarization of human microglia cell 3 (HMC3) cells and human glioma cells (U251) cells toward M1 microglia and A1 astrocytes, respectively, and induced the conversion of M1 microglia and A1 astrocytes to M2 microglia and A2 astrocytes, respectively. In conclusion, daphnetin ameliorates NP by inhibiting the expression of inflammatory factors and chemokines and the polarization of glial cells in the spinal cord of NP rats. This study provides a theoretical basis for the treatment of NP with daphnetin to expand the clinical application of daphnetin.

Daphnetin alleviates neuropathic pain in chronic constrictive injury rats via regulating the NF-κB dependent CXCL1/CXCR2 signaling pathway.

CONTEXT: Daphnetin is a natural product with anti-inflammatory, antioxidant, and neuroprotective properties. Reports have found that it has a strong analgesic effect; however, its analgesic mechanism is unknown. OBJECTIVE: We explored the effect and mechanism of daphnetin on neuropathic pain (NP). MATERIALS AND METHODS: The rat model of NP was established by ligation of the sciatic nerve. Male Sprague-Dawley rats were divided into six groups: Control, Model, Sham, morphine (0.375 mg/kg), and daphnetin (0.0625 and 0.025 mg/kg). Rats were intrathecally injected with drugs or normal saline once daily for three days. Hyperalgesia was evaluated by mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). Protein levels were detected using ELISA, immunofluorescence, and western blotting. RESULTS: Compared to the Model group, daphnetin improved TWT (46.70 °C vs. 42.20 °C) and MWT (45.60 g vs. 23.60 g), reduced the expression of interleukin-1ß (0.99 ng/g vs. 1.42 ng/g), interleukin-6 (0.90 ng/g vs. 1.52 ng/g), and tumor necrosis factor-α (0.93 ng/g vs. 1.52 ng/g) in the sciatic nerve. Daphnetin decreased the expression of toll-like receptor 4 (TLR4) (0.47-fold), phosphorylated inhibitor of NF-κB (p-IKBα) (0.29-fold), nuclear factor kappaB (NF-κB) (0.48-fold), glial fibrillary acidic protein (GFAP) (0.42-fold), CXC chemokine ligand type 1 (CXCL1) (0.84-fold), CXC chemokine receptor type 2 (CXCR2) (0.78-fold) in the spinal cord. DISCUSSION AND CONCLUSIONS: Daphnetin alleviates NP by inhibiting inflammation and astrocyte activation in the spinal cord, providing theoretical support for the extensive clinical treatment of NP.

Influencing Factors of Bidens pilosa L. Hyperaccumulating Cadmium Explored by the Real-Time Uptake of Cd2+ Influx around Root Apexes under Different Exogenous Nutrient Ion Levels.

Though Bidens pilosa L. has been confirmed to be a potential Cd hyperaccumulator, the accumulation mechanism is not yet clear. The dynamic and real-time uptake of Cd2+ influx by B. pilosa root apexes was determined using non-invasive micro-test technology (NMT), which partly explored the influencing factors of the Cd hyperaccumulation mechanism under the conditions of different exogenous nutrient ions. The results indicated that Cd2+ influxes at 300 µm around the root tips decreased under Cd treatments with 16 mM Ca2+, 8 mM Mg2+, 0.5 mM Fe2+, 8 mM SO42- or 18 mM K+ compared to single Cd treatments. The Cd treatments with a high concentration of nutrient ions showed an antagonistic effect on Cd2+ uptake. However, Cd treatments with 1 mM Ca2+, 0.5 mM Mg2+, 0.5 mM SO42- or 2 mM K+ had no effect on the Cd2+ influxes as compared with single Cd treatments. It is worth noting that the Cd treatment with 0.05 mM Fe2+ markedly increased Cd2+ influxes. The addition of 0.05 mM Fe2+ exhibited a synergistic effect on Cd uptake, which could be low concentration Fe2+ rarely involved in blocking Cd2+ influx and often forming an oxide membrane on the root surface to help the Cd uptake by B. pilosa. The results also showed that Cd treatments with high concentration of nutrient ions significantly increased the concentrations of chlorophyll and carotenoid in leaves and the root vigor of B. pilosa relative to single Cd treatments. Our research provides novel perspectives with respect to Cd uptake dynamic characteristics by B. pilosa roots under different exogenous nutrient ion levels, and shows that the addition of 0.05 mM Fe2+ could promote the phytoremediation efficiency for B. pilosa.

Sichen Formula Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Blocking the TLR4 Signaling Pathways.

Purpose: Sichen (SC) formula is a classic prescription of Tibetan medicine. Due to its potential anti-inflammatory effect, the SC formula has been clinically used to treat respiratory diseases for many years in the Chinese Tibet region. The present study aimed to investigate the anti-inflammatory effect of SC and explore the underlying mechanisms. Methods: SC formula was characterized by HPLC analysis. The acute lung injury (ALI) mouse model was induced by direct intratracheal lipopolysaccharide (LPS) instillation, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. Meanwhile, RAW264.7 macrophages were stimulated by LPS. The contents of inflammatory mediators in the culture medium were determined by ELISA. Protein levels were determined by immunohistochemical staining or Western blotting. Nuclear localization of NF-κB, AP-1, and IRF3 was performed using immunofluorescence and Western blotting. Results: In the LPS-induced ALI mouse model, SC treatment suppressed the secretion of inflammatory mediators (TNF-α, IL-6, IL-1ß, MCP-1, MIP-1α, and RANTES) in BALF. SC treatment hindered the recruitment of macrophages. SC treatment also inhibited the expression of CD68, p-p65, and TLR4 in the lung tissue. In the LPS-exposed RAW264.7 cells, the cell viability was not changed up to 400 µg/mL of SC. SC concentration-dependently suppressed the production of nitric oxide, prostaglandin E2, TNF-α, IL-6, MCP-1, MIP-1α, and RANTES in LPS-challenged RAW264.7 cells. The expression levels of iNOS, COX-2, p-p38, p-JNK, p-ERK, p-TBK1, p-IKKα/ß, p-IκB, p-p65, p-c-Jun, and p-IRF3 were decreased after SC treatment. Moreover, the nuclear translocation of p65, c-Jun, and IRF3 was also blocked by SC treatment. Conclusion: SC treatment inhibited the inflammatory responses in LPS-induced ALI mouse model/RAW264.7 macrophages. The underlying mechanism of this action may be closely associated with the suppression of TLR4 signaling pathways. These research findings provide further pharmacological justifications for the medicinal use of SC in the management of respiratory diseases.

The effects of salinity and pH variation on hyperaccumulator Bidens pilosa L. accumulating cadmium with dynamic and real-time uptake of Cd2+ influx around its root apexes.

Bidens pilosa L. has been confirmed to be a potential Cd hyperaccumulator by some researchers, but the dynamic and real-time uptake of Cd2+ influx by B. pilosa root apexes was a conundrum up to now. The aim of our study was to investigate the effects of salinity and pH variations on the characteristics of Cd2+ influx around the root apexes of B. pilosa. The tested seedlings of B. pilosa were obtained by sand culture experiments in a greenhouse after 1 month from germination, and the Cd2+ influxes from the root apex of B. pilosa under Cd treatments with different salinity and pH levels were determined with application of non-invasive micro-test technology (NMT). The results showed that Cd2+ influxes at 300 µm from the root tips decreased under Cd treatments with 5 mM and 10 mM NaCl, as compared to Cd stress alone. However, Cd treatments with 2.5 mM NaCl had little effect on the net Cd2+ influxes, as compared to Cd treatments alone. Importantly, Cd treatments at pH = 4.0 markedly increased Cd2+ influxes in roots, and Cd treatment at pH = 7.0 had no significant effect on the net Cd2+ influxes compared to Cd treatments at pH = 5.5. Results also showed that Cd treatments with 10 mM NaCl significantly decreased concentrations of chlorophyll (Chl) a and b in leaves and root vigor of B. pilosa relative to Cd treatments alone, while there were no significant differences between Cd treatments with 2.5 mM NaCl and Cd treatments alone. But root vigor was inhibited significantly under Cd treatments with 5 mM and 10 mM NaCl. A significant increase of root vigor was observed in Cd treatments at pH = 4.0, as compared to pH = 5.5. The Cd treatments with high and medium concentrations of NaCl inhibited the uptake of Cd by B. pilosa roots and affected the Chl and root vigor further. But the Cd treatments at pH = 4.0 could promote the Cd uptake and root vigor. Our results revealed the uptake mechanisms of B. pilosa as a potential phytoremediator under different salinity and pH levels combined with Cd contamination and provided a new idea for screening ideal hyperaccumulator and constructing evaluation system.

Deletion of Meg8-DMR Enhances Migration and Invasion of MLTC-1 Depending on the CTCF Binding Sites.

The Dlk1-Dio3 imprinted domain on mouse chromosome 12 contains three well-characterized paternally methylated differentially methylated regions (DMRs): IG-DMR, Gtl2-DMR, and Dlk1-DMR. These DMRs control the expression of many genes involved in embryonic development, inherited diseases, and human cancer in this domain. The first maternal methylation DMR discovered in this domain was the Meg8-DMR, the targets and biological function of which are still unknown. Here, using an enhancer-blocking assay, we first dissected the functional parts of the Meg8-DMR and showed that its insulator activity is dependent on the CCCTC-binding factor (CTCF) in MLTC-1. Results from RNA-seq showed that the deletion of the Meg8-DMR and its compartment CTCF binding sites, but not GGCG repeats, lead to the downregulation of numerous genes on chromosome 12, in particular the drastically reduced expression of Dlk1 and Rtl1 in the Dlk1-Dio3 domain, while differentially expressed genes are enriched in the MAPK pathway. In vitro assays revealed that the deletion of the Meg8-DMR and CTCF binding sites enhances cell migration and invasion by decreasing Dlk1 and activating the Notch1-Rhoc-MAPK/ERK pathway. These findings enhance research into gene regulation in the Dlk1-Dio3 domain by indicating that the Meg8-DMR functions as a long-range regulatory element which is dependent on CTCF binding sites and affects multiple genes in this domain.

Does completion of radical hysterectomy improve oncological outcomes of women with clinical early-stage cervical cancer and intraoperative detection of nodal involvement?: protocol for a systematic review and meta-analysis.

INTRODUCTION: The management of women with clinical early-stage cervical cancer and lymph node involvement detected intraoperatively is heterogeneous and controversial. This paper presents the protocol of a systematic review and meta-analysis regarding the management of this specific population of patients. This proposed study aims to answer the question: does completion of radical hysterectomy improve the oncological outcomes of women with clinical early-stage cervical cancer and intraoperatively detected nodal involvement? METHODS AND ANALYSIS: This protocol is drafted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines, and the proposed study will be conducted in accordance with the standard guidelines of 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' and 'Meta-analysis of Observational Studies in Epidemiology reporting guideline'. Comprehensive literature searches will be performed in PubMed, Embase, Scopus, and Web of Science. The screening of the eligible studies, the extraction of data of interest, and the quality assessment of the included studies will all be independently performed by different members of our team. The primary outcome of this proposed study will be comparing the risk of recurrence or death from cervical cancer and the risk of all-cause death in patients with two different treatments (completion of radical hysterectomy or abandonment of radical hysterectomy); the secondary outcome of this proposed study will be comparing the risk of the grade 3/4 toxicities associated with the two types of management. Given the clinical heterogeneity among the included studies, data on outcomes will be pooled by random-effects models. Heterogeneity will be evaluated using the I2 statistic. The risk of bias for the included studies will be evaluated using the Newcastle-Ottawa Scale or the Cochrane collaboration's tool. The grade of evidence will be evaluated by two independent members of our team using the Grading of Recommendations, Assessment, Development and Evaluations approach. ETHICS AND DISSEMINATION: Ethical approval is not required because there will no primary data collected. The findings of this proposed study will be published in an international peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021273527.

Incidence of omental metastasis in uterine serous carcinoma: a systematic review and meta-analysis.

OBJECTIVES: Previous studies examining the incidence of omental metastasis in uterine serous carcinoma generally suffered from small sample size, retrospective observational design, and single-center setting. So far, there was no systematic review and meta-analysis available on this topic, we conducted this study to quantitatively synthesize the data relating to this topic. DESIGN: systematic review and meta-analysis. MATERIAL AND METHODS: PubMed, Embase, and Web of Science were searched up until August 15, 2020. Two reviewers independently performed study selection, data extraction, and quality assessment. I2 was employed to assess the heterogeneity among the included studies. Effect sizes along with 95% confidence intervals were calculated to analyze outcomes of interest. Funnel plots and the Egger test were used to detect the risk of publication bias. OUTCOME MEASURES: incidence of omental metastasis in uterine serous carcinoma. RESULTS: A total of 16 studies involving 1012 women with uterine serous carcinoma were included in this study. All the included studies were at low risk of bias, and the heterogeneity among them was low. The pooled incidence of overall omental metastasis, occult omental metastasis, and gross omental metastasis in uterine serous carcinoma were 18% (95% CI, 0.15-0.20), 6% (95% CI, 0.04-0.08), and 10% (95% CI, 0.08-0.13), respectively. CONCLUSIONS: Uterine serous carcinoma has a high tendency of omental metastasis. The main form of omentum involvement is gross metastasis. However, occult metastasis in the normal-looking omentum is also worthy of note.

Pain and Self-Management Status Among Chinese Patients With Cancer During the COVID-19 Pandemic.

BACKGROUND: To investigate the pain and self-management status of patients with cancer and the influencing factors of pain and self-management status during the COVID-19 pandemic. METHODS: A cross-sectional design was used. Eighty-one Chinese patients with cancer were recruited in December 2020. The Brief Pain Inventory, the Pain Management Inventory, and the Pain Self-efficacy Questionnaire were used to evaluate patients' pain and self-management status. Descriptive statistical analysis and multiple linear regression models were conducted for the research aims. RESULTS: Two thirds of the participants experienced moderate to severe pain. Cancer pain had moderate to severe interference on 90.12% of patients' lives. Self-management of pain in these participants was low. The most commonly used methods of pain management included adjusting activity intensity to avoid fatigue, using distraction techniques, and massaging the sore area. The most effective methods to manage pain included taking analgesics prescribed by doctor, taking over-the-counter analgesics, and massaging the sore area. Fifteen patients (18.5%) believed that the COVID-19 pandemic had an impact on pain management and 26 patients (32.1%) needed support. Pain education, pain interference on sleep, chemotherapy, and payment status were significantly associated with cancer patients 'pain self-management. CONCLUSIONS: During the COVID-19 pandemic, patients with cancer had moderate to severe pain intensity with low levels of self-management and self-efficacy towards that pain.

Dissection of the potential pharmacological function of neohesperidin dihydrochalcone - a food additive - by in vivo substances profiling and network pharmacology.

Food additives are widely used in our daily life, and the side-effects caused by them have gained extensive attention around the world. Notably, constituent-oriented metabolites, in some sense, always contribute to pharmacological changes, inducing toxicity, therapeutic effects, etc. Characterization of the metabolites and their potential functions is of great importance to the practical applications. In this work, an integrated strategy by combining metabolite profiling and network pharmacology was applied to characterize the metabolic features and reveal pharmacological changes of neohesperidin dihydrochalcone (NHDC) in vivo to demonstrate its pharmacological mechanism and potential functions. As a result, a total of 19 metabolites (3 in plasma, 19 in urine, 8 in feces, 3 in heart, 5 in liver, 0 in spleen, 1 in lung, 2 in kidneys and 2 in brain) were screened and 18 of them were characterized for the first time. Phase I metabolic reactions of hydrolysis and phase II reactions of glucuronidation, sulfation, glutamylation, N-butyryl glycylation and lactylation were the main metabolic reactions of NHDC in vivo. Moreover, the results analyzed by network pharmacology revealed that, in addition to common pathways (steroid hormone biosynthesis) of NHDC, metabolites' targets were involved in pathways in cancer, ovarian steroidogenesis, proteoglycans in cancer, PI3K-Akt signaling pathway and progesterone-mediated oocyte maturation, indicating that these functional changes might result in potential novel functions or other side-effects, such as a disorder of steroid hormones. Our work provided the metabolic features and functional modifications of NHDC in vivo for the first time, and meaningful information for further pharmacological validations or potential functions is supplied.

Rational Design of Hyaluronic Acid-Based Copolymer-Mixed Micelle in Combination PD-L1 Immune Checkpoint Blockade for Enhanced Chemo-Immunotherapy of Melanoma.

The application of combinational therapy breaks the limitation of monotherapy and achieves better clinical benefit for tumor therapy. Herein, a hyaluronic acid/Pluronic F68-based copolymer-mixed micelle was constructed for targeted delivery of chemotherapeutical agent docetaxel (PHDM) in combination with programmed cell death ligand-1(PD-L1) antibody. When PHDM+anti-PDL1 was injected into the blood system, PHDM could accumulate into tumor sites and target tumor cells via CD44-mediated endocytosis and possess tumor chemotherapy. While anti-PDL1 could target PD-L1 protein expressed on surface of tumor cells to the immune checkpoint blockade characteristic for tumor immunotherapy. This strategy could not only directly kill tumor cells but also improve CD8+ T cell level and facilitate effector cytokines release. In conclusion, the rational-designed PHDM+anti-PDL1 therapy strategy creates a new way for tumor immune-chemotherapy.

EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2.

Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/ß-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE-/- clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

An integrated strategy for revealing the pharmacological changes based on metabolites profiling and network pharmacology: Arctiin as an example.

Traditional Chinese medicine was widely used in China since its definite effects and therapy. The components of TCM were absorbed into the circle system as the format of prototypes or metabolites, which contributed to the therapy or side effects. Declaring the functional changes in this process was of great importance to the clinical applications. In this work, an integrated strategy based on metabolites' profiling and network pharmacology was proposed for exploring the pharmacological changes of compounds in vivo. Arctiin, the main component in Fructus Arctii with various kinds of bioactivities, was used as an example. An ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry and metabolynx™software was applied to characterize the metabolites of arctiin in rats at a dosage of 100 mg/kg; network pharmacology was applied to characterize the functional changes. As a result, fifty-three metabolites (32 in plasma, 40 in urine, 19 in bile, 20 in feces, 1 in brain, 12 in liver and 4 in lungs) were screened out and characterized, and 3 of them were unambitiously identified by comparison with standard substances. Among them, 38 metabolites were reported for the first time. It was found the major metabolic pathways of arctiin in rats were demethylation, lactone-opening and phase II conjugations with sulfate and glucuronide.It also confirmed that M14, M15, M18, M23, M22, M43 and M45 were the major circulating forms of arctiin in rats following oral administration. In addition to the above metabolic reactions, phase I reactions of hydrolysis, demethylation, dehydroxylation were also observed, and dehydrogenation were first revealed metabolic patterns of arctiin in rats. Meanwhile, in addition to the main targets of arctiin (MTOR, EGFR and MAPK14), its metabolites targeted additional 392 targets with additional functions of anti-hepatitis B or viral carcinogenesis (SRC, CAPS3, PIK3CA, CDK4, ESR1, MMP9 and ERBB2). The above results provided very important information for understanding the metabolism and functional changes of arctiinin vivo, and supporting data for further pharmacological evaluation. Our work also provided a newsight for elucidation of functional changes of TCMs in vivo.

Recent advances in duplex-specific nuclease-based signal amplification strategies for microRNA detection.

In recent years, miRNAs had emerged as promising biomarkers for diagnosis and prognosis of the health-threatening diseases (e.g., cancers), which associated with a broad range of pathological and biological processes, including drug resistance, apoptosis, metastasis, and proliferation. Therefore, accurate detection of the levels of miRNA shown excellent prospects for early diagnosis of the health-threatening diseases. Considering that only trace miRNA existed in biological fluids, many newly developed biosensors for miRNA detection mainly focused on introducing various of signal amplification strategies for improving the detection sensitivity. Duplex-specific nuclease (DSN), a nuclease purified from hepatopancreas of Kamchatka crab, was capable of specifically cleaving double-stranded DNA or DNA in DNA-RNA heteroduplexes and was inactive toward single-stranded oligonucleotides or double-stranded RNA, endowing a possibility for construction of newly miRNA biosensors. Recently, many newly developed DSN-based biosensors architectures for miRNA analysis were reported. In this review, we explained the great potential of miRNAs as promising biomarkers by overviewing DSN-based signal amplification strategies for miRNA detection in the last decades.