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Background: Gastric cancer patients are prone to lower extremity deep vein thrombosis (DVT) after surgery, which is an important cause of death in postoperative patients. Therefore, it is particularly important to find a suitable way to predict the risk of postoperative occurrence of DVT in GC patients. This study aims to explore the effectiveness of using machine learning (ML) assisted radiomics to build imaging models for prediction of lower extremity DVT occurrence in GC patients after surgery., Methods: Included in this retrospective study were eligible patients who underwent surgery for GC. CT imaging data from these patients were collected and divided into a training set and a validation set. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to reduce the dimensionality of variables in the training set. Four machine learning algorithms, known as random forest (RF), extreme gradient boosting (XGBoost), support vector machine (SVM) and naive Bayes (NB), were used to develop models for predicting the risk of lower extremity DVT occurrence in GC patients. These models were subsequently validated using the internal validation set and an external validation cohort., Results: LASSO analysis identified 10 variables, based on which four ML models were established, which were then incorporated with the clinical characteristics to predict lower extremity DVT occurrence in the training set. Among these models, RF and NB demonstrated the highest predictive performance, achieving an AUC of 0.928, while SVM and XGBoost achieved a slightly lower AUC of 0.915 and 0.869, respectively., Conclusion: ML algorithms based on imaging information may prove to be novel non-invasive models for predicting postoperative occurrence of DVT in GC patients., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University and conducted in accordance with the ethical standards stipulated in the Declaration of Helsinki. The patient’s written informed consent has been obtained, and their anonymous information will be published in this article. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Sarcopenia was recognized to be one of the common comorbidities in heart failure (HF). The sarcopenia index (SI), based on serum creatinine to cystatin C ratio, was developed as a simple tool to evaluate skeletal muscle mass but has not been well-studied in the correlation of left ventricular ejection fraction (LVEF). The aim of this study is to analyze the SI in patients with HF, especially patients with HF with preserved ejection fraction (HFpEF), and to develop a prediction model for HFpEF., Methods: The training cohort included 229 hospitalized patients with HF and 73 healthy controls (HCs) from the Third Affiliated Hospital of Soochow University between December 2019 and February 2022. An additional 78 patients with HF hospitalized at the same hospital between March 2022 to June 2023 were considered as an external validation cohort. Binary logistic regression model was used to analyze the influence factors of HFpEF. A prediction model was constructed and optimized based on the least absolute shrinkage and selection operator (LASSO), displayed by Nomogram and verified internally by Bootstrap with 500 resamples., Results: SI was significantly different between the HF and HC groups (67.95 ± 13.07 vs. 98.57 ± 31.51) and had a significant negative correlation with LVEF. Multivariate logistic regression demonstrated that SI (OR 0.948, 95% CI 0.914-0.983, P = 0.004) was independently associated with HFpEF. The area under the curve (AUC) for the nomogram constructed based on SI was 0.902. The calibration curve was approximately distributed along the reference line in Bootstrap and the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the good predictive performance of the model., Conclusions: Lower SI is an independent factor associated with hospitalized patients with HF, especially patients with HFpEF. A prediction nomogram based on SI has good predictive power for HFpEF., Trial Registration: The study was registered with the China Clinical Trials Centre Registry (registration number: ChiCTR2200063401)., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University (20/07/2021, registration number: 2021 Scientific Research Project No. 139) and registered with the China Clinical Trials Centre Registry (06/09/2022, registration number: ChiCTR2200063401). All methods were carried out in accordance with the Declaration of Helsinki and written informed consents were obtained from all participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: This study aims to investigate the prevalence, pathogen spectrum, clinical characteristics, and prognosis-related factors of other respiratory pathogens in COVID-19-infected patients, and to explore the application of molecular detection methods in the epidemiological investigation of multiple pathogen infections., Methods: Respiratory samples and clinical data from 384 patients with outpatient and inpatient respiratory infections were collected and analyzed. Multiplex PCR and capillary electrophoresis were conducted to detect the distribution characteristics of 26 pathogen species, comprising 13 viruses, 13 bacteria. Statistical analysis explored the relationship between pathogen distribution with COVID-19 development., Results: There was no statistical difference in prognosis between the 230 COVID-19-positive patients and the 154 COVID-19-positive patients. COVID-19 cases co-infected with other pathogens do not correlate with patient's age and gender. The main distribution of pathogens was mainly mecA (n = 62, 26.96%), followed by SPN(n = 61; 26.52%) and KP(n = 22; 9.57%). Compared with non-COVID-19 cases, COVID-19 infected patients showed a significantly higher mecA carrying rate (26.96% vs. 15.58%, P < 0.01), while there was no statistical difference for other pathogens. Regression analysis found that mecA and KP were independent risk factors for severe illnesses (mechanical ventilation, endotracheal intubation, ECOMO, etc.) or death in COVID-19 patients had 2.391 times and 3.722 times risk of severe disease or death compared with COVID-19 patients without mecA and KP., Conclusion: COVID-19 patients show a higher mecA carrier rate than non-COVID-19 patients, and mecA and KP may increase the risk of severe disease or death in COVID-19 patients, which requires close attention., Competing Interests: Declarations. Ethics approval and consent to participate: This study has been approved by the The First Affiliated Hospital of Ningbo University ethics committee (approval number: 2024-Research No.175RS). Waiver of informed consent was obtained because of the nature of the study. Consent for publication: All authors have approved of the consents of this manuscript and provided consent for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Neonatal respiratory distress syndrome (NRDS) is a primary cause of morbidity and mortality in premature infants. Platelets have a unique role in lung repair and remodeling. This study aimed to determine the relationship between platelet count and NRDS severity., Methods: The study included 234 newborns diagnosed with NRDS from January 2019 to August 2023. This study employed two methods of grouping: the first based on platelet count, dividing participants into thrombocytopenia (platelet count < 150 × 10 9 /L, n = 50) and non-thrombocytopenia groups (platelet count ≥ 150 × 10 9 /L, n = 184), and the second based on the severity of NRDS, categorizing them into severe (n = 24) and mild-moderate (n = 210) groups. Within the first grouping method, the thrombocytopenia group was further subdivided into moderate-severe group (platelet count < 100 × 10 9 /L, n = 4) and mild group (platelet count was between 100.0 × 10 9 /L and 150.0 × 10 9 /L, n = 46). This study aimed to analyze the clinical characteristics of NRDS with thrombocytopenia, explore the correlation between platelet count and clinical indicators of NRDS. Binary Logistic regression analysis was employed to identify independent risk factors for thrombocytopenia in NRDS., Results: A higher proportion of newborns in the severe group exhibited thrombocytopenia (severe group = 41.7%, mild-moderate group = 19.0%). Hospital stay, ventilation time, oxygen therapy duration were longer in the thrombocytopenia group compared to the non-thrombocytopenia group. Hospital stay, ventilation time, oxygen therapy duration, chest radiography score, and C-reactive protein (CRP) levels were inversely associated with platelet count. Conversely, Apgar scores at 1 and 5 min, gestational age, and birth weight showed positive correlations with platelet count. Point-biserail correlation showed that thrombocytopenia was more likely to occur in newborns whose mothers had gestational hypertension, and the lower platelet count, the more severe NRDS. Oxygen therapy duration, birth weight < 1500 g, gestational hypertension and CRP levels emerged as independent risk factors for thrombocytopenia in NRDS. All differences were statistically significant (p all < 0.05)., Conclusion: NRDS accompanied by thrombocytopenia indicates a more severe condition and poorer clinical outcomes. It is hypothesized that NRDS with thrombocytopenia involves a complex multifactorial etiology, including severe lung inflammation., (© 2024. The Author(s).)

Purpose: Lung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches., Methods: We constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts., Results: We developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells., Conclusion: We have identified malignant cell-associated ligand-receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies., (© 2024. The Author(s).)

Background: Preeclampsia, especially early-onset preeclampsia (EO-PE), is a pregnancy complication that has serious consequences for the health of both the mother and the fetus. Although abnormal placentation due to mitochondrial dysfunction is speculated to contribute to the development of EO-PE, the underlying mechanisms have yet to be fully elucidated., Methods: The expression and localization of Siglec-6 in the placenta from normal pregnancies, preterm birth and EO-PE patients were examined by RT-qPCR, Western blot and IHC. Transwell assays were performed to evaluate the effect of Siglec-6 on trophoblast cell migration and invasion. Seahorse experiments were conducted to assess the impact of disrupting Siglec-6 expression on mitochondrial function. Co-IP assay was used to examine the interaction of Siglec-6 with SHP1/SHP2. RNA-seq was employed to investigate the mechanism by which Siglec-6 inhibits mitochondrial function in trophoblast cells., Results: The expression of Siglec-6 in extravillous trophoblasts is increased in placental tissues from EO-PE patients. Siglec-6 inhibits trophoblast cell migration and invasion and impairs mitochondrial function. Mechanismly, Siglec-6 inhibits the activation of NF-κB by recruiting SHP1/SHP2, leading to increased expression of GPR20. Notably, the importance of GPR20 function downstream of Siglec-6 in trophoblasts is supported by the observation that GPR20 downregulation rescues defects caused by Siglec-6 overexpression. Finally, overexpression of Siglec-6 in the placenta induces a preeclampsia-like phenotype in a pregnant mouse model., Conclusions: This study indicates that the regulatory pathway Siglec-6/GPR20 has a crucial role in regulating trophoblast mitochondrial function, and we suggest that Siglec-6 and GPR20 could serve as potential markers and targets for the clinical diagnosis and therapy of EO-PE., (© 2024. The Author(s).)

Background: The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence., Methods: Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cholesterol transporter 1, apolipoprotein C3, angiopoietin-like 3, and lipoprotein[a]) were used as exposures. AF was used as an outcome. The inverse variance weighted method was applied as the primary method. Summary-data-based Mendelian randomization analyses were performed for further validation using expression quantitative trait loci data. Mediation analyses were conducted to explore the indirect effect of coronary heart disease., Results: In the European population, MR analyses demonstrated that elevated levels of lipoprotein(a) increased AF risk. Moreover, analyses focusing on drug targets revealed that the genetically proxied target gene LPA, which simulates the effects of drug intervention by reducing lipoprotein(a), exhibited an association with AF risk. This association was validated in independent datasets. There were no consistent and significant associations observed for other traits when analyzed in different datasets. This finding was also corroborated by Summary-data-based Mendelian randomization analyses between LPA and AF. Mediation analyses revealed that coronary heart disease plays a mediating role in this association. However, in the East Asian population, no statistically significant evidence was observed to support these associations., Conclusions: This study provided genetic evidence that Lp(a) may be a causal factor for AF and that LPA may represent a promising pharmacological target for preventing AF in the European population., (© 2024. The Author(s).)

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability., (© 2024. The Author(s).)

Introduction: The SARS-CoV-2 Omicron variant has decreased virulence and pathogenicity, yet the number of Omicron infections worldwide is unprecedentedly high, with rather high mortality and severe disease rate. Chronic kidney disease (CKD) patients are particularly vulnerable to the SARS-CoV-2 Omicron variant and have unique clinical outcomes., Methods: We retrospectively collected data from 2140 hospitalized patients with SARS-CoV-2 Omicron variant infection from March 29, 2022, to May 17, 2022. Demographic characteristics, ancillary examination results, and clinical treatments were described. Occurrence of critical COVID-19 or death and time of positive-to-negative conversion was defined as primary outcomes. The presence of COVID-19 pneumonia and the usage of respiratory or circulatory support was defined as secondary outcomes. Univariate or multivariate logistic regression analyses were performed to identify risk factors for primary outcomes., Results: 15.74% of CKD patients infected with the SARS-CoV-2 Omicron variant ended up with critical COVID-19 or death. Pre-existing CKD was a risk factor for critical COVID-19 or death and prolonged time of positive-to-negative conversion of SARS-CoV-2. Nirmatrelvir-ritonavir facilitated viral clearance among COVID-19 patients with non-severe CKD., Conclusion: We found patients with CKD and COVID-19 due to Omicron experienced worse clinical outcomes and prolonged time of positive-to-negative conversion of SARS-CoV-2 compared to patients without CKD, which helps rationalize limited medical resources and offers guidance for appropriate clinical treatments., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP., Methods: We recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites., Results: An increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP., Conclusions: Women with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Lemierre's Syndrome is a severe medical condition that can result from oropharyngeal infection, typically caused by Fusobacterium necrophorum, leading to sepsis, internal jugular vein thrombosis, and metastatic septic emboli. However, there is limited literature on this syndrome caused by Streptococcus anginosus, and few previous cases have been reported to have deep neck space infection. We present the first case of Lemierre's Syndrome caused by Streptococcus anginosus with deep neck abscess., Case Presentation: A 53-year-old male patient with no significant medical history presented with right neck pain after accidentally swallowing a fish bone one month ago. Laryngoscopy did not reveal any abnormalities. Five days prior to admission, the patient developed high fever. Imaging studies showed internal jugular vein thrombosis and a neck abscess surrounding the carotid artery sheath. Blood culture results were positive for Streptococcus anginosus infection, and the patient was diagnosed with Lemierre's syndrome. The patient underwent surgical drainage and received antibiotics and anticoagulant therapy, and had satisfactory clinical progress. He was discharged after a 16-day hospitalization., Conclusions: Although Lemierre's syndrome is rare, it needs attention because it can lead to serious complications and requires timely treatment. Deep neck space infections can be life-threatening and doctors must be aware of its potential severity., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Biofilm-immobilized continuous fermentation has the potential to enhance cellular environmental tolerance, maintain cell activity and improve production efficiency., Results: In this study, different biofilm-forming genes (FLO5, FLO8 and FLO10) were integrated into the genome of S. cerevisiae for overexpression, while FLO5 and FLO10 gave the best results. The biofilm formation of the engineered strains 1308-FLO5 and 1308-FLO10 was improved by 31.3% and 58.7% compared to that of the WT strain, respectively. The counts of cells adhering onto the biofilm carrier were increased. Compared to free-cell fermentation, the average ethanol production of 1308, 1308-FLO5 and 1308-FLO10 was increased by 17.4%, 20.8% and 19.1% in the biofilm-immobilized continuous fermentation, respectively. Due to good adhering ability, the fermentation broth turbidity of 1308-FLO5 and 1308-FLO10 was decreased by 22.3% and 59.1% in the biofilm-immobilized fermentation, respectively. Subsequently, for biofilm-immobilized fermentation coupled with membrane separation, the engineered strain significantly reduced the pollution of cells onto the membrane and the membrane separation flux was increased by 36.3%., Conclusions: In conclusion, enhanced biofilm-forming capability of S. cerevisiae could offer multiple benefits in ethanol fermentation., (© 2023. The Author(s).)

Background: Ovarian cancer (OC) is the most lethal malignant gynecological tumor type for which limited therapeutic targets and drugs are available. Enhanced mitochondrial oxidative phosphorylation (OXPHOS), which enables cell growth, migration, and cancer stem cell maintenance, is a critical driver of disease progression and a potential intervention target of OC. However, the current OXPHOS intervention strategy mainly suppresses the activity of the electron transport chain directly and cannot effectively distinguish normal tissues from cancer tissues, resulting in serious side effects and limited efficacy., Methods: We screened natural product libraries to investigate potential anti-OC drugs that target OXPHOS. Additionally, LC-MS, qRT-PCR, western-blot, clonogenic assay, Immunohistochemistry, wound scratch assay, and xenograft model was applied to evaluate the anti-tumor mechanism of small molecules obtained by screening in OC., Results: Gossypol acetic acid (GAA), a widely used gynecological medicine, was screened out from the drug library with the function of suppressing OXPHOS and OC progression by targeting the leucine-rich pentatricopeptide repeat containing (LRPPRC) protein. Mechanically, LRPPRC promotes the synthesis of OXPHOS subunits by binding to RNAs encoded by mitochondrial DNA. GAA binds to LRPPRC directly and induces LRPPRC rapid degradation in a ubiquitin-independent manner. LRPPRC was overexpressed in OC, which is highly correlated with the poor outcomes of OC and could promote the malignant phenotype of OC cells in vitro and in vivo. GAA management inhibits cell growth, clonal formation, and cancer stem cell maintenance in vitro, and suppresses subcutaneous graft tumor growth in vivo., Conclusions: Our study identified a therapeutic target and provided a corresponding inhibitor for OXPHOS-based OC therapy. GAA inhibits OC progression by suppressing OXPHOS complex synthesis via targeting LRPPRC protein, supporting its potential utility as a natural therapeutic agent for ovarian cancer., (© 2023. The Author(s).)

Background: Laparoscopic liver resection (LLR) is controversial in treating intrahepatic cholangiocarcinoma (ICC). Therefore, this study aimed to evaluate the safety and feasibility of LLR for the treatment of ICC and explored the independent factors affecting the long-term prognosis of ICC., Methods: We included 170 patients undergoing hepatectomy for ICC from December 2010 to December 2021 and divided them into LLR group and open liver resection (OLR) group. We used propensity score matching (PSM) analysis to reduce the impact of data bias and confounding variables and then compared the short-term and long-term prognosis of LLR and OLR in treating ICC; Cox proportional hazards regression model was adopted to explore the independent factors affecting the long-term prognosis of ICC., Results: A total of 105 patients (70 in the LLR group and 35 in the OLR group) were included after 2:1 PSM analysis. There was no difference in demographic characteristics and preoperative indexes between the two groups. The perioperative results of the OLR group were worse than those of the LLR group, that is, the intraoperative blood transfusion rate (24 (68.6) vs 21 (30.0)), blood loss (500 (200-1500) vs 200 (100-525)), and the morbidity of major postoperative complications (9 (25.7) vs 6 (8.5)) in the OLR group were worse than those in LLR group. LLR could enable patients to obtain an equivalent long-term prognosis compared to OLR. The Cox proportional hazards regression model exhibited that no matter before or after PSM, preoperative serum CA12-5 and postoperative hospital stay were independent factors affecting overall survival, while only lymph node metastasis independently influenced recurrence-free survival., Conclusions: Compared with ICC treated by OLR, the LLR group obtained superior perioperative period outcomes. In the long run, LLR could enable ICC patients to receive an equivalent long-term prognosis compared to OLR. In addition, ICC patients with preoperative abnormal CA12-5, lymph node metastasis, and more extended postoperative hospital stay might suffer from a worse long-term prognosis. However, these conclusions still need multicenter extensive sample prospective research to demonstrate., (© 2023. The Author(s).)

Backgrounds: Despite publication of international guidelines, there are notable controversial points of clinical target volume (CTV) delineation in nasopharyngeal carcinoma (NPC). Recently, scholars proposed a novel way of delineation of CTV in NPC-individualization of CTV delineation based on T classification and spread patterns, which yielded excellent long-term local control with limited late toxicities. The aim of this study was to clarify the anatomic patterns and pathways of local recurrence of NPC and provide a clinical reference for the delineation of CTV., Methods: A total of 869 patients with non-metastatic NPC were treated with intensity-modulated radiation therapy (IMRT) at our institution between 2009 and 2010. Among the 57 cases of local/locoregional recurrence, 52 cases with traceable radiotherapy plans and magnetic resonance imaging at the time of the first diagnosis of recurrence were included. Anatomical structures and gross tumor volume of local recurrence were contoured. The incidence of relapse of each anatomic structure, route of local recurrence, and their correlation were analyzed., Results: Locally advanced disease had a significantly increased risk of recurrence in the posterior nasal cavity and a trend towards higher risk of recurrence in the clivus, lateral pterygoid muscle, and hypoglossal canal. Based on the incidence of local recurrence, we constructed a high-risk map for the early and locally advanced stages. Local recurrences were classified into five routes, where anterior extension accounted for the majority (30.8%), and caudal tumor extension pathway had the lowest incidence (5.8%). There was a significant correlation between the local recurrences of neural foramina and neighboring anatomical structures along each pathway. All cases relapsed at unilateral cavernous sinus, most at the same side of primary tumor. Based on our findings, we proposed some suggestions on delineations of CTV, based on T classification and local extension pattern., Conclusions: Local recurrence of NPC varied according to T classification, followed a stepwise pattern, spread via neural foramina, and recurred at ipsilateral cavernous sinus. This provides meaningful clinical evidence for delineation of CTV, especially individualized delineation., (© 2023. The Author(s).)

Background: The vitamin niacin is used as a lipid-regulating supplement, but it is unknown whether niacin has a positive influence on cancer prognosis. In this study, we examine the relationship between niacin intake and mortality among patients with cancer., Methods: Our study utilized all available continuous data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014. Multivariable Cox regression models were applied in order to investigate dietary niacin intake's association with mortality. We compared the survival probability between groups of low and high niacin intake by plotting Kaplan-Meier curves. An analysis of subgroups was used to investigate heterogeneity sources., Results: A total of 3504 participants were included in the cohort, with 1054 deaths. One thousand eight hundred forty-seven participants (52.3%) were female, 2548 participants (73.4%) were white, and the mean age (SE) was 65.38 years (0.32). According to multivariate logistic regression analysis, niacin intake was negatively associated with mortality outcomes in patients with cancer, with P values below 0.05 in all models. In subgroup analyses based on sex, age, and BMI, the association persisted. The Kaplan-Meier curves indicate that high niacin intake groups have better survival rates than low intake groups. Niacin supplementation improved cancer mortality but not all-cause mortality., Conclusion: According to our study, higher dietary niacin intake was associated with lower mortality in cancer patients. Niacin supplements improved cancer survival rates, but not all causes of mortality., (© 2022. The Author(s).)

Background: Episiotomy is a surgical solution to relieve perineal stress, resulting in an easily repairable incision, in comparison to the risks of serious vaginal trauma during delivery. The midwife typically adopts such a clinical decision, on experience and subjective judgment. However, the association between perineal stress and episiotomy is poorly characterized. Our aim was to identify a threshold value for perineal stress leading to episiotomy, which eventually may be employed as a clinical tool for assessing whether an episiotomy is required or not., Methods: In total, 245 nulliparous women were investigated for perineal stress during non-instrumental vaginal delivery in Ningbo Women & Children's Hospital. During the second stage of labor, a flexible membrane stress sensor was placed between the fetal head and perineal wall above the anal fissure. Once the entire fetal head pressed against the sensor, real-time perineal stress was measured, and the peak value was recorded. Cases were divided into non-episiotomy group (n = 173) and episiotomy group (n = 72). The correlations between perineal stress and episiotomy was assessed through logistic regression with adjustment for maternal age, estimated birthweight, duration of second stage of labor, maternal body mass index, and presence of analgesia. Midwives were blinded to all stress measurement values. The predictive value of perineal stress on performing episiotomy was evaluated, together with the ideal cut-off perineal stress value for performing episiotomy. A ROC analysis was also performed., Results: The episiotomy group had significantly higher levels of perineal stress in comparison to the non-episiotomy group (140.50 ± 16.03 N versus 118.37 ± 19.21 N, p < 0.01). The episiotomy group was linked to significantly higher perineal stress in comparison to the non-episiotomy group (140.50 ± 16.03 VS 118.37 ± 19.21 N, p < 0.01). ROC analysis between perineal stress and episiotomy revealed a high area under the curve (AUC 0.81, 95% CI 0.75-0.86) and a cut-off value for perineal stress of 124.49 N was identified for episiotomy decision., Conclusion: The level of perineal stress was an independent predictor of performing episiotomy in nulliparous women during non-instrumental vaginal delivery. Perineal stress exceeding 124.49 N was identified as the cut-off prompting midwives to perform episiotomy., (© 2022. The Author(s).)

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC., (© 2022. The Author(s).)

Background: The proliferation ability and autophagy level of pulmonary artery endothelial cells (PAECs) play an important role in promoting the development of pulmonary artery hypertension (PAH), and there is still no effective treatment for PAH. Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway. The intermediate metabolites of this pathway are closely related to the activity of autophagy-associated small G proteins, including Ras-related C3 botulinum toxin substrate 1 (Rac1). Studies have shown that the mevalonate pathway affects the activation levels of different small G proteins, autophagy signaling pathways, vascular endothelial function, and so on. However, the exact relationship between them is still unclear in PAH., Method: In vitro, western blotting and mRFP-GFP-LC3 puncta formation assays were used to observe the expression of FDPS and the level of autophagy in PAECs treated with monocrotaline pyrrole (MCTP). In addition, cell proliferation and migration assays were used to assess the effect of FDPS on endothelial function, and Rac1 activity assays were used to evaluate the effect of Rac1 activation on PAEC autophagy via the PI3K/AKT/mTOR signaling pathway. In vivo, the right heart catheterization method, hematoxylin and eosin (H&E) staining and western blotting were used to determine the effect of FDPS on PAEC autophagy and monocrotaline (MCT)-induced PAH., Results: We show that the expression of FDPS is increased in the PAH module in vitro and in vivo, concomitant with the induction of autophagy and the activation of Rac1. Our data demonstrate that inhibition of FDPS ameliorates endothelial function and decreases MCT-induced autophagy levels. Mechanistically, we found that FDPS promotes autophagy, Rac1 activity and endothelial disfunction through the PI3K/AKT/mTOR signaling pathway., Conclusion: Our study suggests that FDPS contributes to active small G protein-induced autophagy during MCT-induced PAH, which may serve as a potential therapeutic target against PAH., (© 2022. The Author(s).)

Background: The human amnion is an intrauterine tissue which is involved in the initiation of parturition. In-depth understanding of gene expression signatures of individual cell types in the amnion with respect to membrane rupture at parturition may help identify crucial initiators of parturition for the development of specific strategies to prevent preterm birth, a leading cause of perinatal mortality., Results: Six major cell types were revealed in human amnion including epithelial cells, fibroblasts and immunocytes as well as three other cell types expressing dual cell markers including epithelial/fibroblast, immune/epithelial and immune/fibroblast markers. The existence of cell types expressing these dual cell markers indicates the presence of epithelial-mesenchymal (EMT), epithelial-immune (EIT) and mesenchymal-immune (MIT) transitions in amnion at parturition. We found that the rupture zone of amnion exhibited some specific increases in subcluster proportions of immune and EMT cells related to extracellular matrix remodeling and inflammation in labor. The non-rupture zone exhibited some common changes in subcluster compositions of epithelial and fibroblast cells with the rupture zone in labor, particularly those related to oxidative stress and apoptosis in epithelial cells and zinc ion transport in fibroblasts. Moreover, we identified that C-C motif chemokine ligand 20 (CCL20) was among the top up-regulated genes in amnion epithelial cells, fibroblasts and immunocytes in the rupture zone at parturition. Studies in pregnant mice showed that administration of CCL20 induced immunocytes infiltration to tissues at the maternal-fetal interface and led to preterm birth., Conclusions: Apart from the conventional epithelial, fibroblast and immunocytes, human amnion cells may undergo EMT, EIT and FIT in preparation for parturition. Intense inflammation and ECM remodeling are present in the rupture zone, while enhanced apoptosis and oxidative stress in epithelial cells and zinc ion transport in fibroblasts are present in amnion regardless of the rupture zones at parturition. CCL20 derived from the major cell types of the amnion participates in labor onset., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) have made important breakthrough in anti-tumor therapy, however, no single biomarker can accurately predict their efficacy. Studies have found that tumor microenvironment is a key factor for determining the response to ICI therapy. Cytokine receptor 3 (C-X-C Motif Chemokine Receptor 3, CXCR3) pathway has been reported to play an important role in the migration, activation, and response of immune cells. We analyzed survival data, genomics, and clinical data from patients with metastatic urothelial carcinoma (mUC) who received ICI treatment to explore the relationship between CXCR3 pathway activation and the effectiveness of ICIs. The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort and six other cohorts receiving ICI treatment were used for mechanism exploration and validation. In the ICI cohort, we performed univariate and multivariate COX analyses and discovered that patients in the CXCR3-high group were more sensitive to ICI treatment. A Kaplan-Meier analysis demonstrated that patients in the high CXCR3-high group had a better prognosis than those in the CXCR3-low group (P = 0.0001, Hazard Ratio = 0.56; 95% CI 0.42-0.75). CIBERSORT analysis found that mUC patients in the CXCR3-high group had higher levels of activated CD8+ T cells, M1 macrophages, and activated NK cells and less regulatory T cell (Treg) infiltration. Immunogenicity analysis showed the CXCR3-high group had higher tumor neoantigen burden (TNB). Our study suggests that CXCR3 pathway activation may be a novel predictive biomarker for the effectiveness of immunotherapy in mUC patients., (© 2022. The Author(s).)

Background: Accurate assessment of acetabular defects and designing precise and feasible surgical plans are essential for positive outcomes of hip revision arthroplasty. Additive manufacturing (AM) is a novel technique to print physical object models. We propose a three-dimensional acetabular bone defect classification system aided with AM model, and further assess its reliability and validity under blinded conditions., Methods: We reviewed 104 consecutive patients who underwent hip revision arthroplasty at our department between January 2014 and December 2019, of whom 45 had AM models and were included in the reliability and validity tests. Three orthopedic surgeons retrospectively evaluated the bone defects of these 45 patients with our proposed classification, made surgical plans, and repeated the process after 2 weeks. The reliability and validity of the classification results and corresponding surgical plans were assessed using the intra-class correlation coefficient or kappa correlation coefficient., Results: The reliability and validity of the classification results were excellent. The mean initial intra-class correlation coefficient for inter-observer reliability was 0.947, which increased to 0.972 when tested a second time. The intra-observer reliability ranged from 0.958 to 0.980. Validity of the classification results also showed a high kappa correlation coefficient of 0.951-0.967. When considering corresponding surgical plans, the reliability and validity were also excellent, with intra-class correlation coefficients and kappa correlation coefficients measuring all over 0.9., Conclusions: This three-dimensional acetabular defect classification has excellent reliability and validity. Using this classification system and AM models, accurate assessment of bone defect and reliable surgical plans could be achieved. This classification aided with AM is a promising tool for surgeons for preoperative evaluation., (© 2022. The Author(s).)

Background: Thioacetamide (TAA) is used in various fields, such as synthetic drugs, organic chemical synthesis, and materials chemistry. TAA is mainly used to establish animal liver injury models and other organ damage models to explore their mechanisms for helping patients with liver disease. Liver damage can lead to abnormal expression of some enzymes in the serum, so we detected the appropriate enzyme levels in the serum of SD rats to verify the damage of TAA to the liver. More importantly, TAA caused bone damage is barely understood. Therefore, our research aims to establish a rat model reflecting the acute bone damage injury caused by TAA., Methods: The SD rats were intraperitoneally injected with normal saline (0.9%) or TAA (200 mg/kg, 400 mg/kg) for 1 month (once the other day). After the last intraperitoneal injection, serum samples from rats were used for biochemical tests. Masson staining is used to detect liver damage, and micro-CT is used to detect the changes in bone. Moreover, the three-point bending experiment was used to detect the force range of the hind limbs of SD rats., Results: Compared with the control group, after the intraperitoneal injection of TAA, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid (UA), total bile acid (TBA), alkaline phosphatase (ALP), carbamide (UREA) and creatinine (CREA) rose sharply, while the levels of serum content of total protein (TP), lactate dehydrogenase (LDH), calcium (Ca) and phosphorus (P) were severely reduced. After TAA administration, collagen fibers were deposited and liver fibrosis was obvious. Micro-CT results showed that the bone surface, tissue surface, bone volume, and tissue volume of rats with an intraperitoneal injection of TAA were significantly reduced. In addition, the bones of rats with an intraperitoneal injection of TAA can resist less pressure and are prone to fractures., Conclusions: TAA can cause liver damage in SD rats, which is explained by the changes in serum biochemical indicators and the deposition of liver collagen. More importantly, TAA can reduce bone mineral density and increase the separation of bone trabeculae in SD rats, and finally lead to bone injury. This suggests that TAA may become an ideal model to investigate abnormal bone metabolism after liver injury., (© 2022. The Author(s).)

Background: The aim of the study is to identify clinical and dosimetric factors that could predict the risk of hypothyroidism in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT)., Methods: A total of 404 non-metastatic NPC patients were included in our study. All patients were treated with IMRT. The thyroid function were performed for all patients before and after radiation at regular intervals. The time onset for developing hypothyroidism was defined as the time interval between the completion of RT and the first recorded abnormal thyroid hormone test. The cumulative incidence rates of hypothyroidism were estimated using Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to detect the most promising factors that were associated with hypothyroidism., Results: Median follow up was 60.6 months. The 3-, 5- and 7- year cumulative incidence rate of hypothyroidism was 39.4%, 49.1% and 54.7%, respectively. The median time to primary hypothyroidism and central hypothyroidism were 15.4 months (range 2.9-83.8 months) and 29.9 months (range 19.8-93.6 months), respectively. Univariate and multivariate analyses revealed that younger age, female gender and small thyroid volume were the most important factors in predicting the risk of hypothyroidism. Dtmean (mean dose of thyroid), V30-V50 (percentage of thyroid volume receiving a certain dose level) and VS45-VS60 (the absolute volumes of thyroid spared from various dose levels) remained statistically significant in multivariate analyses. Cutoff points of 45 Gy (Dtmean), 80% (Vt40) and 5 cm 3 (VS45Gy) were identified to classify patients as high-risk or low-risk group., Conclusion: Thyroid Vt40 highly predicted the risk of hypothyroidism after IMRT for NPC patients. We recommended plan optimization objectives to reduce thyroid Vt40 to 80%., Trial Registration: Retrospectively registered., (© 2022. The Author(s).)

Osteoarthritis (OA) is a common joint disease caused by progressive articular cartilage degeneration and destruction. Currently, there are no disease-modifying agents officially approved for OA patients. In this study, curcumin was loaded into adipose tissue-derived mesenchymal stem cells (ADMSCs)-derived small extracellular vesicle (ADMSCs-sEV) to synergistically exert chondro-protective effects in vitro and in vivo. We found curcumin primed ADMSCs derived sEV (sEV-CUR) exhibited an enhanced protective effect compared with free curcumin and ADMSCs-sEV in TBHP-induced chondrocytes. Moreover, our study demonstrated sEV-CUR more effectively down-regulated TBHP-induced oxidative stress and chondrocyte apoptosis in vitro. In OA mice model, our results indicated that sEV-CUR showed an improved cartilage protection, as biweekly intra-articular injection of sEV-CUR more efficaciously alleviated oxidative stress and chondrocyte apoptosis in OA cartilage. Overall, our findings showed sEV-CUR exhibited enhanced chondro-protective effects and holds great potential on the recovery of articular cartilage loss and destruction in OA patients., (© 2022. The Author(s).)

Background: The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC)., Methods: Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8-10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA., Results: A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6-26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70-50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29-15.70; P = 0.0008)., Conclusions: Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information., (© 2021. The Author(s).)

Background: Autophagy plays an essential role in metastasis of malignancies. Although our studies showed that Aurora-B facilitate pulmonary metastasis in OS, the mechanism of Aurora-B kinase on autophagy and metastasis in OS has not been explored., Methods: Clinical-pathological parameters and follow-up information was collected in OS patients. Immunohistochemical staining was performed to detect Aurora-B and LC3 protein in OS tissues. Short hairpin RNA transfection was used to silence Aurora-B in OS cells. Real-time quantitative PCR (RT-qPCR) was performed to detect Aurora-B mRNA expression in OS cells. Aurora-B and autophagy related protein were measured by Western blot. Transmission electron microscopy and laser scanning confocal microscopy were performed to observe the formation of autophagosomes and autolysosomes. Migratory and invasive ability of OS cells were measured by Wound healing and transwell assays. Orthotopic xenograft model was used to evaluate the effect of autophagy mediated by Aurora-B inhibition on pulmonary metastasis of OS., Results: The elevated expression of Aurora-B protein in OS tissues negatively associated with the overall survival of OS patients. Further investigation has found that Aurora-B expression was negatively correlative with autophagy related protein LC3 in OS patient tissues. Knockdown Aurora-B stimulates autophagy and inhibits migratory and invasive ability of OS cells. Mechanistically, Aurora-B knockdown suppressed the mTOR/ULK1 signaling pathway and reactivation of the mTOR/ULK1 pathway decreased autophagy level. Furthermore, the inhibition effect of silencing Aurora-B on migration and invasion of OS was reversed by chloroquine and mTOR activator in vitro and vivo., Conclusions: Our results suggest that silencing of Aurora-B stimulate autophagy via decreasing mTOR/ULK1 and result in inhibiting OS metastasis. Targeted Aurora-B/mTOR/ULK1 pathway may be a promising treatment strategy for OS patients.

Background: Biofilms, as a kind of fixed-cell community, can greatly improve industrial fermentation efficiency in immobilized fermentation, but the regulation process is still unclear, which restricts their application. Ca 2+ was reported to be a key factor affecting biofilm formation. However, the effect of Ca 2+ on biofilm structure and microbiology was yet only studied in bacteria. How Ca 2+ -mediated calcineurin signaling pathway (CSP) alters biofilm formation in bacteria and fungi has rarely been reported. On this basis, we investigated the regulation of CSP on the formation of biofilm in Aspergillus niger ., Results: Deletion of the key genes MidA , CchA , CrzA or CnaA in the CSP lowered the Ca 2+ concentration in the mycelium to a different extent, inhibited the formation of A. niger biofilm, reduced the hydrophobicity and adhesion of spores, destroyed the cell wall integrity of hyphae, and reduced the flocculation ability of hyphae. qRT-PCR results showed that the expression of spore hydrophobic protein RodA , galactosaminogalactan (GAG) biosynthesis genes ( uge3 , uge5 , agd3 , gtb3 ), and α-1,3-glucan biosynthesis genes ( ags1 , ags3 ) in the ∆ MidA , ∆ CchA , ∆ CrzA , ∆ CnaA strains were significantly down-regulated compared with those of the wild type (WT). In addition, the transcription levels of the chitin synthesis gene ( chsB , chsD ) and β-1,3-glucan synthesis gene ( FksA ) were consistent with the change in chitin and β-1,3-glucan contents in mutant strains., Conclusion: These results indicated that CSP affected the hydrophobicity and adhesion of spores, the integrity of mycelial cell walls and flocculation by affecting Ca 2+ levels in mycelium, which in turn affected biofilm formation. This work provides a possible explanation for how CSP changes the formation of A. niger biofilm, and reveals a pathway for controlling biofilm formation in industrial immobilized fermentation., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: The optimal treatment for elderly patients with early-stage non-small cell lung cancer (NSCLC) remains inconclusive. Previous studies have shown that stereotactic body radiotherapy (SBRT) provides encouraging local control though higher incidence of toxicity in elderly than younger populations. The objective of this study was to compare the outcomes of SBRT and surgical treatment in elderly patients with clinical stage I-II NSCLC., Methods: This retrospective analysis included 205 patients aged ≥70 years with clinical stage I NSCLC who underwent SBRT or surgery at Zhejiang Cancer Hospital (Hangzhou, China) from January 2012 to December 2017. A propensity score matching analysis was performed between the two groups. In addition, we compared outcomes and related toxicity in both study arms., Results: Each group included 35 patients who met the inclusion criteria. Median follow-up was 50.1 (0.8-74.4) months for surgery and 35.5 (11.5-71.4) months for SBRT. The rate of cancer-specific survival was similar between the two treatment arms (p = 0.958). In patients who underwent surgery, the corresponding 3- and 5-year cancer-specific survival rates were 85.3 and 81.7%, respectively. In those who received radiotherapy, these rates were 91.3 and 74.9%, respectively. Moreover, the 3- and 5-year locoregional control in patients who underwent surgery were 90.0 and 80.0%, respectively. In those who received radiotherapy, these rates were 91.1 and 84.1%, respectively. Notably, the observed differences in progression-free survival were not statistically significant (p = 0.934). In the surgery group, grade 1-2 complications were observed in eleven patients (31%). One patient died due to perioperative infection within 30 days following surgery. There was no grade 3-5 toxicity observed in the SBRT group., Conclusions: The outcomes of surgery and SBRT in elderly patients with early-stage NSCLC were similar.

Background: Flesh color is one of the most important traits for the commercial value of peach fruit. To unravel the underlying regulatory network in Prunus mira, we performed an integrated analysis of the transcriptome and metabolome of 3 fruit types with various flesh pigmentations (milk-white, yellow and blood) at 3 developmental stages (pit-hardening, cell enlargement and fruit ripening)., Results: Transcriptome analysis showed that an intense transcriptional adjustment is required for the transition from the pit-hardening to the cell enlargement stage. In contrast, few genes were differentially expressed (DEGs) from the cell enlargement to the fruit ripening stage and importantly, the 3 fruits displayed diverse transcriptional activities, indicating that difference in fruit flesh pigmentations mainly occurred during the ripening stage. We further investigated the DEGs between pairs of fruit types during the ripening stage and identified 563 DEGs representing the 'core transcriptome' associated with major differentiations between the 3 fruit types, including flesh pigmentation. Meanwhile, we analyzed the metabolome, particularly, at the ripening stage and uncovered 40 differential metabolites ('core metabolome') between the 3 fruit types including 5 anthocyanins, which may be the key molecules associated with flesh coloration. Finally, we constructed the regulatory network depicting the interactions between anthocyanins and important transcripts involved in fruit flesh coloration., Conclusions: The major metabolites and transcripts involved in fruit flesh coloration in P. mira were unraveled in this study providing valuable information which will undoubtedly assist in breeding towards improved fruit quality in peach.

Purpose: To develop and validate a quantitative complication model of temporal lobe necrosis (TLN). To analyze the effect of clinical and dosimetric factors on TLN., Patients and Methods: In this study the prediction model was developed in a training cohort that consisted of 256 nasopharyngeal carcinoma (NPC) patients from January 2009 to December 2009. Dosimetric and clinical factors were extracted for model building. Dosimetric factors including the maximum dose, minimum dose, mean dose, dose covering specific volume and dose of percentage volume. Clinical factors include age, gender, T/N-stage, overall stage, diabetes and hypertension. LASSO (least absolute shrinkage and selection operator) regression model was used for feature selection, and prediction model building. A testing cohort containing 493 consecutive patients from January 2010 to December 2010 was used for model validation. The performance of the prediction model was assessed with respect to its calibration, discrimination., Results: The prediction model, which consisted of two dosimetric features (D0.5cc and D10), is significantly associated with LN status (P < .001 for both training and testing cohorts). None of clinical factors show direct prediction value. The model shows good discrimination, with a C-index of 0.685 (95% CI: 0.6048-0.765) on testing set, and a consistent trend in calibration on testing set., Conclusion: This study presents a prediction model can be conveniently used to facilitate the individualized prediction of TLN in patients with NPC. Clinical factors have no direct impact on TLN.

Background: Biofilms with immobilized cells encased in extracellular polymeric substance are beneficial for industrial fermentation. Their formation is regulated by various factors, including nitric oxide (NO), which is recognized as a quorum-sensing and signal molecule. The mechanisms by which NO regulates bacterial biofilms have been studied extensively and deeply, but were rarely studied in fungi. In this study, we observed the effects of low concentrations of NO on biofilm formation in Saccharomyces cerevisiae. Transcriptional and proteomic analyses were applied to study the mechanism of this regulation., Results: Adding low concentrations of NO donors (SNP and NOC-18) enhanced biofilm formation of S. cerevisiae in immobilized carriers and plastics. Transcriptional and proteomic analyses revealed that expression levels of genes regulated by the transcription factor Mac1p was upregulated in biofilm cells under NO treatment. MAC1 promoted yeast biofilm formation which was independent of flocculation gene FLO11 . Increased copper and iron contents, both of which were controlled by Mac1p in the NO-treated and MAC1 -overexpressing cells, were not responsible for the increased biofilm formation. CTR1 , one out of six genes regulated by MAC1 , plays an important role in biofilm formation. Moreover, MAC1 and CTR1 contributed to the cells' resistance to ethanol by enhanced biofilm formation., Conclusions: These findings suggest that a mechanism for NO-mediated biofilm formation, which involves the regulation of CTR1 expression levels by activating its transcription factor Mac1p, leads to enhanced biofilm formation. The role of CTR1 protein in yeast biofilm formation may be due to the hydrophobic residues in its N-terminal extracellular domain, and further research is needed. This work offers a possible explanation for yeast biofilm formation regulated by NO and provides approaches controlling biofilm formation in industrial immobilized fermentation by manipulating expression of genes involved in biofilm formation.

Background: Biofilms are cell communities wherein cells are embedded in a self-produced extracellular polymeric substances (EPS). The biofilm of Clostridium acetobutylicum confers the cells superior phenotypes and has been extensively exploited to produce a variety of liquid biofuels and bulk chemicals. However, little has been known about the physiology of C. acetobutylicum in biofilm as well as the composition and biosynthesis of the EPS. Thus, this study is focused on revealing the cell physiology and EPS composition of C. acetobutylicum biofilm., Results: Here, we revealed a novel lifestyle of C. acetobutylicum in biofilm: elimination of sporulation and vegetative growth. Extracellular polymeric substances and wire-like structures were also observed in the biofilm. Furthermore, for the first time, the biofilm polysaccharides and proteins were isolated and characterized. The biofilm contained three heteropolysaccharides. The major fraction consisted of predominantly glucose, mannose and aminoglucose. Also, a great variety of proteins including many non-classically secreted proteins moonlighting as adhesins were found considerably present in the biofilm, with GroEL, a S-layer protein and rubrerythrin being the most abundant ones., Conclusions: This study evidenced that vegetative C. acetobutylicum cells rather than commonly assumed spore-forming cells were essentially the solvent-forming cells. The abundant non-classically secreted moonlighting proteins might be important for the biofilm formation. This study provides the first physiological and molecular insights into C. acetobutylicum biofilm which should be valuable for understanding and development of the biofilm-based processes.

Background: To evaluate the effectiveness and toxicities of intensity-modulated radiotherapy (IMRT) for locally recurrent nasopharyngeal carcinoma (NPC)., Methods: One hundred and eighty-four previously irradiated NPC patients with recurrent disease and re-irradiated by IMRT between February 2005 to May 2013 had been reviewed. The disease was re-staged I in 33, II in 27, III in 70 and IV in 54 patients. Seventy-five percent of the patients received cisplatin-based chemotherapy., Results: The median survival time was 33 months. The 3-year actuarial rates of local recurrence-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) rates were 85.1, 91.1, and 46.0%, respectively. About 53% of the patients experienced Grade 3-4 late toxicities. Forty-four patients died of massive hemorrhage of the nasopharynx caused by radiation induced mucosal necrosis. Multivariate analysis indicated that chemotherapy and time interval between initial radiotherapy and re-irradiation were independent predictors for DMFS., Conclusion: IMRT is an effective method for patients with locally recurrent NPC. Massive hemorrhage of the nasopharynx is the major sever late complication and also the leading cause of death. Early recurrence is negative factor for DMFS. Combination of chemotherapy can improve DMFS, but not for OS. Optimal salvage treatment strategies focusing on improvement of survival and minimization of late toxicities are warranted.

Background: Few objective tests can be performed at admission for kidney transplantation [KT] to discern risk of increased length of stay [LOS], which is important for patient counseling and is associated with increased costs and mortality. The short physical performance battery [SPPB] is an easily administered, potentially modifiable, 3-part test of lower extremity function. SPPB score is associated with longer hospital LOS in older adults, and may provide similar utility in KT recipients given that ESRD is a disease of accelerated aging. The aim of this study was to characterize the association between SPPB-derived lower extremity function and LOS., Methods: The SPPB was administered at KT admission in a prospective cohort of 595 recipients (8/2009-6/2016). The independent association between SPPB impairment (score ≤ 10) and LOS was tested with an adjusted conventional generalized gamma parametric survival model., Results: Impaired recipients experienced longer LOS (median: 10 vs. 8 days; P <  0.001) with the greatest difference in percent discharged on day 10 (impaired: 54.5%, unimpaired: 73.3%). Discharge typically took 13% longer in the impaired group (relative time = 1.13; 95%CI: 1.05, 1.21, P = 0.001). Discharge for impaired recipients compared to unimpaired was least likely at day 5 (hazard ratio = 0.71; 95% CI:0.68, 0.74, P <  0.001). No differences in the SPPB impairment-LOS relationship were found by age (interaction P = 0.74)., Conclusions: Pre-KT SPPB impairment was independently associated with longer LOS regardless of age, indicating that it is a useful, objective tool for pre-KT risk assessment in younger and older recipients that may help inform discharge planning.

Background: The Fried frailty phenotype, a measure of physiologic reserve defined by 5 components (exhaustion, unintentional weight loss, low physical activity, slow walking speed, and poor grip strength), is associated with poor outcomes among ESRD patients. However, these 5 components may not fully capture physiologic reserve in this population. We aimed to ascertain opinions of ESRD clinicians and patients about the usefulness of the Fried frailty phenotype and interventions to improve frailty in ESRD patients, and to identify novel components to further characterize frailty in ESRD., Methods: Clinicians who treat adults with ESRD completed a 2-round Delphi study (n = 41 and n = 36, respectively; response rate = 87%). ESRD patients completed a survey at transplant evaluation (n = 460; response rate = 81%). We compared clinician and patient opinions on the constituent components of frailty., Results: Clinicians were more likely than patients to say that ESRD makes patients frail (97.6% vs. 60.2%). There was consensus among clinicians that exhaustion, low physical activity, slow walking speed, and poor grip strength characterize frailty in ESRD patients; however, 29% of clinicians thought weight loss was not relevant. Patients were less likely than clinicians to say that the 5 Fried frailty components were relevant. Clinicians identified 10 new ESRD-specific potential components including falls (64%), physical decline (61%), and cognitive impairment (39%). Clinicians (83%) and patients (80%) agreed that intradialytic foot-peddlers might make ESRD patients less frail., Conclusions: There was consensus among clinicians and moderate consensus among patients that frailty is more common in ESRD. Weight loss was not seen as relevant, but new components were identified. These findings are first steps in refining the frailty phenotype and identifying interventions to improve physiologic reserve specific to ESRD patients.

Background: The six-carbon circular non-proteinogenic compound L-pipecolic acid is an important chiral drug intermediate with many applications in the pharmaceutical industry. In the present study, we developed a metabolically engineered strain of Escherichia coli for the overproduction of L-pipecolic acid from glucose., Results: The metabolic pathway from L-lysine to L-pipecolic acid was constructed initially by introducing lysine cyclodeaminase (LCD). Next, L-lysine metabolic flux from glucose was amplified by the plasmid-based overexpression of dapA, lysC, and lysA under the control of the strong trc promoter to increase the biosynthetic pool of the precursor L-lysine. Additionally, since the catalytic efficiency of the key enzyme LCD is limited by the cofactor NAD + , the intracellular pyridine nucleotide concentration was rebalanced by expressing the pntAB gene encoding the transhydrogenase, which elevated the proportion of LCD with bound NAD + and enhanced L-pipecolic acid production significantly. Further, optimization of Fe 2+ and surfactant in the fermentation process resulted in 5.33 g/L L-pipecolic acid, with a yield of 0.13 g/g of glucose via fed-batch cultivation., Conclusions: We expanded the metabolic pathway for the synthesis of the chiral pharmaceutical intermediate L-pipecolic acid in E. coli. Using the engineered E. coli, a fast and efficient fermentative production of L-pipecolic acid was achieved. This strategy could be applied to the biosynthesis of other commercially and industrially important chiral compounds containing piperidine rings.

Thyroid hormone (TH) signaling plays critical roles in the differentiation, growth, metabolism, and physiological function of all organs or tissues, including heart and skeletal muscle. Due to the significant progress in our understanding of the molecular mechanisms that underlie TH action, it's widely accepted that TH signaling is regulated at multiple levels. A growing number of discoveries suggest that microRNAs (miRNAs) act as fine-tune regulators of gene expression and adds sophisticated regulatory tiers to signaling pathways. Recently, some pioneering studies in cardiac and skeletal muscle demonstrating the interplay between miRNAs and TH signaling suggest that miRNAs might mediate and/or modulate TH signaling. This review presents recent advances involving the crosstalk between miRNAs and TH signaling and current evidence showing the importance of miRNA in TH signaling with particular emphasis on the study of muscle-specific miRNAs (myomiRs) in cardiac and skeletal muscle. Although the research of the reciprocal regulation of miRNAs and TH signaling is only at the beginning stage, it has already contributed to our current understanding of both TH action and miRNA biology. We also encourage further investigations to address the relative contributions of miRNAs in TH signaling under physiological and pathological conditions and how a group of miRNAs are coordinated to integrate into the complex hierarchical regulatory network of TH.

Background: Hemorrhagic shock is the leading cause of trauma-related death in the military setting. Definitive surgical treatment of a combat casualty can be delayed and life-saving fluid resuscitation might be necessary in the field. Therefore, improved resuscitation strategies are critically needed for prolonged field and en route care. We developed an automated closed-loop control system capable of titrating fluid infusion to a target endpoint. We used the system to compare the performance of a decision table algorithm (DT) and a fuzzy logic controller (FL) to rescue and maintain the mean arterial pressure (MAP) at a target level during hemorrhages. Fuzzy logic empowered the control algorithm to emulate human expertise. We hypothesized that the FL controller would be more effective and more efficient than the DT algorithm by responding in a more rigid, structured way., Methods: Ten conscious sheep were submitted to a hemorrhagic protocol of 25 ml/kg over three separate bleeds. Automated resuscitation with lactated Ringer's was initiated 30 min after the first hemorrhage started. The endpoint target was MAP. Group differences were assessed by two-tailed t test and alpha of 0.05., Results: Both groups maintained MAP at similar levels throughout the study. However, the DT group required significantly more fluid than the FL group, 1745 ± 552 ml (42 ± 11 ml/kg) versus 978 ± 397 ml (26 ± 11 ml/kg), respectively ( p  = 0.03)., Conclusion: The FL controller was more efficient than the DT algorithm and may provide a means to reduce fluid loading. Effectiveness was not different between the two strategies. Automated closed-loop resuscitation can restore and maintain blood pressure in a multi-hemorrhage model of shock.

Background: Finding highly relevant articles from biomedical databases is challenging not only because it is often difficult to accurately express a user's underlying intention through keywords but also because a keyword-based query normally returns a long list of hits with many citations being unwanted by the user. This paper proposes a novel biomedical literature search system, called BiomedSearch, which supports complex queries and relevance feedback., Methods: The system employed association mining techniques to build a k-profile representing a user's relevance feedback. More specifically, we developed a weighted interest measure and an association mining algorithm to find the strength of association between a query and each concept in the article(s) selected by the user as feedback. The top concepts were utilized to form a k-profile used for the next-round search. BiomedSearch relies on Unified Medical Language System (UMLS) knowledge sources to map text files to standard biomedical concepts. It was designed to support queries with any levels of complexity., Results: A prototype of BiomedSearch software was made and it was preliminarily evaluated using the Genomics data from TREC (Text Retrieval Conference) 2006 Genomics Track. Initial experiment results indicated that BiomedSearch increased the mean average precision (MAP) for a set of queries., Conclusions: With UMLS and association mining techniques, BiomedSearch can effectively utilize users' relevance feedback to improve the performance of biomedical literature search.

Background: Heterosis or hybrid vigour is a phenomenon in which hybrid progeny exhibit superior performance compared to their parental inbred lines. Most commercial Chinese cabbage cultivars are F1 hybrids and their level of hybrid vigour is of critical importance and is a key selection criterion in the breeding system., Results: We have characterized the heterotic phenotype of one F1 hybrid cultivar of Chinese cabbage and its parental lines from early- to late-developmental stages of the plants. Hybrid cotyledons are larger than those of the parents at 4 days after sowing and biomass in the hybrid, determined by the fresh weight of leaves, is greater than that of the larger parent line by approximately 20% at 14 days after sowing. The final yield of the hybrid harvested at 63 days after sowing is 25% greater than the yield of the better parent. The larger leaves of the hybrid are a consequence of increased cell size and number of the photosynthetic palisade mesophyll cells and other leaf cells. The accumulation of plant hormones in the F1 was within the range of the parental levels at both 2 and 10 days after sowing. Two days after sowing, the expression levels of chloroplast-targeted genes in the cotyledon cells were upregulated in the F1 hybrid relative to their mid parent values. Shutdown of chlorophyll biosynthesis in the cotyledon by norflurazon prevented the increased leaf area in the F1 hybrid., Conclusions: In the cotyledons of F1 hybrids, chloroplast-targeted genes were upregulated at 2 days after sowing. The increased activity levels of this group of genes suggested that their differential transcription levels could be important for establishing early heterosis but the increased transcription levels were transient. Inhibition of the photosynthetic process in the cotyledon reduced heterosis in later seedling stages. These observations suggest early developmental events in the germinating seedling of the hybrid may be important for later developmental vigour and yield advantage.

Background: Optineurin is a gene associated with normal tension glaucoma and amyotrophic lateral sclerosis. It has been reported previously that in cultured RGC5 cells, the turnover of endogenous optineurin involves mainly the ubiquitin-proteasome pathway (UPP). When optineurin is upregulated or mutated, the UPP function is compromised as evidenced by a decreased proteasome β5 subunit (PSMB5) level and autophagy is induced for clearance of the optineurin protein., Results: Adeno-associated type 2 viral (AAV2) vectors for green fluorescence protein (GFP) only, GFP-tagged wild-type and Glu50Lys (E50K) mutated optineurin were intravitreally injected into rats for expression in retinal ganglion cells (RGCs). Following intravitreal injections, eyes that received optineurin vectors exhibited retinal thinning, as well as RGC and axonal loss compared to GFP controls. By immunostaining and Western blotting, the level of PSMB5 and autophagic substrate degradation marker p62 was reduced, and the level of autophagic marker microtubule associated protein 1 light chain 3 (LC3) was enhanced. The UPP impairment and autophagy induction evidently occurred in vivo as in vitro. The optineurin level, RGC and axonal counts, and apoptosis in AAV2-E50K-GFP-injected rat eyes were averted to closer to normal limits after treatment with rapamycin, an autophagic enhancer., Conclusions: The UPP function was reduced and autophagy was induced when wild-type and E50K optineurin was overexpressed in rat eyes. This study validates the in vitro findings, confirming that UPP impairment and autophagy induction also occur in vivo. In addition, rapamycin is demonstrated to clear the accumulated mutant optineurin. This agent may potentially be useful for rescuing of the adverse optineurin phenotypes in vivo.

Background: Inflammation plays an integral role in carcinogenesis and tumor progression. Inflammatory response biomarkers have shown to be promising prognostic factors for improving the predictive accuracy in various cancers. The aim of this study is to investigate the prognostic significance of pre-operative neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) in gastric cancer (GC)., Methods: 389 patients who had undergone gastrectomy were enrolled from 2007 to 2009 in this study. NLR, dNLR, PLR and LMR were calculated from peripheral blood cell count taken at pre-operation. Receiver operating curve (ROC) was used to determine the optimal cut-off levels for these biomarkers. A predictive model or nomogram was established to predict prognosis for cancer-specific survival (CSS) and disease-free survival (DFS), and the predictive accuracy of the nomogram was determined by concordance index (c-index)., Results: The median follow-up period was 24 months ranging from 3 months to 60 months. The optimal cut-off levels were 2.36 for NLR, 1.85 for dNLR, 132 for PLR and 4.95 for LMR by ROC curves analysis. Elevated NLR, dNLR and PLR were significantly associated with worse overall survival (OS), CSS and DFS, however, elevated LMR showed an adverse effect on worse OS, CSS and DFS. Multivariate analysis revealed that elevated dNLR was an independent factor for worse OS, and NLR was superior to dNLR, PLR and LMR in terms of hazard ratio (HR = 1.53, 95% CI = 1.11-2.11, P = 0.010), which was shown to be independent prognostic indicators for both CSS and DFS. Moreover, the nomogram could more accurately predict CSS (c-index: 0.89) and DFS (c-index: 0.84) in surgical GC patients., Conclusions: Pre-operative NLR and dNLR may serve as potential prognostic biomarkers in patients with GC who underwent surgical resection. The proposed nomograms can be used for the prediction of CSS and DFS in patients with GC who have undergone gastrectomy.

Background: It has been widely demonstrated that the hedgehog pathway is strongly associated with basal cell carcinoma of the skin (NBCCS). To assess potential DNA alterations related to keratocystic odontogenic tumors (KCOTs), we sequenced smoothened (SMO) genes in 12 sporadic KCOTs., Methods: Polymerase chain reaction (PCR), capillary electrophoresis and dideoxy chain-termination sequencing were used to examine potential DNA alterations in sporadic KCOTs., Results: Five alterations in SMO genes were detected. Four of these mutations consisted of two synonymous and three missense mutations; two of which have not been reported to date (c.T776A, c.T1281G)., Conclusions: SMO genes may play an important role in the sonic hedgehog (SHH) pathway and could also be responsible for generating KCOTs and NBCCS. However, their influence on SHH signaling remains to be elucidated.

Background: Thyroid hormones (THs) are potent hormones modulating liver lipid homeostasis. The perturbation of lipid homeostasis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a very common liver disorder. It was reported that NAFLD patients were associated with higher incidence of hypothyroidism. However, whether abnormal thyroid function contributes to the pathogenesis of NAFLD remains unclear., Results: We used in vivo models to investigate the influence of hypothyroidism and TH on hepatic lipid homeostasis. We did not observe hepatic triglyceride accumulation in the liver of hypothyroid mice, although the liver was enlarged. We then characterized the hepatic fatty acid composition with gas chromatography-mass spectrometry in mice under different thyroid states. We found that hypothyroidism decreased saturated fatty acid (SFA) content while TH treatment restored the level of SFA. In agreement with this finding, we observed that the expression of acetyl-CoA carboxylase 1 and fatty acid synthase, the rate-limit enzymes for de novo lipogenesis (DNL), decreased in hypothyroid mice while increased after TH treatment. We also found that the ratio of C18:1n-9/C18:0 and C16:1n-7/C16:0 was decreased by TH treatment, suggesting the activity of stearoyl-CoA desaturase-1 was suppressed. This finding indicated that TH is able to suppress triglyceride accumulation by reducing fatty acid desaturation. Additionally, we found that hepatic glycogen content was substantially influenced by TH status, which was associated with glycogen synthase expression. The increased glycogen storage might explain the enlarged liver we observed in hypothyroid mice., Conclusions: Taken together, our study here suggested that hypothyroidism in mice might not lead to the development of NAFLD although the liver became enlarged. However, disturbed TH levels led to altered hepatic fatty acid composition and glycogen accumulation.

Background: Anaplastic thyroid carcinoma (ATC) is a malignancy with one of the highest fatality rates. We reviewed our recent clinical experience with intensity modulated radiotherapy (IMRT) combined with surgery and chemotherapy for the management of ATC., Methods: 13 patients with ATC who were treated by IMRT in our institution between October 2008 and February 2011, have been analyzed. The target volume for IMRT was planned to include Gross tumor volume (GTV): primary tumor plus any N + disease (66 Gy/33 F/6.6 W), with elective irradiation of thyroid bed, bilateral level II through VI and mediastinal lymph nodes to the level of the carina (54-60 Gy). Seven patients received surgical intervention and eleven patients had chemotherapy., Results: The median radiotherapy dose to GTV was 60 Gy/30 fractions/6 weeks. The median survival time of the 13 patients was 9 months. The direct causes of death were distant metastases (75%) and progression of the locoregional disease (25%). Ten patients were spared dyspnea and tracheostomy because their primary neck lesion did not progress., Conclusion: The results showed that IMRT combined by surgery and chemotherapy for ATC might be beneficial to improve locoregional control. Further new therapies are needed to control metastases.

Background: To analyze patterns of local-regional failure after primary intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC)., Methods: A total of 370 non-metastatic NPC patients consecutively treated with IMRT (with or without chemotherapy) were analyzed. Radiotherapy was administered using a simultaneous integrated boost (SIB) technique at the total prescribed dose of 66-70.4 Gy (2.0-2.2 Gy per fraction). The location and extent of local-regional failures were transferred to the pretreatment planning computed tomography (CT) for dosimetric analysis. The dose of radiation received by V(recur) (volume of recurrence) was calculated and analyzed with dose-volume histogram (DVH). Failures were classified as: "in field" if 95% of V(recur) was within the 95% isodose, "marginal" if 20% to 95% of V(recur) was within the 95% isodose, or "outside" if less than 20% of V(recur) was inside the 95% isodose., Results: With a median follow up of 26 months, 25 local-regional failures were found in 18 patients. The 1- and 2-year actuarial local-regional control rates for all patients were 99.7% and 95.5% respectively. Among the 22 local-regional failures with available diagnostic images, 16 (64%) occurred within the 95% isodose lines and were considered in-field failures; 3 (12%) were marginal and 3 (12%) were outside-field failures., Conclusions: Intensity-modulated radiotherapy provides excellent local-regional control for NPC. In-field failures are the main patterns for local-regional recurrence. Reducing the coverage of critical adjacent tissues in CTV purposefully for potential subclinical diseases was worth of study. Great attention in all IMRT steps is necessary to reduce potential causes of marginal failures. More studies about radioresistance are needed to reduce in-field failures.

Background: miRNAs are proved to have causal roles in tumorgenesis involving various types of human cancers, but the mechanism is not clear. We aimed to explore the effect of miRNAs on the development of ovarian cancer and the underlying mechanism., Methods: The miRNA expression profile GSE31801 was downloaded from GEO (Gene Expression Omnibus) database. Firstly, the differentially expressed miRNAs were screened. Target genes of the miRNAs were collected from TargetScan, PicTar, miRanda, and DIANA-microT database, then the miRNA-miRNA co-regulating network was constructed using miRNA pairs with common regulated target genes. Next, the functional modules in the network were studied, the miRNA pairs regulated at least one modules were enriched to form the miRNA functional synergistic network (MFSN)., Results: Risk miRNA were selected in MFSN according to the topological structure. Transcript factors (TFs) in MFSN were identified, followed by the miRNA-transcript factor networks construction. Totally, 42 up- and 61 down-regulated differentially expressed miRNAs were identified, of which 68 formed 2292 miRNA pairs in the miRNA-miRNA co-regulating network. GO: 0007268 (synaptic transmission) and GO: 0019226 (transmission of nerve impulse) were the two common functions of miRNAs in MFSN, and hsa-miR-579 (36), hsa-miR-942 (31), hsa-miR-105 (31), hsa-miR-150 (34), and hsa-miR-27a* (32) were selected as the hub nodes in MFSN., Conclusions: In all, 17 TFs, including CREM, ERG, and CREB1 were screened as the cancer related TFs in MFSN. Other TFs, such as BIN1, FOXN3, FOXK1, FOXP2, and ESRRG with high degrees may be inhibited in ovarian cancer. MFSN gave us a new shed light on the mechanism studies in ovarian cancer.