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METHODS We collected the clinical data of 260 patients admitted to the hospital from April 2003 to September 2019 with pathologically confirmed intravenous leiomyomatosis (IVL) and followed up with these patients regularly. Univariate and multivariate logistic regression analyses were carried out on the relevant recurrence factors. RESULTS A total of 166 patients were regularly followed up, the median follow-up time was 36 (range 2-168) months, 14 (5.4%) patients eventually relapsed, and the median recurrence time was 8.5 (range 2-42) months. The univariate analysis showed that age (p = 0.003) and surgical type (p

BACKGROUND: Non-infectious diarrhea is a common symptom in infants and young children. We aimed to analyze the intestinal flora and serum inflammatory cytokine levels of children with non-infectious diarrhea. METHODS: Eighty-nine children with non-infectious diarrhea and 76 healthy children were enrolled from the First Affiliated Hospital of Hainan Medical University between February 2017 and June 2020. Fecal bacterial samples were collected in sterile containers. Following serial dilution, the bacterial samples were cultured in an aerobic medium to cultivate Escherichia coli (E. coli), Enterococci, Lactobacilli, and Bifidobacteria. The levels of inflammatory cytokines in the serum, including interleukin (IL)-2, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α), were determined by enzyme-linked immunosorbent assay. Results between the groups were compared using the paired t-test. The chi-square test was employed to analyze categorical data, with analysis of variance used for multiple-group comparisons. RESULTS: No significant differences were observed between the diarrhea and control groups in terms of sex, age, or body mass index distribution. Compared to the control group, the diarrhea group had significantly elevated levels of E. coli and Enterococci but significantly decreased levels of Bifidobacteria and Lactobacilli. In terms of inflammatory cytokines, the levels of IL-2, IL-8, IL-10, and TNF-α were significantly higher in the diarrhea group than in the control group (all P

• COVID-19 has become a global pandemic. • Gynecologic malignancies with lung metastasis should be alert to asymptomatic infection. • Gynecologic malignancies with asymptomatic COVID-19 can be controlled under strict measures.

Emiliania huxleyi (Coccolithophore) plays a prominent role in the global carbon cycle and in climate processes. The annual collapse of massive E. huxleyi blooms in the marine environment has been shown to be frequently linked to viral control. These host-virus interactions shape the evolution and dynamics of oceanic microscale ecosystems, yet we still understand little of the molecular mechanism of these virus-mediated processes. Here, we present a detailed characterization of the lipidome of E. huxleyi BOF92 strain, both of uninfected cells and those infected with its specific lytic virus EhV-99B1. Non-targeted lipidomics analysis was performed in order to evaluate the dynamic alterations underlying virus-induced metabolic remodeling. The host lipidome (both lipid content and composition) significantly changed in response to the viral infection. The most statistically significant differential lipids were screened as potential biomarkers for assessing E. huxleyi population sensitivity to EhV infection. Our results reveal that the remodeling of lipid metabolism that underlies the pathogenesis of this infection primarily involved sphingolipid, glycerolipid and fatty acid metabolic pathways. Our study provides insights into how viruses shape their hosts metabolism to support their unique life cycle and a lipid-based chemical arms race during host-virus dynamic interactions in a marine environment.

Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

α-L-Rhamnosidase is a glycoside hydrolase capable of removing naringin from citrus juice. However, α-L-rhamnosidases always have broad substrate spectra, causing negative effects on citrus juice. In this study, a α-L-rhamnosidase-expressing fungal strain, JMU-TS529, was identified, and its α-L-rhamnosidase was characterized. As a result, JMU-TS529 was identified as Aspergillus tubingensis via morphological and molecular characteristics. The predicted protein sequence shared an amino acid identity of less than 30% with previously characterized α-L-rhamnosidases. The optimal pH and temperature were 4.0 and 50-60 °C, respectively. Most importantly, the α-L-rhamnosidase showed a strong ability to hydrolyze naringin but scarcely acted on other substrates. Furthermore, the enzyme could efficiently remove naringin from pomelo juice without changing its attractive aroma. These results indicate that the present enzyme represents a new clade of Aspergillus α-L-rhamnosidase that is desirable for debittering citrus juice, providing a better alternative for improving the quality of citrus juice.

Objective: To investigate the spectrum of diseases in female children and adolescents hospitalized for obstetric and gynecological conditions. Methods: This retrospective study included patients (age ≤19 years) admitted to the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, between January 2003 and December 2017. Their medical records – age, principal diagnosis, and treatment – were reviewed and analyzed. Diagnoses were divided into eight disease classifications. Comparison between groups was analyzed with Student's t-test. Results: This study enrolled 4,628 inpatients. The number of inpatients increased each year, especially in the groups of gynecologic tumors, pregnancy-related conditions, and disorders of the breast. The mean age was 16.33 ± 2.42 years (range: 2–19 years). Of all the inpatients, 41.9% (n = 1,939) were hospitalized for gynecologic tumors, and 85.5% (n = 1,657) of the tumors were benign. Altogether, ovarian cysts (28.66%, n = 1,325) were the most common disease observed in this group. In addition, 32.9% (n = 1,524) of the inpatients were hospitalized for pregnancy, childbirth, and puerperium; within this group, 21.9% (n = 1,014) were hospitalized for artificial abortions. Conclusions: The efforts of all stakeholders toward the implementation of government policies to promote sexual and reproductive health among children and adolescents in China have been effective.

Radiotherapy is an effective treatment for lung cancer but lacks a reliable prediction method. Cell-free nucleic acids in plasma have been reported as a novel tumor marker. Here, we evaluate circulating succinate dehydrogenase 5 (SDH5) mRNA in plasma and SDH5 protein in tumors, assess their predictive value in lung cancer patients undergoing radiotherapy, and explore the underlying mechanisms. Methods: SDH5 expression was measured in peripheral blood samples and fresh tumor specimens from 208 non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant RNA and protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect protein-protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. Results: Plasma and tumor SDH5 mRNA levels were positively correlated (rho=0.894, P

106 Background: Current first-line standard therapy (SOC) for R/M CC is platinum-based chemotherapy +/- bevacizumab (bev). AK104 monotherapy has shown promising efficacy and tolerable toxicity in pretreated R/M CC (NCT04380805). In this study, we report the efficacy and safety of AK104 combined with SOC for the first-line treatment of R/M CC (NCT04868708). Methods: The multicenter, open-label, phase II study enrolled R/M CC pts without previous systemic therapy. Eligible pathological types were squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma. Pts were assigned to 3 cohorts (A-15/A-10: AK104 15/10 mg/kg + PTX 175mg/m2 + DDP 50 mg/m2/CBP AUC 5, q3w; B-10: AK104 10 mg/kg + PTX 175 mg/m2 + DDP 50 mg/m2/CBP AUC 5 + bev 15 mg/kg, q3w). All pts received AK104 until PD or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included ORR, PFS per RECIST1.1, and OS, etc. Results: 45 pts were enrolled at 6 centers from Jun 3, 2021, to Nov 5, 2021. As of Jan 10, 2022, we assessed safety in all pts and efficacy in pts with at least one tumor assessment result. TRAEs of any grade occurred in 43 (95.6%) pts. Grade ≥3 TRAEs occurred in 23 (51.1%) pts. The most common TRAEs were anemia (55.6%), white blood cell count decreased (46.7%), rash (24.4%), and hypoesthesia (24.4%). The most common grade ≥ 3 TRAEs were anemia (15.6%), white blood cell count decreased (11.1%), neutrophil count decreased (8.9%), and platelet count decreased (8.9%). TRSAE occurred in 17 (37.8%) pts. IrAEs of any grade, assessed by INV, occurred in 24 (53.3%) pts. Grade ≥ 3 irAE occurred in 8 (17.8%) pts. One death due to hemorrhagic shock occurred in cohort B-10 and was judged as treatment-related. ORR were 73.3% (11/15) for A-15, 68.8% (11/16) for A-10, 92.3% (12/13) for B-10, respectively. The response to the treatment was favorable regardless of CPS (Table). PFS or OS data are not mature by cut-off date. Conclusions: AK104 combined with standard therapy was well tolerated, with encouraging antitumor activity in pts with R/M CC. Meanwhile, long-term safety evaluation still needs following up. A phase III trial is ongoing to evaluate the efficacy of AK104 plus standard therapy in first-line treatment for R/M CC (NCT04982237). Clinical trial information: NCT04868708. [Table: see text]

BackgroundOvarian clear cell carcinoma (OCCC) has an abysmal prognosis with a median overall survival (OS) of 25.3 months because of a low response to chemotherapy. The 5-year disease-specific survival rate after recurrence is 13.2%, with more than two-thirds of the patients dying within a year. Therefore, it is urgent to explore new therapeutic options for OCCC. Based on the characteristic immune-suppressive tumour microenvironment derived from the gene expression profile of OCCC, the combination of immunoantiangiogenesis therapy might have certain efficacy in recurrent/persistent OCCC. This trial aims to evaluate the efficacy and safety of sintilimab and bevacizumab in patients who have failed platinum-containing chemotherapy with recurrent or persistent OCCC.Method and analysisIn this multicentre, single-arm, open-label, investigator-initiated clinical trial, 38 patients will be assigned to receive sintilimab 200 mg plus bevacizumab 15 mg/kg every 3 weeks. The eligibility criteria include histologically diagnosed patients with recurrent or persistent OCCC who have been previously treated with at least one-line platinum-containing chemotherapy; patients with Eastern Cooperative Oncology Group (ECOG) performance status 0–2 with an expected survival greater than 12 weeks. The exclusion criteria include patients previously treated with immune checkpoint inhibitor and patients with contraindications of bevacizumab and sintilimab. The primary endpoint is the objective response rate. The secondary endpoints are progression-free survival, time to response, duration of response, disease control rate, OS, safety and quality of life. Statistical significance was defined as pEthics and disseminationThis trial was approved by the Research Ethics Commission of Tongji Medical College of Huazhong University of Science and Technology (2020-S337). The protocol of this study is registered at www.clinicaltrials.gov. The trial results will be published in peer-reviewed journals and at conferences.Trial registration numberNCT04735861; Clinicaltrials. gov.

As novel amphiphilic materials, six uncharged alkyl rhamnosides incorporating various alkyl chain and one rhamnose amine quaternary ammonium salt were successfully synthesized in this study. Their amphiphilic properties (HLB and CMC), antimicrobial and anti-biofilm activity against S. aureus and P. aeruginosa were investigated. Differentially regulated proteins and pathways were identified by comparative proteomics research to first give a sight on how alkyl rhamnosides performed the anti-biofilm activity at protein and pathway levels. Among the uncharged alkyl rhamnosides, dodecyl rhamnoside and octyl rhamnoside showed the best antimicrobial and anti-biofilm ability against S. aureus and against P. aeruginosa, respectively. Interestingly, the relationships between amphiphilic properties or MIC with anti-biofilm activity were first established. Uncharged alkyl rhamnoside with an optimized HLB value of 5.0 had both the strongest antibacterial and anti-biofilm activity against S. aureus, and MIC was the maximum biofilm inhibitory concentration for all alkyl rhamnosides. Alkyl rhamnosides have a significant overall regulatory effect on the proteomics and pathways of bacterial biofilms, including energy production, substrates transportation, signal transduction, key molecules balance, and so on. These amphiphilic materials have a great potential to be used as additives in pharmaceutic, cosmetic, food industry, hospital and in other non-medical fields.

Reactive oxygen species (ROS) are mitochondrial respiration byproducts, the accumulation of which may cause oxidative damage and is associated with several chronic health problems. As an essential unsaturated fatty acid, eicosapentaenoic acid (EPA) provides various physiological functions; however, its exact regulatory role remains elusive. The current study aimed to address how EPA regulates cellular antioxidant capacity and the possible mechanisms of action. Upon 48 h of EPA treatment, the ROS levels of HepG2 cells were reduced by at least 40%; the total cellular antioxidant capacity was increased by approximately 50–70%, accompanied by enhanced activities and expression of major antioxidant enzymes. Furthermore, the mitochondrial membrane potential and the mitochondrial biogenesis were dramatically improved in EPA-treated cells. These data suggest that EPA improves cellular antioxidant capacity by enhancing mitochondrial function and biogenesis, which sheds light on EPA as a dietary complement to relieve the oxidative damage caused by chronic diseases.

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) occurs more frequently in cancer patients than in the general population. A retrospective cross-sectional study was carried out in patients with solid tumor complicated with VTE admitted to the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 1st, 2008 and December 31th, 2017. The incidence of VTE in hospitalized cancer patients was 1.8%, twice the incidence of VTE in hospitalized non-cancer patients. The annual incidence of cancer-associated VTE in our center varied between 1.6% in 2015 and 0.4% in 2009 with an overall average incidence of 1.3% over the research decade. BMI values of 549(67.7%) cancer patients were within the normal range, but none of patients had BMI greater than 35 kg/m2. 747(92.1%) cancer patients had ECOG PS score ≤ 2 and 481(59.3%) had distant metastasis. Patients with pancreatic, bladder, ovarian and endometrial cancer had the highest incidence of VTE. Upper extremity DVT (47.2%) was more common in cancer patients and might be closely associated with CVC (74.9%), while lower extremities DVT (36.1%) intended to PE development (15.0%). The annual incidence rates showed a fluctuating and upward trend over the research decade. VTE occurrence was closely related to tumor stage, tumor site, catheterization and anti-neoplasm therapy in cancer patients.

Objectives: This sub-analysis investigated treatment response to niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (PSROC) included in the NORA trial who had measurable lesions after finishing chemotherapy and before initiating niraparib. Methods: In the double-blind, phase III NORA trial, 265 adult (≥18 years) Chinese women with PSROC were randomised 2:1 to receive oral niraparib (n=177; 300 mg/day, patients with bodyweight Results: Of the 265 patients included in the NORA study, 64 (24.2%) had measurable lesions at baseline (niraparib, n=43; placebo, n=21), 21.9% (14/64) of whom had received secondary cytoreductive surgery before the last round of chemotherapy. Among patients with measurable lesions, those who received niraparib achieved a higher ORR compared with those receiving placebo (32.6 vs 14.3%; OR=2.7, 95% CI, 0.67-11.18), and niraparib also led to a higher ORR regardless of germline BRCA mutation status (gBRCA mutation: 50.0 vs 28.6%, non-gBRCA mutation: 25.8 vs 7.1%) (Table). Niraparib was well tolerated by patients in this sub-analysis, with a safety profile in-line with previous reports. Download : Download high-res image (98KB) Download : Download full-size image Conclusions: Among patients included in the NORA study with measurable lesions at baseline, niraparib maintenance therapy induced additional antitumour activity versus placebo, with a higher ORR regardless of germline BRCA mutation status, and was well tolerated. The high rates of tumour response observed for niraparib-treated patients in the NORA study further support the role of niraparib as maintenance treatment for patients with PSROC and measurable lesions after chemotherapy.

Reactive oxygen species (ROS) are single-electron-bearing oxidation-reduction products that are mainly produced in mitochondria. Excessive ROS accumulation may lead to oxidative damage. Docosahexaenoic acid (DHA) is an essential component of brain phospholipids and is mainly derived from the diet. Its antioxidant activities have been extensively studied. However, its regulatory roles in mitochondria and the underlying mechanism remain to be elucidated. In this study, the DHA's effect on cellular antioxidant capacity and mitochondrial functions was examined in HepG2 cells. The results showed that 100 μM DHA decreased cellular and mitochondrial ROS levels to 75.2 ± 9.4% (P < 0.05) and 55.1 ± 1.4% (P < 0.01), respectively. It also increased the total antioxidant capacity by 55.6 ± 0.1 and 49.2 ± 1.1% (P < 0.05), based on ABTS and FRAP assay results, respectively. Consistently, it increased the activities and gene expression of major antioxidant enzymes by at least 35 and 40% (P < 0.05), respectively. Furthermore, DHA promoted mitochondrial functions and biogenesis. These data suggested that DHA's antioxidant activity can be attributed to its enhancement of mitochondrial functions and biogenesis. This study may shed light on the molecular mechanisms underlying DHA's function in improving resistance to and relieving the symptoms of chronic disease.

Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat. Levodopa is a common clinical drug for controlling the symptoms of PD, but it only replenishes the missing dopamine, can’t protect dopaminergic neurons. While curcumin as a neuroprotective agent has been reported for treatment of PD. Herein, we present a novel organic-inorganic composite nanoparticle with brain targeting (lf-protocells) for co-delivery of levodopa and curcumin, and demonstrate its attractive use as a biocompatible platform for PD treatment. The nanoparticle system is comprised of a lactoferrin (lf) modified lipid bilayer (LB) containing curcumin as its outer membrane and mesoporous silica nanoparticles (MSNs) containing levodopa as its supporting inner core. Our studies illustrate that the lf-protocells have a spherical morphology, and can be used to co-load levodopa and curcumin efficiently; the combination of curcumin and levodopa alleviates the apoptosis of PD cells, decreases the expression of a-synuclein and increase the expression of tyrosine hydroxylase in SH-SY5Y cells as compared to single drug; the binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs; lf-protocells improve significantly the distribution in brain compared with unmodified protocells; binary-drug loaded lf-protocells have better performance of motor function in mouse than unmodified protocells and combination of free drugs. In conclusion, binary-drug loaded lf-protocells show better therapeutic efficacy in both cell model and mouse model of PD than combination of free drugs and lower toxicity than bare MSNs. These results suggest that lf-protocells can be used as a promising drug delivery platform for targeted therapy against PD and other diseases of the central nervous system.

Monascus pigments (MPs) with different color characteristics, produced by submerged fermentation of Monascus purpureus M9, have potential application in food industry. In the present study, the effects and regulatory mechanisms of ammonium nitrate (AN) on the color characteristics of MPs were investigated. The concentration of intracellular pigments was significantly decreased when subjected to AN. The hue and lightness value indicated AN altered the total pigments appearance from original red to orange. The HPLC analysis for six major components of MPs showed that the production of rubropunctatin or monascorubrin, was significantly reduced to the undetectable level, whereas the the yields of monascin, ankaflavin, rubropunctamine and monascorubramine, were apparently increased with AN supplement. To be noted, via real-time quantitative PCR strategy, the expression level of mppG, closely relative to orange pigments biosynthesis, was significantly down-regulated. However, the expression of mppE, involved in yellow pigments pathway, was up-regulated. Moreover, the broth pH value was dropped to 2.5-3.5 in the fermentation process resulted from AN treatment, along with the increased extracellular polysaccharide biosynthesis. Taken together, the change of MPs categories and amounts by AN might be the driving force for the color characteristics variation in M. purpureus M9. The present study provided useful data for producing MPs with different compositions and modified color characteristics.

Additional file 1: Supplementary Table 1. The efficacy analysis of patients with high-grade serous cancer. ORR, objective response rate; DCR, disease control rate; a Twelve patients receiving less than 2 cycles of PLD and 4 patients without efficacy assessments after 2 cycles of PLD were excluded. Moreover, 1 patient had a postbaseline efficacy assessment that could not be confirmed and was thus excluded; b Including patients with complete and partial responses; c Including patients with complete and partial responses and stable disease.

The marine horseshoe crab (Tachypleus tridentatus) has been considered as food and traditional medicine for many years. Kynurenic acid (KA) was isolated from horseshoe crab in this study for the first time in the world. A previous study in 2018 reported that intraperitoneal administration of KA prevented high-fat diet- (HFD-) induced body weight gain. Now, we investigated the effects of intragastric gavage of KA on HFD mice and found that KA (5 mg/kg/day) inhibited both the body weight gain and the increase of average daily energy intake. KA reduced serum triglyceride and increased serum high-density lipoprotein cholesterol. KA inhibited HFD-induced the increases of serum low-density lipoprotein cholesterol, coronary artery risk index, and atherosclerosis index. KA also suppressed HFD-induced the increase of the ratio of Firmicutes to Bacteroidetes (two dominant gut microbial phyla). KA partially reversed HFD-induced the changes in the composition of gut microbial genera. These overall effects of KA on HFD mice were similar to that of simvastatin (positive control). But the effects of 1.25 mg/kg/day KA on HFD-caused hyperlipidemia were similar to the effects of 5 mg/kg/day simvastatin. The pattern of relative abundance in 40 key genera of gut microbiota from KA group was closer to that from the normal group than that from the simvastatin group. In addition, our in vitro results showed the potential antioxidant activity of KA, which suggests that the improvement effects of KA on HFD mice may be partially associated with antioxidant activity of KA. Our findings demonstrate the potential role of KA as a functional food ingredient for the treatment of obesity and hyperlipidemia as well as the modulation of gut microbiota.

Supplemental Material, sj-pdf-1-cat-10.1177_1076029620975484 for Solid Tumor Complicated With Venous Thromboembolism: A 10-Year Retrospective Cross-Sectional Study by Miao Peng, Shengli Yang, Guiling Li, Tao Zhang, Xiaojuan Qin, Chen Shi, Jian Chang, Mengni Chen, Chen Chen, Bingjie Li, Sihang Cao, Ting Li, Renwang Chen, Prapti Bakhshi, Min Jin, Gang Wu and Jianli Hu in Clinical and Applied Thrombosis/Hemostasis

Additional file 2:Supplementary Table 2. Predictive impact of factors on efficacy evaluated by the RECIST or the GCIG criteria. ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; GCIG, Gynecologic Cancer InterGroup.

Additional file 1. Tab. S1 Primers for RT-qPCR analyzing pigment biosynthetic genes. Fig. S1 The mass spectra and spectrum of Rubropunctatamine (R1) and Monascorubramine (R2), Monascin (Y1), and Ankaflavin (Y2), Rubropunctatin (O1) and Monascorubrin (O2), and three low-level amounts red pigments RX1, RX2, and RX3.

Additional file 3:Supplementary Table 3. Predictive impact of a CA125 decrease after the first cycle on efficacy evaluated by the RECIST or the GCIG criteria. ORR, objective response rate; DCR, disease control rate; a chi-square test; b Including patients with complete and partial responses; c Including patients with complete and partial responses and stable disease. RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; GCIG, Gynecologic Cancer InterGroup.

Background: COVID-19 patients develop hypolipidemia. However, it is unknown whether lipid levels have improved in recovered patients.Objective: In this follow-up study, we evaluated serum lipidemia and other physiopathological laboratory values in recovered patients.Methods: A 3–6 month follow-up study was performed between June 15 and September 3, 2020, to examine serum levels of laboratory values in 107 discharged COVID-19 patients (mild = 59; severe/critical = 48; diagnoses on admission). 61 patients had a revisit chest CT scan. A Wilcoxon signed-rank test was used to analyze changes in laboratory values at admission and follow-up.Results: LDL-c and HDL-c levels were significantly higher at follow-up than at admission in severe/critical cases (p < 0.05). LDL-c levels were significantly higher at follow-up than at admission in mild cases (p < 0.05). With adjustment of the factor of traditional Chinese medicine, LDL-c and HDL-c levels were significantly improved at follow-up than at admission in severe/critical cases (p < 0.05). Coagulation and liver laboratory values were significantly lower at follow-up than at admission for patients (p < 0.05). Increases in HDL-c significantly correlated with increases in numbers of white blood cells (pp < 0.05) during patients’ recovery. Residue lesions were observed in CT images in 69% (42 of 61) of follow-up patients.Conclusions: Improvements of LDL-c, HDL-c and incomplete absorption of lung lesions were observed at 3–6 month follow-up for recovered patients, indicating that a long-term recovery process could be required.

Aims To search for a set of reference genes for reliable gene expression analysis in the globally important marine coccolithophore Emiliania huxleyi-virus model system. Methods and results Fifteen housekeeping genes (CDKA, CYP15, EFG3, POLAI, RPL30, RPL13, SAMS, COX1, GPB1-2, HSP90, TUA, TUB, UBA1, CAM3 and GAPDH) were evaluated for their stability as potential reference genes for qRT-PCR using ΔCt, geNorm, NormFinder, Bestkeeper and RefFinder software. CDKA, TUA and TUB genes were tested as loading controls for Western blot in the same sample panel. Additionally, target genes associated with cell apoptosis, that is metacaspase genes, were applied to validate the selection of reference genes. The analysis results demonstrated that putative housekeeping genes exhibited significant variations in both mRNA and protein content during virus infection. After a comprehensive analysis with all the algorithms, CDKA and GAPDH were recommended as the most stable reference genes for E huxleyi virus (EhV) infection treatments. For Western blot, significant variation was seen for TUA and TUB, whereas CDKA was stably expressed, consistent with the results of qRT-PCR. Conclusions CDKA and GAPDH are the best choice for gene and protein expression analysis than the other candidate reference genes under EhV infection conditions. Significance and impact of the study The stable internal control genes identified in this work will help to improve the accuracy and reliability of gene expression analysis and gain insight into complex E. huxleyi-EhV interaction regulatory networks.

BackgroundNovel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy.MethodsBlood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo.ResultsWe found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96−CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models.ConclusionsOur findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.

Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germlineThis open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germlineA total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5-18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6-78.2] and 70.8% (95% CI, 61.5-79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3-13.9) and 10.3 months (95% CI, 9.2-12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2-96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred.Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline

Background. In the past few years, the immune system and tumor immune microenvironment are becoming increasingly popular as more work has been accomplished in this field. However, nomograms based on immune-related characteristics for prognosis prediction of cervical cancer have not been fully explored to our knowledge. We constructed a novel immune score-based nomogram to predict patients with high risk and poor prognosis. Materials and Methods. 198 patients with cervical cancer from The Cancer Genome Atlas (TCGA) database were included in our study. Immune scores were generated with Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and clinic-pathological characteristics were also included for subsequent analysis. Cox proportional hazards regression models were performed for univariate and multivariate analyses to screen the significant factors, and a prognostic nomogram was built. Bootstrap resampling analysis was used for internal validation. The calibration curve and concordance index (C-index) were used to assess the predictive performance of the nomogram. Results. Patients were split into three subgroups based on immune scores. We found that patients with high immune scores conferred significantly better overall survival (OS) compared with those with medium and low immune scores (hazard ratio (HR), 0.305; 95% confidence interval (CI), 0.108-0.869). A nomogram with a C-index of 0.720 had a favorable performance for predicting survival rate for clinical use by combining immune scores with other clinical features. The calibration curves at 3 and 5 years suggested a good consistency between the predicted OS and the actual OS probability. Conclusions. Our work highlights the potential clinical application significance of immune score-based nomogram in predicting the OS of cervical cancer patients.

Objective To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. Methods This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. Results Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2–6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4–46.4%), and the DCR was 65.2% (95% CI, 56.4–74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. Conclusions For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat, partly because the blood-brain barrier blocks passage of most drugs. Levodopa is a common clinical drug for controlling the symptoms of PD, but it only replenishes the missing dopamine, can’t protect dopaminergic neurons. While curcumin as a neuroprotective agent has been reported for treatment of PD. Herein, we present a novel organic-inorganic composite nanoparticle with brain targeting (denoted as lf-protocells) for co-delivery of levodopa and curcumin, and demonstrate its attractive use as a biocompatible platform for PD treatment. The nanoparticle system is comprised of a lactoferrin (lf) modified lipid bilayer (LB) containing curcumin as its outer membrane and mesoporous silica nanoparticles (MSNs) containing levodopa as its supporting inner core. Our studies illustrate that the lf-protocells have a size of about 180 nm and spherical morphology, and can be used to co-load levodopa and curcumin efficiently. Further, a cell model and a mouse model induced by rotenone (Rot) and MPTP respectively are used to investigate the effects of binary-drug loaded lf-protocells on PD. Our results demonstrate that the combination of curcumin and levodopa alleviate the apoptosis of PD cells, enhance the cell viability as compared to levodopa used alone; levodopa together with curcumin also efficiently decrease the expression of a-synuclein, increase the expression of tyrosine hydroxylase in SH-SY5Y cells, and transform more levodopa into dopamine for supplement the loss of the brain. Moreover, the resulting binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs. In addition, testing in a mouse model indicate that lf-protocells can improve significantly the motor function and distribution in brain compared with unmodified protocells. In conclusion, binary-drug loaded lf-protocells show much better therapeutic efficacy in both the cell model and the mouse model of PD than single free drug and lower toxicity than bare MSNs. These results suggest that lf-protocells can be used as a promising drug delivery platform for targeted therapy against PD and other diseases of the central nervous system.

Background Most cancers favor glycolytic-based glucose metabolism. Hexokinase-2 (HK2), the first glycolytic rate-limiting enzyme, shows limited expression in normal adult tissues but is overexpressed in many tumor tissues, including ovarian cancer. HK2 has been shown to be correlated with the progression and chemoresistance of ovarian cancer and could be a therapeutic target. However, the systemic toxicity of HK2 inhibitors has limited their clinical use. Since follicle-stimulating hormone (FSH) receptor (FSHR) is overexpressed in ovarian cancer but not in nonovarian healthy tissues, we designed FSHR-mediated nanocarriers for HK2 shRNA delivery to increase tumor specificity and decrease toxicity. Results HK2 shRNA was encapsulated in a polyethylene glycol-polyethylenimine copolymer modified with the FSH β 33–53 or retro-inverso FSH β 33–53 peptide. The nanoparticle complex with FSH peptides modification effectively depleted HK2 expression and facilitated a shift towards oxidative glucose metabolism, with evidence of increased oxygen consumption rates, decreased extracellular acidification rates, and decreased extracellular lactate and glucose consumption in A2780 ovarian cancer cells and cisplatin-resistant A2780CP counterpart cells. Consequently, cell proliferation, invasion and migration were significantly inhibited, and tumor growth was suppressed even in cisplatin-resistant ovarian cancer. No obvious systemic toxicity was observed in mice. Moreover, the nanoparticle complex modified with retro-inverso FSH peptides exhibited the strongest antitumor effects and effectively improved cisplatin sensitivity by regulating cisplatin transport proteins and increasing apoptosis through the mitochondrial pathway. Conclusions These results established HK2 as an effective therapeutic target even for cisplatin-resistant ovarian cancer and suggested a promising targeted therapeutic approach.

Three-dimensional (3D) bioprinting is a novel technology utilizing biocompatible materials, cells, drugs, etc. as basic microcomponents to form 3D artificial structures and is believed as a promising method for regenerative medicine. Droplet-based bioprinting can precisely generate microspheres and manipulate them into organized structures with high fidelity. Biocompatible hydrogels are usually used as bioinks in 3D bioprinting, however, the viscosity of the bioink could be increased due to the additives such as cells, drugs, nutrient factors and other functional polymers in some particular applications, making it difficult to form monodispersed microspheres from high-viscosity bioink at the orifice of the nozzle. In this work, we reported a novel microfluidic-based printing nozzle to prepare monodispersed microspheres from high-viscosity bioink using the phase-inversion method. Different flowing conditions can be achieved by changing the flow rates of the fluids to form monodispersed solid and hollow microspheres using the same nozzle. The diameter of the microspheres can be tuned by changing the flow rate ratio and the size distribution of the microspheres is narrow. The prepared calcium alginate microspheres could also act as micro-carriers in drug delivery.

Bisphenol S (BPS) is the major substitute for the production of bisphenol A (BPA)-free products and detected in both food and environment. Although the relationship between BPA exposure and increased risk of obesity and diabetes has been noted, the potential influence of BPS is not fully understood. Herein, a non-targeted lipidomic study was performed to explore BPA/BPS exposure actions using the 3T3-L1 preadipocyte differentiation model, and revealed the comprehensive lipidome disturbance induced by either BPA or BPS exposure at different doses of 0.01, 1 and 100 μM. BPA was more potent than BPS in disturbance of lipid metabolism. A considerable similarity of BPS exposure to BPA was discovered. The key lipid remodeling in response to exposure was found to involve the cardiolipins, phosphatidylglycerols and fatty acids metabolic pathways, providing novel clues of potential mechanism in which both BPA and BPS exposure could be associated with increased risk of insulin resistance. Our study supplies the perspective into the lipidome response to environmental stress induced by BPA/BPS, and shows that BPA-free products are not necessarily safer. Substitution of BPA by its structural analog BPS should be therefore performed with caution.

Purpose COVID-19 broke out in late 2019 and rapidly spread around the world and became a pandemic. This highly contagious disease affects routine health care services and patients with cancer who are susceptible to it. Delivering brachytherapy on time is critical for patients with cancer to get better prognosis. The purpose of this study is to present workflow and standard for radiation centers to deliver brachytherapy and avoid cross-infection during the COVID-19 pandemic. Methods and Materials This study combined previous literature and guidelines of precaution with clinical experience in the COVID-19 pandemic. Results A workflow covering patients' screening, health care workers’ precaution, training, and other aspects of the whole brachytherapy procedure was established. Conclusions From the reopening of radiation center to mid-May in 2020, there is no hospital infection of COVID-19 in patients or health care workers. This recommendation is effective and helpful to other cancer centers.

Summary Background Patients with cancer are a high-risk population in the COVID-19 pandemic. We aimed to describe clinical characteristics and outcomes of patients with cancer and COVID-19, and examined risk factors for mortality in this population. Methods We did a retrospective, multicentre, cohort study of 205 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and with a pathological diagnosis of a malignant tumour in nine hospitals within Hubei, China, from Jan 13 to March 18, 2020. All patients were either discharged from hospitals or had died by April 20, 2020. Clinical characteristics, laboratory data, and cancer histories were compared between survivors and non-survivors by use of χ2 test. Risk factors for mortality were identified by univariable and multivariable logistic regression models. Findings Between Jan 13 and Mar 18, 2020, 205 patients with cancer and laboratory-confirmed SARS-CoV-2 infection were enrolled (median age 63 years [IQR 56–70; range 14–96]; 109 [53%] women). 183 (89%) had solid tumours and 22 (11%) had haematological malignancies. The median duration of follow-up was 68 days (IQR 59–78). The most common solid tumour types were breast (40 [20%] patients), colorectal (28 [14%]), and lung cancer (24 [12%]). 54 (30%) of 182 patients received antitumour therapies within 4 weeks before symptom onset. 30 (15%) of 205 patients were transferred to an intensive care unit and 40 (20%) died during hospital admission. Patients with haematological malignancies had poorer prognoses than did those with solid tumours: nine (41%) of 22 patients with haematological malignancies died versus 31 (17%) of 183 patients with solid tumours (hazard ratio for death 3·28 [95% CI 1·56–6·91]; log rank p=0·0009). Multivariable regression analysis showed that receiving chemotherapy within 4 weeks before symptom onset (odds ratio [OR] 3·51 [95% CI 1·16–10·59]; p=0·026) and male sex (OR 3·86 [95% CI 1·57–9·50]; p=0·0033) were risk factors for death during admission to hospital. Interpretation Patients with cancer and COVID-19 who were admitted to hospital had a high case-fatality rate. Unfavourable prognostic factors, including receiving chemotherapy within 4 weeks before symptom onset and male sex, might help clinicians to identify patients at high risk of fatal outcomes. Funding National Natural Science Foundation of China.

In the recommendation system, the collaborative filtering algorithm is widely used. However, there are lots of problems which need to be solved in recommendation field, such as low precision, the long tail of items. In this paper, we design an algorithm called FSTS for solving the low precision and the long tail. We adopt stability variables and time-sensitive factors to solve the problem of user's interest drift, and improve the accuracy of prediction. Experiments show that, compared with Item-CF, the precision, the recall, the coverage and the popularity have been significantly improved by FSTS algorithm. At the same time, it can mine long tail items and alleviate the phenomenon of the long tail.

Additional file 1: Table S1. DLS size and zeta potential of nanoparticles with different N/P ratios. Figure S1. Relative FSHR mRNA expression in human normal tissues ( https://gtexportal.org/home/gene/FSHR ). Figure S2. FTIR of FSH (A), DFSH (B), PEG (C), PEI (D), FSH-PEG (E) and DFSH-PEG (F). Figure S3. In vitro effects of HK2 shRNA-loaded nanoparticles on different cancer cell lines. (A) Cell viability according to a CCK-8 assay. (B) Cell apoptosis according to flow cytometry. Figure S4. In vitro effects of scramble shRNA-loaded nanoparticles on A2780 and A2780CP cells. A2780 and A2780CP cells were treated with scramble shRNA-loaded nanoparticles at a plasmid-equivalent concentration of 1.0 μg/ml. (A) Cell viability according to a CCK-8 assay. (B) Cell apoptosis according to flow cytometry.

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Location-based services (LBS) have become an important part of people’s daily life. However, while providing great convenience for mobile users, LBS result in a serious problem on personal privacy, i.e., location privacy and query privacy. However, existing privacy methods for LBS generally take into consideration only location privacy or query privacy, without considering the problem of protecting both of them simultaneously. In this paper, we propose to construct a group of dummy query sequences, to cover up the query locations and query attributes of mobile users and thus protect users’ privacy in LBS. First, we present a client-based framework for user privacy protection in LBS, which requires not only no change to the existing LBS algorithm on the server-side, but also no compromise to the accuracy of a LBS query. Second, based on the framework, we introduce a privacy model to formulate the constraints that ideal dummy query sequences should satisfy: (1) the similarity of feature distribution, which measures the effectiveness of the dummy query sequences to hide a true user query sequence; and (2) the exposure degree of user privacy, which measures the effectiveness of the dummy query sequences to cover up the location privacy and query privacy of a mobile user. Finally, we present an implementation algorithm to well meet the privacy model. Besides, both theoretical analysis and experimental evaluation demonstrate the effectiveness of our proposed approach, which show that the location privacy and attribute privacy behind LBS queries can be effectively protected by the dummy queries generated by our approach.

Additional file 1 Table S1. The AJCC Staging Definitions, the ENETS Staging Definitions, and the Modified 7th AJCC Staging Definitions Staging Definitions for pNECs Table S2. Multivariate Analyses of other predictors of tumor-related death among the local patients (N = 154) using the definitions of the ENETS, 8th AJCC, 7th AJCC staging systems for pNECs Table S3. Univariate Analyses of other predictors of tumor-related death among 568 patients using the definitions of the ENETS, 8th AJCC, 7th AJCC staging systems for pNECs Table S4. Multivariate Analyses of other predictors of tumor-related death among 568 patients using the definitions of the ENETS, 8th AJCC, 7th AJCC staging systems for pNECs.

Additional file 2: Table S2. Correlation between the clinicopathologic variables and expression of NEK2 in 123 paraffin-embedded cervical cancer tissues.

Additional file 1: Table S1. Sequences of primers used for Real-time quantitative PCR.

Ethnopharmacological relevance Pinellia pedatisecta Schott extract (PE), a traditional Chinese medicine, has been used to reduce swelling, dry dampness and suppress cervical tumors. Aims To evaluate the roles of PE in the regulation of anti-tumor effects and the cellular immune response in the tumor microenvironment. Methods The immune microenvironment of HPV+TC-1 tumors was examined by immunohistochemistry, real-time PCR and flow cytometry. Results Our study demonstrated that PE in vitro could significantly increase the percentage of apoptosis and necrosis in HPV+TC-1 cells and block the cell cycle phase. In vivo treatment with PE eradicated established subcutaneous HPV+TC-1 tumors in wild-type C57BL/6 mice by infiltrating CD8+ T cells and CD4+ T cells and by directly suppressing tumor growth and resistance to avascular necrosis. The key factors in the canonical Wnt signaling pathway in the experimental group (PE+mDC+naive CD4+T cells) were challenged, and the levels of beta-catenin, C-myc, cyclin D1 and PPAR1 were significantly enhanced at the 5th day. In particular, the subset proportion of Th1 cells (characterized by IFNγ production and the transcription factor Tbet) increased significantly, and both Th2 cells (characterized by IL-4 production and the transcription factor GATA3) and Th17 cells (characterized by IL-17 production and the transcription factor RoRγt) decreased profoundly. Conclusions These findings linked the anti-tumor properties of PE with the immune microenvironment to present a reliable basis for the future practical application of PE in cervical cancer as a novel and pharmacologically safe immunotherapy strategy.