Aflatoxin B1 inhibited the development of primary myoblasts of grass carp (Ctenopharyngodon idella) by degrading extracellular matrix.

According to the International Agency for Research on Cancer (IARC), aflatoxin B1 (AFB1) has been recognized as a major contaminant in food and animal feed and which is a common mycotoxin with high toxicity. Previous research has found that AFB1 inhibited zebrafish muscle development. However, the potential mechanism of AFB1 on fish muscle development is unknown, so it is necessary to conduct further investigation. In the present research, the primary myoblast of grass carp was used as a model, we treated myoblasts with AFB1 for 24 h. Our results found that 5 µM AFB1 significantly inhibited cell proliferation and migration (P < 0.05), and 10 µM AFB1 promoted lactate dehydrogenase (LDH) release (P < 0.05). Reactive oxygen species (ROS), protein carbonyl (PC) and malondialdehyde (MDA) levels were increased in 15, 5 and 10 µM AFB1 (P < 0.05), respectively. Catalase (CAT), glutathione peroxidase (GPx) and total superoxide dismutase (T-SOD) activities were decreased in 10, 10 and 15 µM AFB1 (P < 0.05), respectively. Furthermore, 15 µM AFB1 induced oxidative damage by Nrf2 pathway, also induced apoptosis in primary myoblast of grass carp. Meanwhile, 15 µM AFB1 decreased MyoD gene and protein expression (P < 0.05). Importantly, 15 µM AFB1 decreased the protein expression of collagen Ⅰ and fibronectin (P < 0.05), and increased the protein levels of urokinase plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), and p38 mitogen-activated protein kinase (p38MAPK) (P < 0.05). As a result, our findings suggested that AFB1 damaged the cell morphology, induced oxidative damage and apoptosis, degraded ECM components, in turn inhibiting myoblast development by activating the p38MAPK/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase (MMPs)/extracellular matrix (ECM) signaling pathway.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Targeting Ferroptosis-Elicited Inflammation Suppresses Hepatocellular Carcinoma Metastasis and Enhances Sorafenib Efficacy.

Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1ß to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1ß precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1ß. Depleting either macrophages or neutrophils or neutralizing IL1ß in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1ß/neutrophil/vasculature axis. SIGNIFICANCE: Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer.

After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.

Treatment and survival analysis for 40-year SEER data on upper esophageal cancer.

Background: Upper esophageal cancer (UEC) is rare in both Eastern and Western countries. The epidemiological characteristics and long-term survival of UEC patients are less known. In addition, the choice of optimal treatment for UEC has been controversial. Methods: Cases of UEC (C15.3 and C15.0) arising during the period from 1973 to 2013 were identified and selected using the SEER database. Student's t-test and Pearson's chi-square test were used to compare the differences in parameters among different groups. Esophageal cancer-specific survival (ECSS) and overall survival (OS) rates were calculated by using the Kaplan-Meier method. Cox proportional hazard regression was used to analyze predictive factors. Results: In the past 40 years, the cases of UEC have gradually increased, and the proportion of adenocarcinoma (AD) has gradually increased (from 3.6% to 11.8%, p < 0.001). There has been a significant increase (1973-1982 vs. 2004-2013) in median OS (7 months vs. 10 months, p < 0.001) and median ECSS (7 months vs. 11 months, p < 0.001) among UEC patients from 1973 to 2013. For the impact of different treatments, the results showed that the ECSS and OS of surgery without radiation (SWR) and radiation plus surgery (R+S) were superior to those of radiation without surgery (RWS). Subgroup analysis showed that ECSS and OS were highest among patients treated with SWR compared with R+S and RWS for patients with localized disease. For regional disease, ECSS and OS were highest among patients with R+S compared with SWR or RWS. Among patients with regional-stage squamous cell carcinoma (SCC), OS was higher with neoadjuvant radiotherapy or adjuvant radiotherapy compared with SWR. Multivariate analysis showed that radiotherapy sequence was dependently associated with OS among patients with regional-stage SCC. Conclusion: Although the long-term survival of UEC remains poor, it has gradually increased since 1973. This should be closely related to the improvement of medical care over the past 40 years. Different treatment methods have a great influence on the long-term survival of UEC. For localized diseases, surgery may be a better choice. For regional disease, surgery plus adjuvant or neoadjuvant radiotherapy may be more beneficial to improve the long-term prognosis of UEC patients.

Seasonal malaria chemoprevention in Africa and China's upgraded role as a contributor: a scoping review.

BACKGROUND: Children under five are the vulnerable population most at risk of being infected with Plasmodium parasites, especially in the Sahel region. Seasonal malaria chemoprevention (SMC) recommended by World Health Organization (WHO), has proven to be a highly effective intervention to prevent malaria. Given more deaths reported during the COVID-19 pandemic than in previous years due to the disruptions to essential medical services, it is, therefore, necessary to seek a more coordinated and integrated approach to increasing the pace, coverage and resilience of SMC. Towards this end, fully leverage the resources of major players in the global fight against malaria, such as China could accelerate the SMC process in Africa. METHODS: We searched PubMed, MEDLINE, Web of Science, and Embase for research articles and the Institutional Repository for Information Sharing of WHO for reports on SMC. We used gap analysis to investigate the challenges and gaps of SMC since COVID-19. Through the above methods to explore China's prospective contribution to SMC. RESULTS: A total of 68 research articles and reports were found. Through gap analysis, we found that despite the delays in the SMC campaign, 11.8 million children received SMC in 2020. However, there remained some challenges: (1) a shortage of fully covered monthly courses; (2) lack of adherence to the second and third doses of amodiaquine; (3) four courses of SMC are not sufficient to cover the entire malaria transmission season in areas where the peak transmission lasts longer; (4) additional interventions are needed to consolidate SMC efforts. China was certified malaria-free by WHO in 2021, and its experience and expertise in malaria elimination can be shared with high-burden countries. With the potential to join the multilateral cooperation in SMC, including the supply of quality-assured health commodities, know-how transfer and experience sharing, China is expected to contribute to the ongoing scale-up of SMC. CONCLUSIONS: A combination of necessary preventive and curative activities may prove beneficial both for targeted populations and for health system strengthening in the long run. More actions are entailed to promote the partnership and China can be one of the main contributors with various roles.

Prevalence and contributing factors of impaired awareness of hypoglycemia in patients with type 2 diabetes: a meta-analysis.

AIMS: To conduct a systematic review to summarize the definition, measurement tools, prevalence, and contributing factors of impaired awareness of hypoglycemia (IAH) in type 2 diabetes mellitus (T2DM). METHODS: A reproducible search strategy was used to identify factors affecting IAH in T2DM in PubMed, MEDLINE, EMBASE, Cochrane, PsycINFO, and CINAHL from inception until 2022. Literature screening, quality evaluation, and information extraction were performed independently by 2 investigators. A meta-analysis of prevalence was performed using Stata 17.0. RESULTS: The pooled prevalence of IAH in patients with T2DM was 22% (95%CI:14-29%). Measurement tools included the Gold score, Clarke's questionnaire, and the Pedersen-Bjergaard scale. IAH in T2DM was associated with sociodemographic factors (age, BMI, ethnicity, marital status, education level, and type of pharmacy patients visited), clinical disease factors (disease duration, HbAlc, complications, insulin therapy regimen, sulfonylureas use, and the frequency and severity of hypoglycemia), and behavior and lifestyle (smoking and medication adherence). CONCLUSION: The study found a high prevalence of IAH in T2DM, with an increased risk of severe hypoglycemia, suggesting that medical workers should take targeted measures to address sociodemographic factors, clinical disease, and behavior and lifestyle to reduce IAH in T2DM and thus reduce hypoglycemia in patients.

Uniportal versus triportal video-assisted thoracic surgery in the treatment of tuberculous empyema.

OBJECTIVE: To examine the effectiveness of decortication to treat chronic tuberculous empyema (TE) using uniport video-assisted thoracoscopic surgery (VATS) versus conventional triport VATS. METHODS: Data from consecutive patients with stage II or III TE who underwent decortication with either uniport VATS (uniportal group) between July and December 2017, or triport VATS between January and July 2018 (triportal group), were retrospectively analysed. VATS procedures were performed under general anaesthesia with double lumen endotracheal intubation and clinical outcomes were compared between the two groups. RESULTS: Clinical data were comparable between the groups (20 patients in each) regarding demographic and baseline characteristics, operative and postoperative characteristics, surgical procedure-related complications, and postoperative adverse events. No surgical procedure-related complications occurred during the perioperative period in either group. Threshold values for mechanical pain at 8 h postoperatively were significantly higher in the triportal group versus the uniportal group. Furthermore, the incidence of nausea and vomiting was significantly lower in the uniportal versus triportal group. In the triportal group, one patient required readmission and further intervention due to recurrence. CONCLUSIONS: Uniport VATS decortication for stages II and III TE may be a feasible and safe procedure in selected patients. Moreover, uniport VATS may be less painful than triport VATS.

Aflatoxin B1 damaged structural barrier through Keap1a/Nrf2/ MLCK signaling pathways and immune barrier through NF-κB/ TOR signaling pathways in gill of grass carp (Ctenopharyngodon idella).

Aquafeeds are susceptible to contamination caused by aflatoxin B1 (AFB1). The gill of fish is an important respiratory organ. However, few studies have investigated the effects of dietary AFB1 exposure on gill. This study aimed to discuss the effects of AFB1 on the structural and immune barrier of grass carp gill. Dietary AFB1 increased reactive oxygen species (ROS) levels, protein carbonyl (PC) and malondialdehyde (MDA) contents, which consequently caused oxidative damage. In contrast, dietary AFB1 decreased antioxidant enzymes activities, relative genes expression (except MnSOD) and the contents of glutathione (GSH) (P < 0.05), which are partly regulated by NF-E2-related factor 2 (Nrf2/Keap1a). Moreover, dietary AFB1 caused DNA fragmentation. The relative genes of apoptosis (except Bcl-2, McL-1 and IAP) were significantly upregulated (P < 0.05), and apoptosis was likely upregulated through p38 mitogen-activated protein kinase (p38MAPK). The relative expressions of genes associated with tight junction complexes (TJs) (except ZO-1 and claudin-12) were significantly decreased (P < 0.05), and TJs were likely regulated by myosin light chain kinase (MLCK). Overall, dietary AFB1 disrupted the structural barrier of gill. Furthermore, AFB1 increased gill sensitivity to F. columnare, increased Columnaris disease and decreased the production of antimicrobial substances (P < 0.05) in grass carp gill, and upregulated the expression of genes involved with pro-inflammatory factors (except TNF-α and IL-8) and the pro-inflammatory response partly attributed to the regulation by nuclear factor κB (NF-κB). Meanwhile, the anti-inflammatory factors were downregulated (P < 0.05) in grass carp gill after challenge with F. columnare, which was partly attributed to the target of rapamycin (TOR). These results suggested that AFB1 aggravated the disruption of the immune barrier of grass carp gill after being challenge with F. columnare. Finally, the upper limit of safety of AFB1 for grass carp, based on Columnaris disease, was 31.10 µg/kg diet.

Efficacy and safety of esophagectomy via left thoracic approach versus via right thoracic approach for middle and lower thoracic esophageal cancer: a multicenter randomized clinical trial (NST1501).

Background: Left thoracic approach (LTA) has been a favorable selection in surgical treatment for esophageal cancer (EC) patients in China before minimally invasive esophagectomy (MIE) is popular. This study aimed to demonstrate whether right thoracic approach (RTA) is superior to LTA in the surgical treatment of middle and lower thoracic esophageal squamous cell carcinoma (TESCC). Methods: Superiority clinical trial design was used for this multicenter randomized controlled two-parallel group study. Between April 2015 and December 2018, cT1b-3N0-1M0 TESCC patients from 14 centers were recruited and randomized by a central stratified block randomization program into LTA or RTA groups. All enrolled patients were followed up every three months after surgery. The software SPSS 20.0 and R 3.6.2. were used for statistical analysis. Efficacy and safety outcomes, 3-year overall survival (OS) and disease-free survival (DFS) were calculated and compared using the Kaplan-Meier method and the log-rank test. Results: A total of 861 patients without suspected upper mediastinal lymph nodes (umLN) were finally enrolled in the study after 95 ineligible patients were excluded. 833 cases (98.7%) were successfully followed up until June 1, 2020. Esophagectomies were performed via LTA in 453 cases, and via RTA in 408 cases. Compared with the LTA group, the RTA group required longer operating time (274.48±78.92 vs. 205.34±51.47 min, P<0.001); had more complications (33.8% vs. 26.3% P=0.016); harvested more lymph nodes (LNs) (23.61±10.09 vs. 21.92±10.26, P=0.015); achieved a significantly improved OS in stage IIIa patients (67.8% vs. 51.8%, P=0.022). The 3-year OS and DFS were 68.7% and 64.3% in LTA arm versus 71.3% and 63.7% in RTA arm (P=0.20; P=0.96). Conclusions: Esophagectomies via both LTA and RTA can achieve similar outcomes in middle or lower TESCC patients without suspected umLN. RTA is superior to LTA and recommended for the surgical treatment of more advanced stage TESCC due to more complete lymphadenectomy. Trial Registration: ClinicalTrials.gov NCT02448979.

Plant-Derived Molecule 4-Methylumbelliferone Suppresses FcεRI-Mediated Mast Cell Activation and Allergic Inflammation.

Mast cells (MCs) are an important treatment target for high-affinity IgE Fc receptor (FcεRI)-mediated allergic diseases. The plant-derived molecule 4-methylumbelliferone (4-MU) has beneficial effects in animal models of inflammation and autoimmunity diseases. The aim of this study was to examine 4-MU effects on MC activation and probe the underlying molecular mechanism(s). We sensitized rat basophilic leukemia cells (RBLs) and mouse bone marrow-derived mast cells (BMMCs) with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated them with exposure to DNP-human serum albumin (HSA), and then treated stimulated cells with 4-MU. Signaling-protein expression was determined by immunoblotting. In vivo allergic responses were examined in IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) mouse models. 4-MU inhibited ß-hexosaminidase activity and histamine release dose-dependently in FcεRI-activated RBLs and BMMCs. Additionally, 4-MU reduced cytomorphological elongation and F-actin reorganization while down-regulating IgE/Ag-induced phosphorylation of SYK, NF-κB p65, ERK1/2, p38, and JNK. Moreover, 4-MU attenuated the PCA allergic reaction (i.e., less ear thickening and dye extravasation). Similarly, we found that 4-MU decreased body temperature, serum histamine, and IL4 secretion in OVA-challenged ASA model mice. In conclusion, 4-MU had a suppressing effect on MC activation both in vitro and in vivo and thus may represent a new strategy for treating IgE-mediated allergic conditions.

Real-World Survival Outcomes Based on EGFR Mutation Status in Chinese Patients With Lung Adenocarcinoma After Complete Resection: Results From the ICAN Study.

INTRODUCTION: The adjuvant treatment of patients with resected lung adenocarcinoma (LUAD) remains unstandardized. We analyzed the survival outcomes of these patients based on EGFR mutation status and adjuvant chemotherapy treatment. METHODS: This noninterventional real-world study (ICAN) enrolled Chinese patients with resected stages I to III LUAD from April 8, 2010, to December 31, 2010. Tumor EGFR mutation status and 3-year disease-free survival (DFS) were determined. The extension phase provided long-term follow-up with overall survival (OS) as the primary end point. Secondary end points included DFS and prognostic factors of survival. Survival outcomes based on adjuvant chemotherapy treatment, EGFR mutation status, and postoperative stage were analyzed post hoc. RESULTS: Among 568 patients in the ICAN cohort, 472 continued to the extension phase and remained eligible. The 3-year DFS rate was 58.8%. In the extension cohort, 260 patients (55.1%) had EGFR-mutant disease and 207 (43.9%) received adjuvant chemotherapy. At a median follow-up of 109.0 (95% confidence interval [CI]: 106.6-111.4) months, median OS and DFS were 103.3 (95% CI: 101.7-104.9) and 67.4 (95% CI: 49.7-85.2) months, respectively. The 5-year OS and DFS rates were 68.9% (95% CI: 64.3-73.6) and 52.9% (95% CI: 48.2-57.7), respectively. EGFR wild-type disease was a significant independent predictor of worse OS (HR = 1.24, 95% CI: 1.07-1.44, p= 0.004) based on the Cox regression analysis of common factors. Post hoc subgroup analysis revealed that survival outcomes were not significantly different with adjuvant chemotherapy regardless of EGFR mutation status across all postoperative stages. CONCLUSIONS: EGFR mutations are common in operable LUAD, and recurrence and mortality after resection were considerable. Adjuvant chemotherapy did not improve survival outcomes, regardless of EGFR mutation status and postoperative stage.

Expression and significance of inflammatory reactions mediated by the IL-33/ST2 signaling pathway in the serum of heart failure patients.

OBJECTIVE: This research aimed to explore the clinical significance of inflammatory reactions mediated by the IL-33/ST2 signaling pathway in heart failure (HF) patients. METHODS: A total of 100 HF patients treated in the Department of Cardiology in our hospital were prospectively regarded as the observation group, and 100 healthy age and gender matched patients who were undergoing physical examination were considered as the control group. The levels of interleukin-33 (IL-33), ST2, tumor necrosis factor-α (TNF-α) and pro B-type natriuretic peptide (pro-BNP) in the peripheral blood of patients were detected. The potential correlation between IL-33 and ST2, TNF-α and pro-BNP was analyzed by Pearson. RESULTS: The levels of IL-33, IL-10, ST2 and pro-BNP in the peripheral blood of patients in the observation group were higher than those in the control group; and they increased with the rise of cardiac function grade (all P<0.05). In addition, IL-33 was positively correlated with TNF-α, ST2 and pro-BNP (r=0.863, 0.879, 0.945; all P<0.05). Multivariate Logistic analysis revealed that the increase of IL-33 and ST2 were independent risk factors of HF. CONCLUSION: The IL-33 and ST2 levels in the peripheral serum of HF patients are correlated with TNF-α and BNP, the finding of which can assist in clinical diagnosis and treatment.

Actirhodobacter atriluteus gen. nov., sp. nov., isolated from the surface water of the Yellow Sea.

A Gram-stain-negative, aerobic, orange-pigmented bacterial strain, designated HHU K3-1 T, was isolated from the surface water of the Yellow Sea. The strain was observed to grow on 2216E agar medium, and growth occurred at pH 6.0-8.0 (optimum 7.0), 28-37 °C (optimum 28 °C), and in the presence of 0.5-5% (w/v) NaCl (optimum 1-3%). The major fatty acids (> 10%) were summed feature 3 (C16:1ω6c/C16:1ω7c), C17:1ω6c and summed feature 8 (C18:1ω6c/C18:1ω7c). Strain HHU K3-1 T was found to contain ubiquinone-10 as the predominant quinone and the major polar lipids were diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and sphingoglycolipid (SGL). The 16S rRNA gene sequence analysis indicated that strain HHU K3-1 T shared highest similarities with Pelagerythrobacter marensis KCTC 22370 T (97.7%) and Qipengyuania oceanensis MCCC 1A09965T (96.9%). However, a phylogenetic tree based on 288 orthologous clusters (OCs) indicated that HHU K3-1 T was close related to Parapontixanthobacter aurantiacus MCCC 1A09962T. The pairwise AAI and evolutionary distance between HHU K3-1 T and Parapontixanthobacter aurantiacus MCCC 1A09962T are 67.1% and 0.43, respectively, which meet the recently proposed standard to differentiate genera in the family Erythrobacteraceae. On the basis of the result obtained by the polyphasic taxonomic study, strain HHU K3-1 T can be considered to represent a novel genus in the family Erythrobacteraceae, for which the name Actirhodobacter atriluteus gen. nov., sp. nov. is proposed. The type strain is HHU K3-1 T (= MCCC 1K04225T = KCTC 72834 T = CGMCC 1.17395 T).

Subfoveal choroidal thickness changes after intravitreal ranibizumab injections in different patterns of diabetic macular edema using a deep learning-based auto-segmentation.

PURPOSE: To evaluate the effect of intravitreal injection of ranibizumab (IVR) on subfoveal choroidal thickness (SFCT) and its relationship with central macular thickness (CMT) and best-corrected visual acuity (BCVA) changes in eyes with center-involving DME (CI-DME) using a deep learning-based auto-segmentation. METHODS: This prospective interventional case series included 68 eyes of 68 patients with CI-DME naive to treatment. Morphological optical coherence tomography (OCT) findings of DME were classified into three patterns of structural change: (i) diffuse retinal thickening (DRT), (ii) cystoid macular edema (CME), and (iii) serous retinal detachment (SRD). All patients underwent 3+prorenata IVR. The treated eyes underwent BCVA evaluation and OCT scanning at baseline and months 1, 3, and 6 after the first injection. Then, the choroid layer was measured using a deep learning-based auto-segmentation. RESULTS: At baseline, the mean SFCT and CMT for SRD, DRT, and CME groups were 324.68 ± 65.58 µm and 624.37 ± 77.92 µm, 348.91 ± 45.81 µm and 443.5 ± 78.33 µm, 361.4 ± 64.62 µm, and 536.5 ± 66.02 µm, respectively. After anti-VEGF treatment, the SFCT and CMT have decreased by varying degrees. At 3 and 6 months of treatment, there were no significant changes among these groups. There was no correlation between baseline SFCT and the resulting BCVA (P = 0.670, P = 0.584). There was also no correlation between changes in SFCT and BCVA, CMT (P = 0.344, P = 0.336). CONCLUSION: After treating CI-DME with IVR, SFCT and CMT significantly decreased. However, there were no significant changes among the SRD, DRT, and CME groups. TRIAL REGISTRATION: Trial registration: ChiCTR, ChiCTR-ROC-17013360. Registered 13 November 2017, http://www.chictr.org.cn/ChiCTR-ROC-17013360 .

Characterization of iron reducibility of soy protein amyloid fibrils and their applications in iron fortification.

Iron deficiency is a common nutritional disorder worldwide. Iron fortification of food is an effective strategy to control iron deficiency anemia (IDA), however, traditional iron fortificants usually provoke undesirable organoleptic changes or have limited colloid stability. In this research, we investigated iron reducibility of soy protein amyloid fibrils made from soy protein isolates (SPI), soy ß-conglycinin (7S) and soy glycinin (11S), and explored their applications in iron fortification. All three protein fibrils showed iron reducibility. The reducibility was utilized to generate fibril-iron nanoparticle composites. The iron reducibility was affected by fibril concentration, degree of fibrillation and reducing amino acid composition. We identified 11S had the most significant effect on reducing Fe (III) to more bioavailable Fe (II) state, whereas 7S showed the optimal result for generation of iron nanoparticle on fibrils in situ. The resulted fibril-iron nanoparticle hybrids showed high dispersibility in various liquid foods, without distinct color change.

Neovagina Creation: A Novel Improved Laparoscopic Vecchietti Procedure in Patients with Mayer-Rokitansky-Küster-Hauster Syndrome.

STUDY OBJECTIVE: To report a new improved laparoscopic Vecchietti vaginoplasty in patients with congenital vaginal agenesis and to investigate its efficacy and safety. DESIGN: A retrospective descriptive and case-control study. SETTING: Single academic institution. PATIENTS: Women who were diagnosed with Mayer-Rokitansky-Küster-Hauster (MRKH) syndrome and underwent our new improved laparoscopic Vecchietti procedure from July 2010 to June 2019 were selected as the study group. The eligible participants had congenital vaginal agenesis with normal 46,XX karyotype and ovarian function. Age-matched, nulliparous, sexually active women were selected as the control group. INTERVENTIONS: Women with MRKH syndrome in the study group underwent the novel improved laparoscopic Vecchietti procedure. All participants in both groups were required to complete Female Sexual Function Index and Female Genital Self-Image Scale questionnaires. MEASUREMENTS AND MAIN RESULTS: The effects of our procedure, including the anatomic and functional efficacy of the neovagina, were the primary outcomes. The secondary outcomes consisted of the perioperative complications, surgical morbidities, and long-term postoperative discomfort. A total of 79 patients with MRKH syndrome underwent our new improved Vecchietti vaginoplasty, of whom 44 (55.7%) were diagnosed as Type I MRKH syndrome, whereas 35 (44.3%) were Type II MRKH syndrome. At a 30-month follow-up after surgery, an anatomic neovagina measuring 10.44 cm in length and 1.30 cm in width was achieved. All 79 patients obtained anatomic success with 92.41% of functional efficacy. Compared with 81 age-matched, nulliparous women in the control group, there was no statistical difference regardless of individual measure or total Female Sexual Function Index scores (p >.05). The Female Genital Self-Image Scale assessment showed a significantly lower score in patients undergoing the vaginoplasty (20.14 ± 3.05 vs 22.95 ± 2.12; p <.001). There were no severe perioperative complications except 1 mild bladder injury and 1 transient fever. CONCLUSION: Our novel improved laparoscopic Vecchietti vaginoplasty is a relatively safe and effective method for surgical treatment of congenital vaginal agenesis. It may be an alternative to neovagina creation for reaching satisfying anatomic and functional efficacy and improving patients' sexual function.

Elevation in the counts of IL-35-producing B cells infiltrating into lung tissue in mycobacterial infection is associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg.

IL-35 is an anti-inflammatory cytokine and is thought to be produced by regulatory T (Treg) cells. A previous study found that IL-35 was upregulated in the serum of patients with active tuberculosis (ATB), and IL-35-producing B cells infiltrated to tuberculous granuloma of patients with ATB. Purified B cells from such patients generated more IL-35 after stimulation by antigens of Mycobacterium tuberculosis and secreted more IL-10. However, the function and the underlying mechanisms of IL-35-producing B cells in TB progression have not been investigated. The present study found that the expression of mRNA of IL-35 subsets Ebi3 and p35 was elevated in mononuclear cells from peripheral blood, spleen, bone marrow, and lung tissue in a mouse model infected with Mycobacterium bovis BCG, as tested by real-time polymerase chain reaction. Accordingly, the flow cytometry analysis showed that the counts of a subset of IL-35+ B cells were elevated in the circulating blood and in the spleen, bone marrow, and lung tissue in BCG-infected mice, whereas anti-TB therapy reduced IL-35-producing B cells. Interestingly, BCG infection could drive the infiltration of IL-35-producing B cells into the lung tissue, and the elevated counts of IL-35-producing B cells positively correlated with the bacterial load in the lungs. Importantly, the injection of exogenous IL-35 stimulated the elevation in the counts of IL-35-producing B cells and was associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg.The study showed that a subset of IL-35-producing B cells might take part in the downregulation of immune response in mycobacterial infection.