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Abstract Background The aim of this study to explore the use of new-media health information and its influence on their health and health management. Methods A total of 208 elderly people in Qiqihar City were selected as the survey objects, and a questionnaire was used to investigate their access to health information through new-media platforms. We analyze the factors ( e.g., education、pre-retirement occupation, etc.) in the use of health information on new-media platforms.Results: Monthly income, educational level, pre-retirement occupation and attention of the new-media of the elderly had significant effects on health information acquisition (p

Dysregulated lipid metabolism in liver is an important hallmark of non-alcoholic fatty liver disease (NAFLD), which may be modulated by dietary polyphenols or microRNAs (miRNAs). However, the underlying epigenetic regulatory mechanism of polyphenols remain unclear. The current study aimed to address how miRNA mediates hepatic lipid metabolic control of curcumin, a polyphenolic food supplement. The results showed that 24 h treatment with 5 - 20 μM curcumin prevented free fatty acid-induced lipid accumulation by around 10 ~ 50% in HepG2 cells, which was attenuated by pre-transfection with 40 nM miR-22-3p mimic for 48 h. In consequence, transfection with 40 nM miR-22-3p inhibitor for 48 h significantly reduced lipid accumulation by around 10%. And 48 h overexpression of miR-22-3p targeting cardiolipin synthase 1 ( CRLS1 ) gene, which encodes a mitochondrial phospholipid synthase, showed a similar regulatory effect. Thus, miR-22-3p and CRLS1 showed opposite effects in modulating lipid metabolism, which probably involved mitochondrial control. In summary, this study demonstrated that curcumin improved hepatic lipid metabolism via targeting the miR-22-3p/ CRLS1 pathway. Identification of the epigenetic regulatory mechanism underlying lipid metabolism may thereby facilitate alleviation of metabolic disorders by natural polyphenols.

Given the worldwide epidemic of overweight and obesity among children, evidence-based dietary recommendations are fundamentally important for obesity prevention. Although the significance of the human gut microbiome in shaping the physiological effects of diet and obesity has been widely recognized, nutritional therapeutics for the mitigation of pediatric obesity globally are only just starting to leverage advancements in the nutritional microbiology field. In this review, we extracted data from PubMed, EMBASE, Scopus, Web of Science, Google Scholar, CNKI, Cochrane Library and Wiley online library that focuses on the characterization of gut microbiota (including bacteria, fungi, viruses, and archaea) in children with obesity. We further review host-microbe interactions as mechanisms mediating the physiological effects of dietary fibers and how fibers alter the gut microbiota in children with obesity. Contemporary nutritional recommendations for the prevention of pediatric obesity are also discussed from a gut microbiological perspective. Finally, we propose an experimental framework for integrating gut microbiota into nutritional interventions for children with obesity and provide recommendations for the design of future studies on precision nutrition for pediatric obesity.

KRAS is a commonly mutated oncogene in human gastric cancer and is often associated with drug resistance and poor prognosis. Co-clinical trial of combined MEK-CDK4/6 inhibition in KRAS mutated cancers demonstrated therapeutic efficacy in patient-derived xenografts and safety in patients. Here, present research focuses on targeting CDK4/6 and MEK synergistically block the proliferation of KRAS-mutated gastric cancer cells in vitro and in vivo and induced autophagy through the AMPK/mTOR pathway. Furthermore, autophagy inhibitor combined with targeting CDK4/6 and MEK therapy had significant antitumor effects on KRAS mutant gastric cancer cells. Clinical trials are needed to determine the mechanism behind this finding and its clinical utility. In conclusion, our results demonstrate autophagy inhibitor combined targeting MEK and CDK4/6 that concurrently block multiple metabolic processes may be an effective therapeutic approach for gastric cancer.

Re-endothelialization has been recognized as a promising strategy to address the tissue hyperplasia and subsequent restenosis which are major complications associated with vascular implant/interventional titanium devices. However, the uncontrollable over-proliferation of smooth muscle cells (SMCs) limits the clinical application of numerous modified strategies. Herein, a novel modified strategy involving with a two-step anodic oxidation and annealing treatment was proposed to achieve rapid re-endothelialization function regulated by regular honeycomb nanotexture and specific anatase phase on the titanium surface. Theoretical calculation revealed that the presence of nanotexture reduced the polar component of surface energy, while the generation of anatase significantly enhanced the polar component and total surface energy. Meanwhile, the modified surface with regular nanotexture and anatase phase produced positive effect on the expression of CD31, VE-Cadherin and down-regulated α-SMA proteins expression, indicating excellent capacity of pro-endothelial regeneration and inhibition of SMCs proliferation and migration. One-month in vivo implantation in rabbit carotid arteries further confirmed that modified tube implant surface effectively accelerated confluent endothelial monolayer formation and promoted native-like endothelium tissue regeneration. By contrast, original titanium tube implant induced a disorganized tissue proliferation in the lumen with a high risk of restenosis. Collectively, this study opens us an alternative route to achieve the function that selectively promotes endothelial cells (ECs) growth and suppresses SMCs on the medical titanium surface, which has a great potential in facilitating re-endothelialization on the surface of blood-contacting titanium implant.

Abstract Background The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCA mut). Results Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6–51.0) and 65.4% (95% CI 50.9–78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7–84.3); this dose was determined to be the RP2D. Patients with gBRCA mut had higher ORR and longer median progression-free survival (PFS) than those with gBRCA wt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. Conclusions Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. Trial registration ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).

Abstract Background The accumulation of reactive oxygen species (ROS) in tumor microenvironment (TME) is an important player for tumorigenesis and progression. We aimed to explore the outcomes of ROS on tumor vessels and the potential regulated mechanisms. Methods Exogenous H2O2 was adopted to simulate the ROS setting. Immunofluorescence staining and ultrasonography were used to assess the vascular endothelial coverage and perfusions in the tumors inoculated with Lewis lung cancer (LLC) and melanoma (B16F10) cells of C57BL/6 mice, respectively. ELISA and western-blot were used to detect the expression of secreted acidic and cysteine-rich protein (SPARC) and Caveale-1 in human umbilical vein endothelial cells (HUVEC) extra- and intracellularly. Intracellular translocation of SPARC was observed using electron microscopy and immunofluorescence approaches. Result Under the context of oxidative stress, the pericyte recruitment of neovascularization in mouse lung cancer and melanoma tissues would be aberrated, which subsequently led to the disruption of the tumor vascular architecture and perfusion dysfunction. In vitro, HUVEC extracellularly SPARC was down-regulated, whereas intracellularly it was up-regulated. By electron microscopy and immunofluorescence staining, we observed that SPARC might undergo transmembrane transport via caveale-1-mediated endocytosis. Finally, the binding of SPARC to phosphorylated-caveale-1 was also detected in B16F10 tissues. Conclusion In the oxidative stress environment, neovascularization within the tumor occurs structural deterioration and decreased perfusion capacity. One of the main regulatory mechanisms is the migration of extracellular SPARC from the endothelium to intracellular compartments via Caveolin-1 carriers.

Melanosomes are specialized membrane-bound organelles where melanin is synthesized and stored. The levels of melanin can be effectively reduced by inhibiting melanin synthesis or promoting melanosome degradation via autophagy. Ceramide, a key component in the metabolism of sphingolipids, is crucial for preserving the skin barrier, keeping it hydrated, and warding off the signs of aging. Our preliminary study indicated that a long-chain C22-ceramide compound (Ehux-C22) isolated from the marine microalga Emiliania huxleyi, reduced melanin levels via melanosomal autophagy in B16 cells. Recently, microRNAs (miRNAs) were shown to act as melanogenesis-regulating molecules in melanocytes. However, whether the ceramide Ehux-C22 can induce melanosome autophagy at the post-transcriptional level, and which potential autophagy-dependent mechanisms are involved, remains unknown. Here, miR-199a-3p was screened and identified as a novel upregulated miRNA in Ehux-C22-treated B16 cells. An in vitro high melanin expression model in cultured mouse melanoma cells (B16 cells) was established by using 0.2 μM alpha-melanocyte-stimulating hormone(α-MSH) and used for subsequent analyses. miR-199a-3p overexpression significantly enhanced melanin degradation, as indicated by a reduction in the melanin level and an increase in melanosome autophagy. Further investigation demonstrated that in B16 cells, Ehux-C22 activated miR-199a-3p and inhibited mammalian target of rapamycin(mTOR) level, thus activating the mTOR-ULK1 signaling pathway by promoting the expression of unc-51-like autophagy activating kinase 1 (ULK1), B-cell lymphoma-2 (Bcl-2), Beclin-1, autophagy-related gene 5 (ATG5), and microtubule-associated protein light chain 3 (LC3-II) and degrading p62. Therefore, the roles of Ehux-C22-regulated miR-199a-3p and the mTOR pathway in melanosomal autophagy were elucidated. This research may provide novel perspectives on the post-translational regulation of melanin metabolism, which involves the coordinated control of melanosomes.

Development of efficient photosensitizers with minimal side effects is highly desirable for photodynamic therapy. Reported herein is the discovery of a novel pyridophenoselenazinium-based NIR-I photosensitizer, termed PPSe, that efficiently generated both type I and II reactive oxygen species (ROS) upon appropriate light irradiation. PPSe exhibited potent phototoxicity as well as excellent phototherapeutic indices against several breast cancer cell lines. PPSe induced DNA damage and breast cancer cell apoptosis via photo-triggered intracellular ROS generation.

ABSTRACT In this study, we screened the tmexCD-toprJ gene cluster among 1,541 samples obtained from patients, healthy individuals, companion animals, pigs, chicken, and pork and chicken meat in Yangzhou, China. As a result, nine strains from humans, animals, and foods were positive for tmexCD1-toprJ1, which was located on plasmids or the chromosome. Seven different sequence types (STs) were identified, including ST15 (n = 2), ST580, ST1944, ST2294, ST5982, ST6262 (n = 2), and ST6265. All the positive strains were clustered into two distinct clades, and they shared a 24,087-bp core structure of tmexCD1-toprJ1, bounded by IS26 in the same orientation. IS26 could facilitate rapid and wide dissemination of tmexCD1-toprJ1 in Enterobacteriaceae from various sources. IMPORTANCE Tigecycline has been regarded as one of the last-resort antibiotics available for the treatment of infections caused by carbapenem-resistant Enterobacterales. The plasmid-mediated resistance-nodulation-division–type efflux pump gene cluster tmexCD-toprJ is a newly identified tigecycline resistance determinant. In this study, we revealed that tmexCD-toprJ has disseminated among Klebsiella pneumoniae strains from poultry, food markets, and patients. It is critical to strengthen continuous monitoring, and control measures should be implemented to prevent the further dissemination of tmexCD-toprJ.

Abstract Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.

The antioxidant activity of curcumin has been extensively investigated for years. However, its molecular function mechanism remained unclear. Our preliminary study showed that curcumin downregulated miR-22-3p expression. This study aimed to address whether miR-22-3p mediated the antioxidant activity of curcumin and the possible action mechanism. The results showed that miR-22-3p repression increased the total cellular antioxidant capacity and enhanced the endogenous antioxidant enzyme system of LO2 cells. In addition, miR-22-3p-deteriorated cellular antioxidant capacity was prevented by curcumin pretreatment. Moreover, miR-22-3p inhibition significantly improved mitochondrial function and biogenesis. Further investigation demonstrated that a mitochondrial key regulator, the cardiolipin synthase gene (CRLS1), was targeted and downregulated by miR-22-3p. CRLS1 overexpression also significantly improved cellular antioxidant capacity and enhanced mitochondrial function and biogenesis in LO2 cells. Taken together, all these data suggested that miR-22-3p modulated the antioxidant effect of curcumin via targeting CRLS1, which may provide novel insights into miRNA-mediated antioxidant mechanism of curcumin.

Abstract Background Most ovarian cancers are diagnosed at advanced stages characterized by abdominal dissemination and frequently exhibit chemoresistance. Pyruvate dehydrogenase kinase 2 (PDK2) regulates the switch between glycolysis and oxidative phosphorylation and contributes to tumor progression and chemoresistance. Here, we investigated the effects of PDK2 blockade on metabolic reprogramming and cisplatin sensitivity and evaluated the in vivo antitumor effects of PDK2 shRNA in chemoresistant ovarian cancer using retro-inverso follicle-stimulating hormone peptide-modified nanoparticle as carriers. Methods The expression of PDK2 was detected by immunohistochemistry, Western blot and real-time PCR. Cell proliferation and apoptosis were detected using CCK-8 and flow cytometry. Cell migration was detected by Transwell assay. Seahorse Analyzer was used to evaluate metabolic changes. The cisplatin-resistant ovarian cancer cells A2780cp were used to establish the mouse model of peritoneal metastatic ovarian cancer. Results A higher expression level of PDK2 was observed in chemoresistant ovarian cancer tissues and cell lines and was associated with shorter progression-free survival. PDK2 knockdown inhibited proliferation and migration and promoted apoptosis of both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Cisplatin sensitivity was increased even in cisplatin-resistant ovarian cancer cells. Mechanistically, PDK2 knockdown resulted in an increased oxygen consumption rate and decreased extracellular acidification rate, along with reduced lactate production, increased PDHC activity and increased levels of electron transport chain complexes III and V. The metabolism switched from glycolysis to oxidative phosphorylation. Finally, to specifically and effectively deliver PDK2 shRNA in vivo, we formulated a targeted delivery system containing retro-inverso follicle-stimulating hormone peptide as a targeting moiety and polyethylene glycol–polyethylenimine copolymers as carriers. The nanoparticle complex significantly suppressed tumor growth and peritoneal metastasis of cisplatin-resistant ovarian cancer without obvious toxicities. Conclusions Our findings showed the link between metabolic reprogramming and chemoresistance in ovarian cancer and provided an effective targeting strategy for switching metabolic pathways in cancer therapy.

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid (PUFA) for human body, which is highly rich in deep sea fish oil and marine microalgae. Mitochondria are the energy factory of cells. Mitochondrial functions and biogenesis can be regulated by DHA which exhibits antioxidation, anti-inflammatory and anti-cancer activities. This article reviews the research progress of mitochondrial-mediated DHA antioxidation and the possible underlying mechanism. The effects of DHA in eliminating reactive oxygen species (ROS) and regulating mitochondrial biogenesis and functions, as well as the microRNA-mediated DHA antioxidant epigenetic mechanism are addressed, which may provide evidence for better DHA product exploration and application.

ObjectiveWe report the efficacy and safety of serplulimab, a novel humanized anti–programmed death-1 antibody, plus nanoparticle albumin-bound (nab)-paclitaxel in previously treated patients with programmed death ligand-1 (PD-L1)–positive advanced cervical cancer.MethodsPatients diagnosed with PD-L1–positive (combined positive score ≥1) cervical cancer were enrolled in this single-arm, open-label, phase II study. They were given serplulimab 4.5 mg/kg for up to 2 years (35 dosing cycles) plus nab-paclitaxel 260 mg/m2 for up to six cycles once every 3 weeks. Primary endpoints were safety and objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST version 1.1. Secondary endpoints included ORR assessed by the investigator, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).ResultsBetween December 2019 and June 2020, 52 patients were screened and 21 were enrolled. IRRC-assessed ORR was 57.1% (95% confidence interval [CI] 34.0–78.2%); 3 (14.3%) patients achieved complete response and 9 (42.9%) partial response. The median DOR was not reached (NR) (95% CI 4.1–NR). IRRC-assessed median PFS was 5.7 months (95% CI 3.0–NR), and median OS was 15.5 months (95% CI 10.5–NR). Investigator-assessed ORR was 47.6% (95% CI 25.7–70.2%). Seventeen (81.0%) patients experienced grade ≥3 treatment-emergent adverse events. Grade ≥3 adverse drug reactions were reported in 7 (33.3%) patients. Immune-related adverse events occurred in 12 (57.1%) patients.ConclusionsIn previously treated patients with PD-L1–positive advanced cervical cancer, serplulimab plus nab-paclitaxel provided durable clinical activity and a manageable safety profile.Clinical trial registrationClinicalTrials.gov, identifier NCT04150575.

Objective. In this study, we utilized gonadotropin-releasing hormone analogue-modified indocyanine green (GnRHa-ICG) to improve the accuracy of intraoperative recognition and resection of endometriotic lesions. Methods. Gonadotropin-releasing hormone receptor (GnRHR) expression was detected in endometriosis tissues and cell lines via immunohistochemistry and western blotting. The in vitro binding capacities of GnRHa, GnRHa-ICG, and ICG were determined using fluorescence microscopy and flow cytometry. In vivo imaging was performed in mouse models of endometriosis using a near-infrared fluorescence (NIRF) imaging system and fluorescence navigation system. The ex vivo binding capacity was determined using confocal fluorescence microscopy. Results. GnRHa-ICG exhibited a significantly stronger binding capacity to endometriotic cells and tissues than ICG. In mice with endometriosis, GnRHa-ICG specifically imaged endometriotic tissues (EMTs) after intraperitoneal administration, whereas ICG exhibited signals in the intestine. GnRHa-ICG showed the highest fluorescence signals in the EMTs at 2 h and a good signal-to-noise ratio at 48 h postadministration. Compared with traditional surgery under white light, targeted NIRF imaging-guided surgery completely resected endometriotic lesions with a sensitivity of 97.3% and specificity of 77.8%. No obvious toxicity was observed in routine blood tests, serum biochemicals, or histopathology in mice. Conclusions. GnRHa-ICG specifically recognized and localized endometriotic lesions and guided complete resection of lesions with high accuracy.

With the widespread use of immune checkpoint inhibitors (ICI), there is growing concern about reports of immune-related adverse events (irAE). In clinical practice, patients who experience severe toxicities by ICI-based therapies would require utmost caution in resuming ICI therapy because of the potential risk of serious irAEs caused by the reintroduction of immunotherapy. In this study, we report a case of recurrent endometrial cancer patient with PD-L1 positive as well as dMMR suffering from immunotherapy-associated myocarditis after first-line treatment with ICI combined with a multi-targeted anti-angiogenic agent. After symptomatic treatment, the patient was in complete remission from treatment toxicities. Subsequently, through MDT discussions, we selected a new PD-1 agent, zimberelimab, for rechallenge therapy, and the patient achieved a sustained disease remission without any treatment-related toxicities. To date, the manner and timing of the ICI re-challenge has been a subject of iterative deliberation. We believe that our experience could shed some light on ICI rechallenge therapy, and we look forward to more literatures to refine the ICI rechallenge scenarios.

Liver fibrosis results from the chronic liver injury and no specific medical therapy is approved so far. Recently, new compound, N-(3,4,5-trichlorophenyl) − 2 (3-nitrobenzenesulfonamido) benzamide, referred to as IMB16–4, was developed to resist liver fibrosis. However, IMB16–4 displays poor aqueous solubility and poor oral bioavailability. To increase the dissolution rate, improve the oral bioavailability and enhance the anti-hepatic fibrosis action of IMB16–4, IMB16–4 self-emulsifying drug delivery systems (SEDDS) with negative charge or positive charge were prepared using simple stirring, respectively. Their stability, oral bioavailability and anti-liver fibrosis effect were evaluated. The results showed IMB16–4 SEDDS in simulated gastric juice were nearly spherical with the diameter of 100～200 nm and possessed good stability in 30 days. The oral bioavailability of IMB16–4 SEDDS with negative charge and positive charge were increased to 33 folds and 58 folds compared with that of pure IMB16–4, respectively. In bile duct ligation (BDL) rats, IMB16–4 SEDDS attenuated the degree of liver damage and decreased collagen accumulation. In addition, IMB16–4 SEDDS with negative charge easily accumulated in the liver and alleviated hepatic fibrosis by TGF-β/Smad signaling. These findings indicate that IMB16- 4 SEDDS may be a potential therapy for the treatment of liver fibrosis.

Polyphenol-rich foods exhibit anti-allergic/-inflammatory properties. As major effector cells of allergies, mast cells undergo degranulation after activation and then initiate inflammatory responses. Key immune phenomena could be regulated by the production and metabolism of lipid mediators by mast cells. Here, we analyzed the antiallergic activities of two representative dietary polyphenols, curcumin and epigallocatechin gallate (EGCG), and traced their effects on cellular lipidome rewiring in the progression of degranulation. Both curcumin and EGCG significantly inhibited degranulation as they suppressed the release of β-hexosaminidase, interleukin-4, and tumor necrosis factor-α from the IgE/antigen-stimulated mast cell model. A comprehensive lipidomics study involving 957 identified lipid species revealed that although the lipidome remodeling patterns (lipid response and composition) of curcumin intervention were considerably similar to those of EGCG, lipid metabolism was more potently disturbed by curcumin. Seventy-eight percent of significant differential lipids upon IgE/antigen stimulation could be regulated by curcumin/EGCG. LPC-O 22:0 was defined as a potential biomarker for its sensitivity to IgE/antigen stimulation and curcumin/EGCG intervention. The key changes in diacylglycerols, fatty acids, and bismonoacylglycerophosphates provided clues that cell signaling disturbances could be associated with curcumin/EGCG intervention. Our work supplies a novel perspective for understanding curcumin/EGCG involvement in antianaphylaxis and helps guide future attempts to use dietary polyphenols.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive malignancy with a poor prognosis. Most patients experience recurrence even after surgery and chemotherapy, and there are no standard treatment options for recurrent disease. Here, we report the case of a 36-year-old woman with SCCOHT who underwent primary cytoreductive surgery without adjuvant chemotherapy and remained disease-free for 9 months. She then developed retroperitoneal lymph node metastasis and was treated with two cycles of bleomycin/etoposide/cisplatin chemotherapy. However, the disease progressed and the patient received four cycles of liposomal doxorubicin/ifosfamide chemotherapy, followed by local radiation to the enlarged retroperitoneal lymph nodes. She achieved partial remission for 13 months, after which the disease progressed again. Tumor tissues and blood samples were sent for next-generation sequencing. The results indicated a somatic SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutation, microsatellite stability, and a tumor mutation burden of 1.0 muts/Mb without any germline mutations. An anti-PD-1 antibody, camrelizumab, and an antiangiogenic agent, apatinib, were administered, and the patient achieved partial remission for 28 months. Our study provides the first clinical evidence that the combination therapy of camrelizumab and apatinib could be an effective treatment for recurrent SCCOHT.

Pickled radish is a general source of natural bioactive compounds that include phenols. Here, we used molecular docking, fluorescence quenching, circular dichroism spectroscopy and molecular dynamics simulations to identify potential inhibitors against xanthine oxidase from a library of pickled radish compounds. The most effective compounds were selected for validation through in vitro experiments including enzyme activity inhibition tests, and cell-based assays. Molecular docking results revealed that 2,6-Dihydroxyacetophenone, 4-Hydroxyphenethyl alcohol, and 4-Hydroxybenzaldehyde exhibited significant effects on xanthine oxidase inhibition. Three phenols have varying degrees of inhibition on xanthine oxidase, which is driven by hydrophobic interactions and hydrogen bonds and affects the secondary structure and hydrophobic homeostasis of xanthine oxidase. The stability of xanthine oxidase inhibition by three phenols was analyzed by molecular dynamics simulation. Finally, cellular experiments confirmed that three phenols reduced uric acid levels by inhibiting the xanthine oxidase enzyme activity of BRL 3A cells.

Background Ovarian 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 analysis In 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 p

Abstract Background COVID-19 patients develop hypolipidemia. However, it is unknown whether lipid levels have improved and there are potential sequlae in recovered patients. Objective In this follow-up study, we evaluated serum lipidemia and various 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). Sixty-one 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

The increasing threat posed by antibiotic-resistant pathogens has prompted a shift to the use of naturally-derived antimicrobial peptides (AMPs) in place of chemical preservatives in controlling foodborne pathogens. In this study, ten peptides were identified from salt-fermented shrimps (Penaeus vannamei) using ultra-performance liquid chromatography-mass spectrometry. One of the peptides, designated PV-Q5 (QVRNFPRGSAASPSALASPR), with most features of an AMP, was further explored and found to possess strong antibacterial activity against Vibrio parahaemolyticus and Escherichia coli, with a minimum inhibitory concentration of 31.25 μg/mL. Moreover, PV-Q5 increased bacterial cell membrane permeability and ruptured bacteria cell membranes, as revealed by transmission electron microscopy. Circular dichroism analysis showed that the conformation of PV-Q5 was a random coil in phosphate-buffered saline and α-helical in sodium dodecyl sulfate, which is conducive for interaction with bacteria cell membranes. These findings indicated that PV-Q5 could find potential use in food preservation to control foodborne pathogenic bacteria.

Abstract 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 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.

Abstract 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.

Abstract 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.

BackgroundIn this study, we enrolled 862 patients with Crohn’s disease (CD) in China to investigate the correlation between serum vitamin D (SVD) and serum lipids, inflammatory biomarkers, and important clinical parameters.Materials and Methods25(OH)D was measured by LS/MS/MS. Correlation analysis, chi-square tests, and logistic regression analysis were performed to determine the correlations between vitamin D and potential risk factors when vitamin D levels were lower than 10 ng/mL or 20 ng/mL.ResultsThe incidence of severe vitamin D deficiency (SVD < 10 ng/mL) in patients with CD was significantly higher than that in healthy controls (28.9 vs. 9.5%). Multinomial logistic regression analysis showed that penetrating disease [odds ratio (OR) = 2.18], low levels of high-density lipoprotein cholesterol (HDL) (OR = 1.91), high erythrocyte sedimentation rate (OR = 1.73), and platelet count (PLT) (OR = 2.71) were regarded as predictors of severe vitamin D deficiency, while only PLT (OR = 1.90) and HDL (OR = 1.76) were considered as predictors of mild vitamin D deficiency (SVD 10–20 ng/mL).ConclusionOur results confirm a higher incidence of severe vitamin D deficiency in patients with CD in China and show that vitamin D deficiency could result from the combined effects of penetrating disease, inflammation, and low levels of HDL.

Background Novel 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.Methods Blood 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.Results We 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.Conclusions Our 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.

Abstract Background NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown. Methods We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. γ-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR. Results We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Conclusions Our results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

Abstract Background The American Joint Committee on Cancer (AJCC) and the European Neuroendocrine Tumor Society (ENETS) staging classifications are two broadly used systems for pancreatic neuroendocrine tumors. This study aims to identify the most accurate and useful tumor–node–metastasis (TNM) staging system for poorly differentiated pancreatic neuroendocrine carcinomas (pNECs). Methods An analysis was performed to evaluate the application of the ENETS, 7th edition (7th) AJCC and 8th edition (8th) AJCC staging classifications using the Surveillance, Epidemiology, and End Results (SEER) registry (N = 568 patients), and a modified system based on the analysis of the 7th AJCC classification was proposed. Results In multivariable analyses, only the 7th AJCC staging system allocated patients into four different risk groups, although there was no significant difference. We modified the staging classification by maintaining the T and M definitions of the 7th AJCC staging and adopting new staging definitions. An increased hazard ratio (HR) of death was also observed from class I to class IV for the modified 7th (m7th) staging system (compared with stage I disease; HR for stage II =1.23, 95% confidence interval (CI) = 0.73–2.06, P = 0.44; HR for stage III =2.20, 95% CI =1.06–4.56, P = 0.03; HR for stage IV =4.95, 95% CI =3.20–7.65, P

The optimization of logistics distribution can be defined as the multiple traveling salesman problem (MTSP). The purpose of existing heuristic algorithms, such as Genetic Algorithm (GA), Ant Colony Algorithm (ACO), etc., is to find the optimal path in a short time. However, two important factors of logistics distribution optimization, including work time window and the carrying capacity of the vehicle in distribution system, have been ignored. In this paper, we consider the influences of time limitation of modern commercial logistics and carrying capacity of the vehicle on the logistics optimization, and then propose a MTSP with constraints of time window and capacity of each salesman. We design a novel hybrid algorithm by combining the minimum spanning 1-tree with ACO to find the optimal solution. In addition, we improve the pheromone update rules to increase the search efficiency of ACO algorithm. The experiments show that the novel hybrid algorithm achieves a shorter path than the other algorithms.

Rhizoctonia cerealis is a worldwide soil-borne pathogenic fungus that significantly infects wheat and causes sharp eyespot in China. However, the biocontrol strains used for the control of Rhizoctonia cerealis are insufficient. In the present study, antagonistic strain B1302 from the rhizosphere of wheat were isolated and identified as Bacillus mojovensis based on their morphological, physiological, and biochemical characteristics, and their 16S rDNA sequence. Culture filtrate of strain B1302 had a broad antifungal spectrum. In order to improve the antifungal activity of B1302, response surface methodology (RSM) was used to optimize the culture conditions. The final medium composition and culture conditions were 13.2 g/L of wheat bran, 14.1 g/L of soybean meal, 224 r/min of rotation speed, 7.50 of initial pH, and 1.5 × 108 CFU/mL of inoculation amount at 35 °C for a culture duration of 72 h. B. mojavensis B1302 inhibited the hyphae growth of R.cerealis and produced hydrolytic enzymes (protease, chitinase, and glucanase), IAA, and had N-fixing potentiality and P-solubilisation capacity. It can also promote wheat seedling growth in potted plants. The disease incidence and index of wheat seedlings were consistent with the effect of commercial pesticides under treatment with culture filtrate. The biocontrol efficacy of culture filtrate was significant—up to 65.25%. An animal toxicological safety analysis suggested that culture filtrate was safe for use and could be developed into an effective microbial fungicide to control wheat sharp eyespot.

Abstract Tumor metastasis has become a key obstacle to cancer treatment, which causes high mortality. Nowadays, it involves multiple complex pathways, and conventional treatments are not effective due to fewer targets. The aims of the present study were to construct a novel liposome delivery system co-loading a specific PLD inhibitor 5-fluoro-2-indolyldes-chlorohalopemide (FIPI) in combination with antitumor drug doxorubicin (DOX) and functional excipient D-alpha tocopheryl acid succinate (α-TOS) for anti-metastasis. In this study, the liposomes containing three components (DFT-Lip) with different physicochemical properties were successfully prepared by film dispersion method combined with pH-gradient method. Physicochemical parameters such as particles size, potential, encapsulation efficiency, stability, and release profiles were investigated. In vitro and in vivo anti-metastasis effectiveness against highly metastatic breast cancer MDA-MB-231 cell line was evaluated. The liposomes showed uniform particle size (approximately 119 nm), high drug encapsulation efficiency (> 90%), slow release characteristics and stability. In vitro anti-tumor cell metastasis study demonstrated DFT-Lip could greatly inhibit motility, migration and invasion of MDA-MB-231 cells compared to other liposomes, predicting a synergistic anti-tumor metastasis effect between FIPI with α-TOS in liposomes. In vivo anti-metastasis study showed that DFT-Lip prevented the initiation and the progression of metastasis of high metastatic breast cancer. These results suggested that the liposomes containing DOX, FIPI, and α-TOS might be a promising strategy for metastatic tumor therapy in clinics.

Energy consumption has overtaken equipment costs given the growth of computing power, thereby becoming the dominant cost to data centers. Constrained by ensuring that peak resource requirements of VMs are met, the effective use of resource fragments is an effective means of energy conservation. We apply resource reservation to the resource-utilization-aware energy efficient server consolidation algorithm (RUAEE), and propose a server consolidation energy-saving algorithm (SCES). We adjust the allocations of VMs by computing the resource reservation and resource allocation ratio dynamically. This technique maintains the host resource utilization to within a reasonable range, reduces resource fragmentation and reserves resources to satisfy the peak resource requests simultaneously. Compared with the RUAEE algorithm, our algorithm can reduce the risk of system overload and improve the stability of the system. The experimental results based on the actual workload of the Google cluster show that the algorithm is effective at reducing resource waste, improving system stability, and achieving energy savings.

As a global health problem, liver fibrosis still does not have approved treatment. It was proved that N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4) has anti-hepatic fibrosis activity. However, IMB16-4 displays poor water solubility and poor bioavailability. We are devoted to developing biodegraded liposome-coated polymeric nanoparticles (LNPs) as IMB16-4 delivery systems for improving aqueous solubility, cellular uptake, and anti-fibrotic effects. The physical states of IMB16-4−LNPs were analyzed using a transmission electron microscope (TEM), high-performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimeter (DSC). The results show that IMB16-4−LNPs increased the drug loading compared to liposomes and enhanced cellular uptake behavior compared with IMB16-4−NPs. In addition, IMB16-4−LNPs could repress the expression of hepatic fibrogenesis-associated proteins, indicating that IMB16-4−LNPs exhibited evident anti-fibrotic effects.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

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/m 2 . 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.

Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase the dissolution, improve the oral bioavailability and enhance the antifibrotic activity of IMB16-4, PVPK30 was selected to establish the IMB16-4 nanoparticles. Drug release behavior, oral bioavailability, and anti-hepatic fibrosis effects of IMB16-4 nanoparticles were evaluated. The results showed that IMB16-4 nanoparticles greatly increased the dissolution rate of IMB16-4. The oral bioavailability of IMB16-4 nanoparticles was improved 26-fold compared with that of pure IMB16-4. In bile duct ligation rats, IMB16-4 nanoparticles significantly repressed hepatic fibrogenesis and improved the liver function. These findings indicate that IMB16-4 nanoparticles will provide information to expand a novel anti-hepatic fibrosis agent.

Programmed death-ligand 1 (PD-L1) is a crucial target for lung cancer immunotherapy. In lung cancer patients with high PD-L1 expression, blocking or reducing its expression can inhibit tumor growth. PD-L1 is regulated by signaling pathways, transcription factors and epigenetic factors, such as the GSK3β/β-catenin pathway, P53 protein and EMT. In our previous study, succinate dehydrogenase 5 (SDH5) was reported to regulate ZEB1 expression, induce EMT and lead to lung cancer metastasis via the GSK3β/β-catenin pathway. It is possible that SDH5 is involved in the mechanisms of PD-L1 regulation.In the present study, we observed a negative correlation between the expression of PD-L1 and SDH5 in vivo and in vitro. The examination of patient tissues also confirmed our results. Furthermore, we also found that SDH5 could reverse PD-L1 expression by the GSK3β/β-catenin/ZEB1 pathways. All these results reveal that SDH5 regulates PD-L1 expression and suggest that SDH5 can be used as a marker to predict tumor immune micro-states and provide guidance for clinical immunotherapy.

Liver fibrosis remains a significant public health problem. However, few drugs have yet been validated. Costunolide (COS), as a monomeric component of the traditional Chinese medicinal herb Saussurea Lappa, has shown excellent anti-fibrotic efficacy. However, COS displays very poor aqueous solubility and poor stability in gastric juice, which greatly limits its application via an oral administration. To increase the stability, improve the dissolution rate and enhance the anti-liver fibrosis of COS, pH-responsive mesoporous silica nanoparticles (MSNs) were selected as a drug carrier. Methacrylic acid copolymer (MAC) as a pH-sensitive material was used to coat the surface of MSNs. The drug release behavior and anti-liver fibrosis effects of MSNs-COS-MAC were evaluated. The results showed that MSNs-COS-MAC prevented a release in the gastric fluid and enhanced the dissolution rate of COS in the intestinal juice. At half the dose of COS, MSNs-COS-MAC still effectively ameliorated parenchymal necrosis, bile duct proliferation and excessive collagen. MSNs-COS-MAC significantly repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers in LX-2 cells and liver tissue. These results suggest that MSNs-COS-MAC shows great promise for anti-liver fibrosis treatment.

Background: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. Methods: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague–Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. Conclusions: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.

CtBP1-S/BARS is required for fission of endomembrane compartments including the Golgi. Here the authors show that CtBP1-S/BARS activates a trans-Golgi lysophosphatidic acid acyltransferase that catalyses the production of phosphatidic acid and is required for fission of the post-Golgi carrier membrane.

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.

Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg2+ or Pb2+. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL−1. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.

MicroRNAs (miRNAs) act as epigenetic markers and regulate the expression of their target genes, including those characterized as regulators in autoimmune diseases. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. The potential roles of miRNA-regulated genes in RA pathogenesis have greatly aroused the interest of clinicians and researchers in recent years. In the current study, RA-related miRNAs records were obtained from PubMed through conditional literature retrieval. After analyzing the selected records, miRNA targeted genes were predicted. We identified 14 RA-associated miRNAs, and their sub-analysis in 5 microarray or RNA sequencing (RNA-seq) datasets was performed. The microarray and RNA-seq data of RA were also downloaded from NCBI Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA), analyzed, and annotated. Using a bioinformatics approach, we identified a series of differentially expressed genes (DEGs) by comparing studies on RA and the controls. The RA-related gene expression profile was thus obtained and the expression of miRNA-regulated genes was analyzed. After functional annotation analysis, we found GO molecular function (MF) terms significantly enriched in calcium ion binding (GO: 0005509). Moreover, some novel dysregulated target genes were identified in RA through integrated analysis of miRNA/mRNA expression. The result revealed that the expression of a number of genes, including ROR2, ABI3BP, SMOC2, etc., was not only affected by dysregulated miRNAs, but also altered in RA. Our findings indicate that there is a close association between negatively correlated mRNA/miRNA pairs and RA. These findings may be applied to identify genetic markers for RA diagnosis and treatment in the future.

Nicotinamide N-methyltransferase (NNMT) has been found involved in cell proliferation of several malignancies. However, the functional role of NNMT in breast cancer has not been elucidated. In the present study, we showed that NNMT was selectively expressed in some breast cancer cell lines, down-regulation of NNMT expression in Bcap-37 and MDA-MB-231 cell lines by NNMT shRNA significantly inhibited cell growth in vitro, decreased tumorigenicity in mice and induced apoptosis. The silencing reciprocal effect of NNMT was confirmed by over-expressing NNMT in the MCF-7 and SK-BR-3 breast cancer cell lines which lack constitutive expression of NNMT. In addition, down-regulation of NNMT expression resulted in reducing expression of Bcl-2 and Bcl-xL, up-regulation of Bax, Puma, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, increasing reactive oxygen species production and release of cytochrome c from mitochondria, and decreasing the phosphorylation of Akt and ERK1/2. These data suggest that down-regulation of NNMT induces apoptosis via the mitochondria-mediated pathway in breast cancer cells.