Search

Background: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine)., Methods: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log 10 plaque forming units (PFU; low-dose v7D group), 3·9 log 10 PFU (medium-dose v7D group), and 4·2 log 10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434., Findings: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related., Interpretation: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future., Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests J-ZJ, J-LH, and X-ZY are employees of and have stock options in Beijing Wantai. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs)., Aim: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort., Methods: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed., Results: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods., Conclusion: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The challenges of the COVID-19 pandemic have highlighted an increasing clinical demand for safe and effective treatment options against an overzealous immune defence response, also known as the "cytokine storm". Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. However, its cytokine-inhibiting activity, in direct comparison to commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), has not been extensively investigated in existing literature. The anti-inflammatory activities of andrographolide and common NSAIDs, such as diclofenac, aspirin, paracetamol and ibuprofen were measured on lipopolysaccharide (LPS) and interferon-γ induced RAW264.7 cells. The levels of PGE2, nitric oxide (NO), TNF-α & LPS-induced release of pro-inflammatory cytokines on differentiated human macrophage THP-1 cells were measured against increasing concentrations of andrographolide and aforementioned NSAIDs. The associated mechanistic pathway was examined on NFκB using flow cytometry on the human endothelial-leukocyte adhesion molecule (ELAM9) (E-selectin) transfected RAW264.7 cells with green fluorescent protein (GFP). Andrographolide exhibited broad and potent anti-inflammatory and cytokine-inhibiting activity in both cell lines by inhibiting the release of IL-6, TNF-α and IFN-γ, which are known to play a key role in the etiology of cytokine storm and the pathogenesis of inflammation. In comparison, the tested NSAIDs demonstrated weak or no activity against proinflammatory mediators except for PGE2, where the activity of andrographolide (IC50 = 8.8 μM, 95% CI = 7.4 to 10.4 μM) was comparable to that of paracetamol (IC50 = 7.73 μM, 95% CI = 6.14 to 9.73 μM). The anti-inflammatory action of andrographolide was associated with its potent downregulation of NFκB. The wide-spectrum anti-inflammatory activity of andrographolide demonstrates its therapeutic potential against cytokine storms as an alternative to NSAIDs., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Low et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In this study, a series of H-bonded arylamide foldamers bearing benzoselenadiazole ends with solvent-responsive properties have been synthesized. In dichloromethane or dimethyl sulfoxide solvents, the molecules exhibit meniscus or linear structures, respectively, which can be attributed to the unique intramolecular hydrogen bonding behavior evidenced by 1D 1 H NMR and 2D NOESY spectra. UV-vis spectroscopy experiments show that the absorption wavelength of H-bonded arylamide foldamers are significantly red-shifted due to the presence of benzoselenadiazole group. In addition, the crystal structures reveal that effective intermolecular dual Se ⋅ ⋅ ⋅ N interactions between benzoselenadiazole groups induce further assembly of the monomers. Remarkably, supramolecular linear and double helices structures are constructed under the synergistic induction of intramolecular hydrogen bonding and intermolecular chalcogen bonding. Additionally, 2D DOSY diffusion spectra and theoretical modelling based on density functional theory (DFT) are performed to explore the persistence of intermolecular Se ⋅ ⋅ ⋅ N interactions beyond the crystalline state., (© 2024 Wiley-VCH GmbH.)

Australian fruits such as native currant ( Acrotriche depressa ) and lemon aspen ( Acronychia acidula ) are under-examined in terms of their therapeutic potential. In this study, the in vitro antiproliferative activity of native currant and lemon aspen extracts (water and ethanol) against MCF7 breast adenocarcinoma cells was determined using the Alamar blue assay. The most potent extracts (native currant water, NC-W; native currant ethanol, NC-Et; lemon aspen ethanol, LA-Et) were further evaluated using flow cytometry to detect the potential induction of apoptosis in MCF7 cells whereas 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay was implemented to understand the impact of the extracts on the intracellular reactive oxygen species (ROS) levels in MCF7 cells. Furthermore, the antioxidant activity of the extracts was assessed using ABTS [2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate)], and CUPRAC (cupric reducing antioxidant capacity) assays. The antimicrobial susceptibility testing of NC-W, NC-Et, and LA-Et was carried out against Gram-positive ( Staphylococcus aureus ), Gram-negative ( Escherichia coli ), and yeast ( Candida albicans ) strains using a resazurin-based assay. Additionally, potential metabolites in the NC-W and NC-Et extracts were analysed with liquid chromatography-mass spectrometry (LC-MS) driven metabolomics and chemometrics to spot differential and major metabolites. A dose-dependent antiproliferative activity was conferred by the NC extracts against MCF7 cells. Of the two LA extracts, only LA-Et showed a dose-dependent antiproliferative activity at higher concentrations. Both NC extracts and LA-Et induced apoptosis in MCF7 cells. None of the extracts increased the production of ROS significantly in MCF7 cells compared to the untreated control. A dose-dependent antioxidant activity was observed in both antioxidant assays. Both NC and LA extracts showed a similar minimum inhibitory concentration (MIC) value against S. aureus . Only LA-Et showed activity against E. coli , while NC-W and NC-Et were less active. All extracts showed MIC values of >1500 μg mL -1 against C. albicans . The metabolomics analysis revealed an abundance of flavonoids, fatty acyl derivatives, carbohydrates, carboxylic acids and their derivatives, and alkaloid compounds as potential bioactive metabolites in the NC extracts. In conclusion, both NC and LA showed antiproliferative (against MCF7 breast adenocarcinoma cells through the induction of apoptosis), strong antioxidant and minimal antimicrobial properties.

Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1 SMKO ) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1 SMKO mice can be considered a novel CSVD animal model. Here, we found that MYPT1 SMKO mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1 SMKO mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1 SMKO mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1 SMKO mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1 SMKO mice are a novel age- and hypertension-dependent animal model of CSVD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4 + T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-β superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15., Methods: In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15 high macrophages., Results: We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population (~1%) of GDF15 high cells. GDF15 high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, the in vitro derived GDF15 high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, these GDF15 high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15 high macrophage. Also, we provided evidence showing that GDF15 high macrophages were present in other macrophage-residing human tissues in addition to the lungs. Further scRNA-seq analysis in rat lung macrophages confirmed the presence of a GDF15 high sub-population. However, these data indicated that GDF15 high macrophages in the body were not a uniform population based on their molecular signatures. More importantly, as compared to the in vitro derived GDF15 high macrophage, whether the tissue resident GDF15 high counterpart is also associated with anti-inflammatory functions remains to be determined. We cannot exclude the possibility that the in vitro priming/induction protocol used in our study has a determinant role in inducing the anti-inflammatory phenotype in the resulting GDF15 high macrophage cells., Conclusion: In summary, our results suggest that the GDF15 high macrophage cells obtained by in vitro induction may represent a distinct cluster with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dai, Zhang, Zheng, Li, Ma, Gao, Zhang, Jiang and Cui.)

A growing body of literature underlines the fundamental role of gut microbiota in the occurrence, treatment, and prognosis of cancer. In particular, the activity of gut microbial metabolites (also known as postbiotics) against different cancer types has been recently reported in several studies. However, their in-depth molecular mechanisms of action and potential interactions with standard chemotherapeutic drugs remain to be fully understood. This research investigates the antiproliferative activities of postbiotics- short-chain fatty acid (SCFA) salts, specifically magnesium acetate (MgA), sodium propionate (NaP), and sodium butyrate (NaB), against the AGS gastric adenocarcinoma cells. Furthermore, the potential synergistic interactions between the most active SCFA salt-NaB and the standard drug dexamethasone (Dex) were explored using the combination index model. The molecular mechanisms of the synergy were investigated using reactive oxygen species (ROS), flow cytometry and biochemometric and liquid chromatography-mass spectrometry (LC-MS)-driven proteomics analyses. NaB exhibited the most significant inhibitory effect ( p  < 0.05) among the tested SCFA salts against the AGS gastric cancer cells. Additionally, Dex and NaB exhibited strong synergy at a 2:8 ratio (40 μg/mL Dex + 2,400 μg/mL NaB) with significantly greater inhibitory activity ( p  < 0.05) compared to the mono treatments against the AGS gastric cancer cells. MgA and NaP reduced ROS production, while NaB exhibited pro-oxidative properties. Dex displayed antioxidative effects, and the combination of Dex and NaB (2,8) demonstrated a unique pattern, potentially counteracting the pro-oxidative effects of NaB, highlighting an interaction. Dex and NaB individually and in combination (Dex:NaB 40:2400 μg/mL) induced significant changes in cell populations, suggesting a shift toward apoptosis ( p  < 0.0001). Analysis of dysregulated proteins in the AGS cells treated with the synergistic combination revealed notable downregulation of the oncogene TNS4, suggesting a potential mechanism for the observed antiproliferative effects. These findings propose the potential implementation of NaB as an adjuvant therapy with Dex. Further investigations into additional combination therapies, in-depth studies of the molecular mechanisms, and in vivo research will provide deeper insights into the use of these postbiotics in cancer, particularly in gastric malignancies., Competing Interests: As a medical research institute, NICM Health Research Institute (NICM HRI) receives grants and donations from foundations, universities, government agencies, individuals, and industry. Sponsors and donors also provide untied funding to advance the vision and mission of NICM HRI. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eladwy, Alsherbiny, Chang, Fares, Li and Bhuyan.)

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody., (© 2024. The Author(s).)

Background: Robotic hepatectomy (RH) is currently widely accepted and it is associated with some benefits when compared to open hepatectomy (OH). However, whether such benefits can still be achieved for patients with large hepatocellular carcinoma (HCC) remain unclear. This study aimed to evaluate the short-term and long-term outcomes of patients undergoing RH or OH., Methods: Perioperative and survival data from patients with large HCC who underwent RH or OH between January 2010 and December 2020 were collected from eight centres. Propensity score matching (PSM) was performed to minimise potential biases., Results: Using predefined inclusion criteria, 797 patients who underwent OH and 309 patients who underwent RH were enroled in this study. After PSM, 280 patients in the robotic group had shorter operative time (median 181 vs. 201 min, P <0.001), lower estimated blood loss (median 200 vs. 400 ml, P <0.001), and shorter postoperative length of stay (median 6 vs. 9 days, P <0.001) than 465 patients in the open group. There were no significant differences between the two groups in overall survival and recurrence-free survival. Cox analysis showed AFP greater than 400 ng/ml, tumour size greater than 10 cm, and microvascular invasion were independent risk factors for overall survival and recurrence-free survival. After PSM, subgroup analysis showed that patients with a huge HCC (diameter >10 cm) who underwent RH had significantly lower estimated blood loss (median 200.0 vs. 500.0 min, P <0.001), and shorter length of stay (median 7 vs. 10 days, P <0.001) than those who underwent OH., Conclusion: Safety and feasibility of RH and OH for patients with large HCC were comparable. RH resulted in similar long-term survival outcomes as OH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: The utilization of plants with therapeutic properties in traditional medicine has a longstanding practice. Among them, the well-known Allium cepa L. commonly known as onion has been valued for its anti-inflammatory and antioxidant potential in the treatment of various ailments, including gastric ulcers., Aim of the Study: This study investigated the gastroprotective potential of red onion peel extract and its fractions in a rat model of ethanol-induced gastric ulcer. Moreover, their phytochemical profiles were compared to identify the active metabolites., Materials and Methods: Mass spectrometry-based metabolomics and chemometrics were performed for phytochemical analysis. Ethanol-induced gastric ulcer model was used to assess the gastroprotective activity. Nine groups of rats were allocated as follows: Group 1 was the normal control; Group 2 rats were used as a positive control/model and received 1 mL of absolute ethanol; and Group 3 rats were treated with famotidine at a dose of 20 mg/kg orally. Group 4 and 5 rats were treated with total acidified ethanolic extract (T1, T2). Group 6 and 7 rats were treated with anthocyanins-rich fractions (P1, P2). Groups 8 and 9 were the flavonoids-rich fraction (S1, S2) treatment. Prior to scarification, the ulcer index in mm was obtained from gastric tissues photographed beside a ruler with further analysis using ImageJ software., Results: Seventy key major and discriminatory metabolites were identified including flavonoids, anthocyanins, phenolic acids, and miscellaneous compounds. The examined extract and its fractions significantly reduced the ulcer index and inflammatory cytokines via downregulating HMGB-1/NF-κB. Also, they augmented the expression of Nrf2/HO-1 and reduced NOX1/4 mRNA expression. Moreover, there was a significant reduction in the oxidative stress and apoptotic biomarkers as well as a noticeable enhancement in histopathological changes of the stomach tissues., Conclusion: Red onion peels have a promising dose dependent gastroprotective potential in alcohol-induced ulcers via modulating Nrf2/HO-1 and HMGB-1/NF-κB trajectories. This highlights the potential of red onion peels in treating gastric ulcers., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication of “Gastroprotective Potential of Red Onion (Allium cepa L.) Peel in Ethanol-Induced Gastric Injury in Rats: Involvement of Nrf2/HO-1 and HMGB-1/NF-κB Trajectories” to be published in Journal of Ethnopharmacology. With the submission of this manuscript I would like to undertake that the above mentioned manuscript has not been published elsewhere, accepted for publication elsewhere or under editorial review for publication elsewhere; and that my Institute's (Faculty of Pharmacy, Cairo University) representative is fully aware of this submission., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study aimed to compare the postoperative analgesic efficacy and motor recovery of a novel lumbar plexus block (LPB) with that of a femoral nerve block (FNB) after total knee arthroplasty (TKA). Forty patients who underwent TKA were randomised equally into an lumbar plexus and sciatic nerve (LS) group (receiving novel LPB) and an femoral and sciatic nerves (FS) group (receiving FNB). The assessed variables were the onset time of pain, time to the first analgesic request, pain scores, motor block at 6, 12, and 24 h after TKA, and the number of patients receiving successful blockade for each branch of the lumbar plexus. In the LS group, the femoral, lateral femoral cutaneous, genitofemoral, iliohypogastric, ilioinguinal, and obturator nerves were blocked in 18, 20, 16, 18, 15, and 19 patients. Compared to the FS group, the LS group had a significantly shorter onset time of pain and time to the first analgesic request, a significantly larger total postoperative dose of sufentanil, significantly higher numeric rating scale scores for both rest and dynamic pain at 6, 12, and 24 h, and faster motor recovery. Novel ultrasound-guided LPB has a high blocking success rate and provides inferior postoperative analgesia, but faster motor recovery after TKA than FNB., Competing Interests: Conflict of interest: The authors declare that they have no known conflict of interest or personal relationships that could have appeared to influence the work reported in this article., (© 2024 the author(s), published by De Gruyter.)

Microbial exopolysaccharides (EPSs) can promote plants growth and protect them against various abiotic stresses, but the role of actinobacteria-produced EPSs in plant growth promoting is still less known. Here, we aim to explore the effect of EPSs from an endophyte Glutamicibacter halophytocota KLBMP 5180 on tomato seeds germination and seedlings growth under salt stress. Our study revealed that 2.0 g/L EPSs resulted in increased seed germination rate by 23.5 % and 11.0 %, respectively, under 0 and 200 mM NaCl stress conditions. Further pot experiment demonstrated that EPSs significantly promoted seedlings growth under salt stress, with increased height, root length and fibrous roots number. Plant physiological traits revealed that EPSs increased chlorophyll content, enhanced the activity of antioxidant enzymes, soluble sugar, and K + concentration in seedlings; malondialdehyde and Na + contents were reduced. Additionally, auxin, abscisic acid, jasmonic acid, and salicylic acid were accumulated significantly in seedlings after EPSs treatment. Furthermore, we identified 1233 differentially expressed genes, and they were significantly enriched in phytohormone signal transmission, phenylpropanoid biosynthesis, and protein processing in endogenous reticulum pathways, etc. Our results suggest that KLBMP 5180-produced EPSs effectively ameliorated NaCl stress in tomato plants by triggering complex regulation mechanism, and showed application potentiality in agriculture., Competing Interests: Declaration of competing interest All authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

As global supply is still inadequate to address the worldwide requirements for HPV vaccines, we assessed the safety and immunogenicity of a new bivalent HPV16/18 vaccine. In this randomized, double-blind, placebo-controlled, phase 2 trial, healthy 9-45-year-old Chinese females in three age cohorts (600 aged 9-17 years; 240 aged 18-26 years; 360 aged 27-45 years) were randomized 1:1 to receive three doses (0,2,6 months) of HPV16/18 vaccine or placebo. We measured neutralizing antibodies against HPV 16 and 18 at 7 months and monitored safety to 12 months in all age cohorts; 9-17-year-old girls were monitored for safety and immunogenicity to 48 months. In vaccinees, 99.8% seroconverted for HPV 16 and 18 types at 7 months; respective GMTs of 5827 (95% CI: 5249, 6468) and 4223 (3785, 4713) were significantly ( p  < .001) higher than controls for all comparisons. GMTs in the 9-17-year-olds, which were significantly higher than in older women at 7 months, gradually declined to 48 months but remained higher than placebo with seropositivity rates maintained at 98.5% and 97.6% against HPV 16 and 18, respectively. Adverse events occurred at similar rates after vaccine and placebo (69.8% vs. 72.5%, p  = .308), including solicited local reactions and systemic adverse events which were mainly mild-to-moderate. The bivalent HPV16/18 vaccine was well tolerated and induced high levels of neutralizing antibodies in all age groups which persisted at high levels to 48 months in the 9-17-year-old age group which would be the target for HPV vaccination campaigns.

Backgrounds: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties., Methods: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4 + T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4 + T cells., Results: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4 + T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4 + T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4 + T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role., Conclusion: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation., (© 2023. The Author(s).)

Regulatory T cells (Tregs) have critical roles in maintaining immune hemostasis and have important anti-inflammatory functions in diseases. Recently, we identified that CX-5461 (a selective RNA polymerase I inhibitor and p53 activator) acted as a potent immunosuppressive agent, which prevented allogeneic acute rejection in animal models via a molecular mechanism distinct from all those of conventional immunosuppressive drugs. Unexpectedly, we discovered that CX-5461 could promote Treg differentiation. In this review, we have summarized the evidence for a potential role of p53 in mediating Treg differentiation and its possible mechanisms, including regulation of FoxP3 transcription, regulation of the expression of PTEN (phosphatase and tensin homolog), as well as protein-protein interaction with the transcription factor STAT5 (signal transducer and activator of transcription 5). Evidence also suggests that pharmacological p53 activators may potentially be used to boost Treg-mediated immune tolerance. Based on these data, we argue that novel p53 activators such as CX-5461 may represent a distinct class of immunosuppressants that repress conventional T cell-mediated alloimmunity with concomitant boosting of Treg-dependent immune tolerance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer poses a substantial risk to human life and wellbeing as a result of its elevated incidence and fatality rates. Endoplasmic reticulum stress (ERS) is an important pathway that regulates cellular homeostasis. When ERS is under- or overexpressed, it activates the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-, inositol-requiring enzyme 1 (IRE1)- and activating transcription Factor 6 (ATF6)-related apoptotic pathways to induce apoptosis. Tumor cells and microenvironment are susceptible to ERS, making the modulation of ERS a potential therapeutic approach for treating tumors. The use of natural products to treat tumors has substantially progressed, with various extracts demonstrating antitumor effects. Nevertheless, there are few reports on the effectiveness of natural products in inducing apoptosis by specifically targeting and regulating the ERS pathway. Further investigation and elaboration of its mechanism of action are still needed. This paper examines the antitumor mechanism of action by which natural products exert antitumor effects from the perspective of ERS regulation to provide a theoretical basis and new research directions for tumor therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Yuan, Li, Zhang, Han and Li.)

Background: We assessed the safety, immunogenicity and antibody persistence of two- and three-dose schedules of the novel bivalent HPV16/18 vaccine (HPV-2, Walrinvax) in the per-protocol target population of initially seronegative 9-14 year-old girls, including a non-inferiority comparison with the three-dose schedule in 18-26 year-old women., Methods: This randomized phase 3b trial in Guangxi Zhuang Autonomous Region, China, involved healthy Chinese females in two age cohorts; 600 girls aged 9-14 years and 300 women aged 18-26 years. Girls were randomly assigned (1:1) to receive either two (Months 0,6) or three (Months 0,2,6) intramuscular doses of HPV-2. All participants were monitored for immunogenicity as neutralizing antibodies up to 36 months. Primary objectives were non-inferiority analyses of immunogenicity between two- and three-dose girl groups and adult women at Month 7; safety assessments were based on participant-completed diary cards., Results: All groups demonstrated marked increases in neutralizing antibodies against HPV 16 and 18 that persisted above baseline to 36 months. Month 7 responses in both girl groups were non-inferior to those in the women and were statistically higher after two-doses than girls or women who received three doses. GMTs waned after month 7, but then maintained a plateau level until month 36. Vaccination was well tolerated in all groups with no serious adverse events reported., Conclusions: Immune responses to two doses of HPV-2 vaccine in adolescent girls were non-inferior to those after three doses in young women, an age cohort in which clinical efficacy of HPV-2 against cervical cancer has been demonstrated., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B-W Yu, K Li, M Ji, Q Yang and L-Y Zhou are full-time employees of the manufacturer. Other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The gut microbiota undergoes metabolic processes to produce by-products (gut metabolites), which play a vital role in the overall maintenance of health and prevention of disease within the body. However, the use of gut metabolites as anticancer agents and their molecular mechanisms of action are largely unknown. Therefore, this study evaluated the anti-proliferative effects of three key gut microbial metabolites-sodium butyrate, inosine, and nisin, against MCF7 and MDA-MB-231 breast adenocarcinoma cell lines. To determine the potential mechanistic action of these gut metabolites, flow cytometric assessments of apoptotic potential, reactive oxygen species (ROS) production measurements and proteomics analyses were performed. Sodium butyrate exhibited promising cytotoxicity, with IC 50 values of 5.23 mM and 5.06 mM against MCF7 and MDA-MB-231 cells, respectively. All three metabolites were found to induce apoptotic cell death and inhibit the production of ROS in both cell lines. Nisin and inosine indicated a potential activation of cell cycle processes. Sodium butyrate indicated the possible initiation of signal transduction processes and cellular responses to stimuli. Further investigations are necessary to ascertain the effective therapeutic dose of these metabolites, and future research on patient-derived tumour spheroids will provide insights into the potential use of these gut metabolites in cancer therapy.

Objectives: We applied a fully automated pixel-wise post-processing framework to evaluate fully quantitative cardiovascular magnetic resonance myocardial perfusion imaging (CMR-MPI). In addition, we aimed to evaluate the additive value of coronary magnetic resonance angiography (CMRA) to the diagnostic performance of fully automated pixel-wise quantitative CMR-MPI for detecting hemodynamically significant coronary artery disease (CAD)., Methods: A total of 109 patients with suspected CAD were prospectively enrolled and underwent stress and rest CMR-MPI, CMRA, invasive coronary angiography (ICA), and fractional flow reserve (FFR). CMRA was acquired between stress and rest CMR-MPI acquisition, without any additional contrast agent. Finally, CMR-MPI quantification was analyzed by a fully automated pixel-wise post-processing framework., Results: Of the 109 patients, 42 patients had hemodynamically significant CAD (FFR ≤ 0.80 or luminal stenosis ≥ 90% on ICA) and 67 patients had hemodynamically non-significant CAD (FFR ˃ 0.80 or luminal stenosis < 30% on ICA) were enrolled. On the per-territory analysis, patients with hemodynamically significant CAD had higher myocardial blood flow (MBF) at rest, lower MBF under stress, and lower myocardial perfusion reserve (MPR) than patients with hemodynamically non-significant CAD (p < 0.001). The area under the receiver operating characteristic curve of MPR (0.93) was significantly larger than those of stress and rest MBF, visual assessment of CMR-MPI, and CMRA (p < 0.05), but similar to that of the integration of CMR-MPI with CMRA (0.90)., Conclusions: Fully automated pixel-wise quantitative CMR-MPI can accurately detect hemodynamically significant CAD, but the integration of CMRA obtained between stress and rest CMR-MPI acquisition did not provide significantly additive value., Key Points: • Full quantification of stress and rest cardiovascular magnetic resonance myocardial perfusion imaging can be postprocessed fully automatically, generating pixel-wise myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) maps. • Fully quantitative MPR provided higher diagnostic performance for detecting hemodynamically significant coronary artery disease, compared with stress and rest MBF, qualitative assessment, and coronary magnetic resonance angiography (CMRA). • The integration of CMRA and MPR did not significantly improve the diagnostic performance of MPR alone., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have been used to diagnose lesion-specific ischemia in patients with coronary artery disease. The aim of this study was to investigate the diagnostic performance of CCTA-derived plaque characteristic index compared with myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) derived from CMR perfusion in the assessment of lesion-specific ischemia., Methods: Between October 2020 and March 2022, consecutive patients with suspected or known coronary artery disease, who were clinically referred for invasive coronary angiography were prospectively enrolled. All participants sequentially underwent CCTA and CMR and invasive fractional flow reserve within 2 weeks. The diagnostic performance of CCTA-derived plaque characteristics, CMR perfusion-derived stress MBF, and MPR were compared. Lesions with fractional flow reserve ≤0.80 were considered to be hemodynamically significant stenosis., Results: Nighty-two patients with 141 vessels were included in this study. Plaque length, minimum luminal area, plaque area, percent area stenosis, total atheroma volume, vessel volume, lipid-rich volume, spotty calcium, napkin-ring signs, stress MBF, and MPR in flow-limiting stenosis group were significantly different from nonflow-limiting group. The overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of lesion-specific ischemia diagnosis were 61.0%, 55.3%, 63.1%, 35.6%, and 79.3% for stress MBF, and 89.4%, 89.5%, 89.3%, 75.6%, 95.8% for MPR; meanwhile, 82.3%, 79.0%, 84.5%, 65.2%, and 91.6% for CCTA-derived plaque characteristic index., Conclusions: In our prospective study, CCTA-derived plaque characteristics and MPR derived from CMR performed well in diagnosing lesion-specific myocardial ischemia and were significantly better than stress MBF in stable coronary artery disease., Competing Interests: Disclosures None.

Background: Williams syndrome is an autosomal dominant multisystem disorder caused by a 1.5-1.8 Mb deletion on chromosome 7q11.23. It is characterized by facial deformations, cardiovascular abnormalities, developmental delays, gastrointestinal manifestations, and endocrine disorders., Case Description: A 1-year-old child presenting with developmental delays, special facial features, gastrointestinal bleeding, renal calcium deposition, and hypotonia was admitted to the hospital for "hypercalcemia and gastrointestinal bleeding." Genetic testing showed a deletion mutation in the 7q11.23 region. Currently, the child receiving treatment to promote calcium excretion and rehabilitation training, but hypercalcemia has recurred., Conclusion: The clinical phenotype of Williams syndrome is complex, and different severities, characterized by developmental delays, facial deformities, cardiovascular abnormalities, gastrointestinal symptoms and endocrine disorders, should be considered in children. The syndrome may require thorough genetic testing for diagnosis and early intervention treatment to improve patient quality of life., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Hepatic portal blood flow occlusion is a common technique for reducing hepatic hemorrhage during hepatectomy. We designed a novel Y-Z magnetic hepatic portal blocking band (Y-Z MHPBB) based on the principle of magnetic compression technique., Aim: To introduce the Y-Z MHPBB device and verify the feasibility of this device for hepatic portal blood flow occlusion in dogs., Methods: Ten beagles were randomly divided into the experimental group and control group. The operation time, intraoperative blood loss, the number of portal blood flow occlusions, the total time spent on adjusting the blocking band, and the average time spent on adjusting the blocking band were recorded. The surgeons evaluated the feasibility and flexibility of the two portal occlusion devices., Results: Laparoscopic hepatectomy was successfully performed in both the experimental group and control group. There was no statistical difference between the two groups in the operation time, intraoperative blood loss, and the number of hepatic portal blood flow occlusions. With respect to the total time spent on adjusting the blocking band and the average time spent on adjusting the blocking band, the experimental group showed significantly better outcomes than the control group, with a statistical difference ( P < 0.05). The operators found that the Y-Z MHPBB was superior to the modified T-tube in terms of operational flexibility., Conclusion: The Y-Z MHPBB seems to be an ingenious design, accurate blood flow occlusion effect, and good flexibility; and it can be used for hepatic portal blood flow occlusion during laparoscopic hepatectomy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Magnetic compression anastomosis (MCA) is a simple procedure contributing to a reliable anastomosis. However, digestive-tract reconstruction after total gastrectomy using MCA has not yet been reported., Aim: To investigate the feasibility of MCA for simultaneous esophagojejunostomy and jejunojejunostomy after total gastrectomy using beagle dogs., Methods: Sixteen beagles were randomly divided into an MCA group (study group, n = 8) and a manual-suture anastomosis group (control group, n = 8). Two different magnetic anastomosis devices were used in the study group for esophagojejunal and jejunojejunal anastomoses. Both devices included a pair of circular daughter and parent magnets each. The time of esophagojejunostomy and jejunojejunostomy, postoperative complications, and survival rate of the two groups were compared. The dogs were sacrificed one month after the operation and their anastomotic specimens were obtained. Healing was observed by the naked eye and a light microscope., Results: Digestive-tract reconstruction after total gastrectomy was successfully completed in both groups (survival rate = 100%). In the study group, esophagojejunal and jejunojejunal anastomoses took 6.13 ± 0.58 and 4.06 ± 0.42 min, respectively, significantly lower than those in the control group (15.63 ± 1.53 min, P < 0.001 and 10.31 ± 1.07 min, P < 0.001, respectively). Complications such as bleeding, anastomotic leakage, and anastomotic stenosis were not observed. In the study group, the magnets did not interfere with each other. Discharge time of the jejunojejunal magnetic anastomosis device was 10.75 ± 1.28 d, while that of the esophagojejunal magnetic anastomosis device was 12.25 ± 1.49 d. Residual silk was found in the control group. The study group showed a greater smoothness of the anastomosis than that of the control group. All layers of anastomosis healed well in both groups., Conclusion: MCA is a safe and feasible procedure for digestive-tract reconstruction after total gastrectomy in this animal model., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs., Methods: Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems., Results: sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs., Conclusions: We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation., (© 2023. The Author(s).)

Renal cell carcinoma (RCC) is the most common form of kidney cancer, consisting of multiple distinct subtypes. RCC has the highest mortality rate amongst the urogenital cancers, with kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and kidney chromophobe carcinoma (KICH) being the most common subtypes. The Paired-box ( PAX ) gene family encodes transcription factors, which orchestrate multiple processes in cell lineage determination during embryonic development and organogenesis. Several PAX genes have been shown to be expressed in RCC following its onset and progression. Here, we performed real-time quantitative polymerase chain reaction (RT-qPCR) analysis on a series of human RCC cell lines, revealing significant co-expression of PAX2 , PAX6 , and PAX8 . Knockdown of PAX2 or PAX8 mRNA expression using RNA interference (RNAi) in the A498 RCC cell line resulted in inhibition of cell proliferation, which aligns with our previous research, although no reduction in cell proliferation was observed using a PAX2 small interfering RNA (siRNA). We downloaded publicly available RNA-sequencing data and clinical histories of RCC patients from The Cancer Genome Atlas (TCGA) database. Based on the expression levels of PAX2 , PAX6 , and PAX8 , RCC patients were categorized into two PAX expression subtypes, PAXClusterA and PAXClusterB, exhibiting significant differences in clinical characteristics. We found that the PAXClusterA expression subgroup was associated with favorable clinical outcomes and better overall survival. These findings provide novel insights into the association between PAX gene expression levels and clinical outcomes in RCC patients, potentially contributing to improved treatment strategies for RCC.

Background: Robotic hepatectomy (RH) has gradually been accepted as it has overcome some of the limitations of open hepatectomy (OH). This study was to compare short-term outcomes in RH and OH for overweight (preoperative body mass index ≥ 25 kg/m²) patients with hepatocellular carcinoma (HCC)., Methods: Perioperative and postoperative data from these patients who underwent RH or OH between January 2010 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) analysis was performed to determine the impact of RH versus OH on the prognosis of overweight HCC patients., Results: All 304 overweight HCC patients were included, 172 who were underwent RH, and 132 who were underwent OH. After the 1:1 PSM, there were 104 patients in both RH and OH groups. After PSM, the RH group of patients had a shorter operative time, less estimated blood loss (EBL), a longer total clamping time, a shorter postoperative length of stay (LOS), less chance of surgical site infection and less rates of blood transfusion (all P < 0.05) compared to the OH patients. The differences between operative time, EBL and LOS were more significant in obese patients. RH was found to be an independent protective factor of EBL ≥ 400ml relative to OH in overweight patients for the first time., Conclusions: RH was safe and feasible in overweight HCC patients. Compared with OH, RH has advantages in terms of operative time, EBL, postoperative LOS, and surgical site infection. Carefully selected overweight patients should be considered for RH., (© 2023. The Author(s).)

The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial that was conducted at nine major medical centers in Guangdong Province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n = 384) or the VCR/DEX pulse (treatment group, n = 375). When limited to the SR cohort, 10-year EFS was 82.6% (95% CI: 75.9-89.9) in the control group and 80.7% (95% CI: 74-88.1) in the treatment group (p non-inferiority  = .0002). Similarly, patients with IR also demonstrated non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6% [95% CI: 67.6-80] vs. 77.6% [95% CI: 71.8-83.9]; p non-inferiority  = .005). Among the HR cohort, compared with the control group, patients in the treatment group experienced a significant benefit in terms of 10-year EFS (61.1% [95% CI: 47.7-78.2] vs. 72.6% [95% CI: 55.6-94.7], p = .026) and a trend toward higher 10-year OS (73.8% [95% CI: 61.6-88.4] vs. 87.9% [95% CI: 579.2-97.5], p = .068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs. 100%, p = .033; 37.5% vs. 60%, p = .036). Conversely, the total prevalence of chemotherapy-induced thrombocytopenia was higher for patients in the treatment group than in the control group (88.9% vs. 40%, p = .027). Pediatric acute lymphoblastic leukemia with high risk is suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses., (© 2023 Wiley Periodicals LLC.)

The U6 promoter is an important element driving sgRNA transcription in the CRISPR/Cas9 system. Seven PqU6 promo-ter sequences were cloned from the gDNA of Panax quinquefolium, and the transcriptional activation ability of the seven promoters was studied. In this study, seven PqU6 promoter sequences with a length of about 1 300 bp were cloned from the adventitious roots of P. quinquefolium cultivated for 5 weeks. Bioinformatics tools were used to analyze the sequence characteristics of PqU6 promoters, and the fusion expression vectors of GUS gene driven by PqU6-P were constructed. Tobacco leaves were transformed by Agrobacterium tumefaciens-mediated method for activity detection. The seven PqU6 promoters were truncated from the 5'-end to reach 283, 287, 279, 289, 295, 289, and 283 bp, respectively. The vectors for detection of promoter activity were constructed with GUS as a reported gene and used to transform P. quinquefolium callus and tobacco leaves. The results showed that seven PqU6 promoter sequences(PqU6-1P to PqU6-7P) were cloned from the gDNA of P. quinquefolium, with the length ranged from 1 246 bp to 1 308 bp. Sequence comparison results showed that the seven PqU6 promoter sequences and the AtU6-P promoter all had USE and TATA boxes, which are essential elements affecting the transcriptional activity of the U6 promoter. The results of GUS staining and enzyme activity test showed that all the seven PqU6 promoters had transcriptional activity. The PqU6-7P with a length of 1 269 bp had the highest transcriptional activity, 1.31 times that of the positive control P-35S. When the seven PqU6 promoters were truncated from the 5'-end(PqU6-1PA to PqU6-7PA), their transcriptional activities were different in tobacco leaves and P. quinquefolium callus. The transcriptional activity of PqU6-7PA promoter(283 bp) was 1.59 times that of AtU6-P promoter(292 bp) when the recipient material was P. quinquefolium callus. The findings provide more ideal endogenous U6 promoters for CRISPR/Cas9 technology in ginseng and other medicinal plants.

Background: We evaluated the safety and immunogenicity of high and low doses of a novel pichia pastoris-expressed bivalent (types 16 and 18) human papillomavirus (HPV) virus-like particle vaccine., Methods: In this randomized, double-blind, placebo-controlled phase 1 trial, we enrolled 160 healthy females aged 9-45 years in Guangxi, China who were randomized (1:1:2) to receive either low (0.5 mL) or high (1.0 mL) dosages of bivalent HPV vaccine, or placebo (aluminum adjuvant) in a 0, 2, 6 months schedule. Adverse events and other significant conditions that occurred within 30 days after each vaccination were recorded throughout the trial. Sera were collected at days 0, 60, 180 and 210 to measure anti-HPV 16/18 neutralizing antibodies., Results: A total of 160 participants received at least one dose of the HPV vaccine and 152 completed the three dose vaccination series. Reporting rates of adverse events in placebo, low dose (0.5 mL) and high dose (1.0 mL) groups were 47.5 %, 55.0 % and 55.0 %, respectively. No serious adverse events occurred during this trial. 100 % of the participants who received three doses of the HPV vaccine produced neutralizing antibodies against HPV 16/18 vaccine. For HPV 16 and HPV 18, the geometric mean titers (GMTs) were similar between the low dose group (GMT HPV 16  = 10816 [95 % CI: 7824-14953]), GMT HPV 18  = 3966 [95 % CI: 2693-5841]) and high dose group (GMT HPV 16  = 14482 [95 % CI: 10848-19333], GMT HPV 18  = 3428 [95 % CI: 2533-4639])., Conclusion: The pichia pastoris-expressed bivalent HPV vaccine was safe and immunogenic in Chinese females aged 9-45 years. The low dosage (0.5 mL) was selected for further immunogenicity and efficacy study., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B-W Yu, L-Y Zhou and L Shi were full-time employees of the manufacturer at the time of the study, other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: M2-type macrophages are inflammation-suppressing cells that are differentiated after induction by cytokines such as IL-4 or IL-13, which play an important regulatory role in inflammation and influence the regression of inflammation-related diseases. All-trans retinoic acid (ATRA) has an important role in suppressing immune-mediated inflammatory responses but the effect and underlying mechanism of ATRA on the polarization of M2 macrophages remains unclear., Methods: Macrophages were isolated from peritoneal wash fluid, and IL-4 (20 ng/mL) was used to construct a m2-type macrophage polarization model. The model was incubated with different concentrations of ATRA (15 µg/ml, 30 µg/ml, 45 µg/ml) for 24 h, and pretreated macrophages with p38MAPKα inhibitor SB202190 (20 μM). MTT, Trypan blue staining, Annexin V-PE/7-AAD staining, flow cytometry, real-time PCR and western blotting were used to investigate the effect and mechanism of ATRA on the polarization of M2 macrophages., Results: Compared with the IL-4 group, the proportion of F4/80 + CD206 + M2-type macrophages was significantly higher in the ATRA group ( P  < 0.01). mRNA and protein expression levels of Arg-1, IL-10 and TGF-β1 were as significantly higher ( P  < 0.01) in the ATRA group as phosphorylation levels of STAT6 and p38MAPK ( P  < 0.01). After pretreatment with the addition of the inhibitor SB202190, M2-type macrophages proportion and their associated factors expression were significantly ( P  < 0.01) reduced, as compared with those in the ATRA group, but they were comparable ( P  > 0.05) with the IL-4 group., Conclusion: The combination of ATRA and IL-4 activated the p38MAPK/STAT6-signaling pathway to promote polarization of M2 macrophages.

Background: Microvascular invasion (MVI) is a risk factor for postoperative survival outcomes for patients with hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to evaluate the impact of anatomical resection (AR) versus nonanatomical resection (NAR) combined with resection margin (RM) (narrow RM <1 cm vs. wide RM ≥1 cm) on long-term prognosis in hepatitis B virus-related HCC patients with MVI., Materials and Methods: Data from multicenters on HCC patients with MVI who underwent hepatectomy was analyzed retrospectively. Propensity score matching analysis was performed in these patients., Results: The 1965 enrolled patients were divided into four groups: AR with wide RM ( n =715), AR with narrow RM ( n =387), NAR with wide RM ( n =568), and NAR with narrow RM ( n =295). Narrow RM ( P <0.001) and NAR ( P <0.001) were independent risk factors for both overall survival and recurrence-free survival in these patients based on multivariate analyses. For patients in both the AR and NAR groups, wide RM resulted in significantly lower operative margin recurrence rates than those patients in the narrow RM groups after propensity score matching ( P =0.002 and 0.001). Patients in the AR with wide RM group had significantly the best median overall survival (78.9 vs. 51.5 vs. 48.0 vs. 36.7 months, P <0.001) and recurrence-free survival (23.6 vs. 14.8 vs. 17.8 vs. 9.0 months, P <0.001) than those in the AR with narrow RM, NAR with wide RM or with narrow RM groups, respectively., Conclusions: If technically feasible and safe, AR combined with wide RM should be the recommended therapeutic strategy for HCC patients who are estimated preoperatively with a high risk of MVI., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The lack of a gold standard synergy quantification method for chemotherapeutic drug combinations warrants the consideration of different synergy metrics to develop efficient predictive models. Furthermore, neglecting combination sensitivity may lead to biased synergistic combinations, which are ineffective in cancer treatment. In this paper, we propose a deep learning-based model, SynPredict, which effectively predicts synergy in five synergy metrics together with the combination sensitivity score. SynPredict assesses the impact of multimodal fusion architectures of the input data, including the gene expression data of cancer cells, along with the representative chemical features of drugs in pairwise combinations. Both ONEIL and ALMANAC anticancer combination datasets are employed comparatively. The impact of the training datasets was more significant and consistent across most synergy models than input data fusion architectures. Synpredict outperforms the state-of-the-art predictive models, including DeepSynergy, AuDNN synergy, TranSynergy and DrugComb, with up to 74% decline in the mean square error. We highlight the pivotal need to consider a multiplex of synergy metrics and the combined sensitivity in the predictive models.

Increased expression of NUSAP1 has been identified as a robust prognostic biomarker in prostate cancer and other malignancies. We have previously shown that NUSAP1 is positively regulated by E2F1 and promotes cancer invasion and metastasis. To further understand the biological function of NUSAP1, we used affinity purification and mass spectrometry proteomic analysis to identify NUSAP1 interactors. We identified 85 unique proteins in the NUSAP1 interactome, including ILF2, DHX9, and other RNA-binding proteins. Using proteomic approaches, we uncovered a function for NUSAP1 in maintaining R-loops and in DNA damage response through its interaction with ILF2. Co-immunoprecipitation and colocalization using confocal microscopy verified the interactions of NUSAP1 with ILF2 and DHX9, and RNA/DNA hybrids. We showed that the microtubule and charged helical domains of NUSAP1 were necessary for the protein-protein interactions. Depletion of ILF2 alone further increased camptothecin-induced R-loop accumulation and DNA damage, and NUSAP1 depletion abolished this effect. In human prostate adenocarcinoma, NUSAP1 and ILF2 mRNA expression levels are positively correlated, elevated, and associated with poor clinical outcomes. Our study identifies a novel role for NUSAP1 in regulating R-loop formation and accumulation in response to DNA damage through its interactions with ILF2 and hence provides a potential therapeutic target.

As evidenced by the worldwide pandemic, respiratory infectious diseases and their airborne transmission must be studied to safeguard public health. This study focuses on the emission and transport of speech-generated droplets, which can pose risk of infection depending on the loudness of the speech, its duration and the initial angle of exhalation. We have numerically investigated the transport of these droplets into the human respiratory tract by way of a natural breathing cycle in order to predict the infection probability of three strains of SARS-CoV-2 on a person who is listening at a one-meter distance. Numerical methods were used to set the boundary conditions of the speaking and breathing models and large eddy simulation (LES) was used for the unsteady simulation of approximately 10 breathing cycles. Four different mouth angles when speaking were contrasted to evaluate real conditions of human communication and the possibility of infection. Breathed virions were counted using two different approaches: the breathing zone of influence and direction deposition on the tissue. Our results show that infection probability drastically changes based on the mouth angle and the breathing zone of influence overpredicts the inhalation risk in all cases. We conclude that to portray real conditions, the probability of infection should be based on direct tissue deposition results to avoid overprediction and that several mouth angles must be considered in future analyses., Competing Interests: The authors do not have any competing interests., (Copyright: © 2023 Murga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Mutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH., Methods: SMC-specific Bmpr2 -/- mice ( BKO SMC ) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKO SMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism., Results: BKO SMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension., Conclusions: Agents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D)., Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay., Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3)., Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine., Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered potential competing interests: The study funder, Beijing Wantai Biological Pharmacy Enterprise, prepared the vaccines in the phase 1 trial. Q-Q S, J-Z J, J-L H, Y-M L and X-Z Y are employees of Beijing Wantai Biological Pharmacy Enterprise. X-Z Y and Y-M L have stock options in Beijing Wantai Biological Pharmacy Enterprise CO. All other authors declare no competing interests., (© 2023 The Author(s).)

Background: Osteoporosis has already been a growing health concern worldwide. The influence of living area, lifestyle, socioeconomic, and medical conditions on the occurrence of osteoporosis in the middle-aged and elderly people in China has not been fully addressed., Methods: The study was a multicenter cross-sectional study on the middle-aged and elderly permanent residents, which gathered information of 22,081 residents from June 2015 to August 2021 in seven representative regions of China. The bone mineral density of lumbar vertebrae and hip were determined using the dual-energy X-ray absorptiometry densitometer instruments. Serum levels of bone metabolism markers were also measured. Information about education, smoking, and chronic diseases were also collected through face-to-face interviews. Age-standardized prevalence and 95% confidence intervals (CIs) of osteopenia and osteoporosis by various criteria were estimated by subgroups and overall based on the data of China 2010 census. The relationships between the osteoporosis or osteopenia and sociodemographic variables or other factors were examined using univariate linear models and multivariable multinomial logit analyses., Results: After screening, 19,848 participants (90%) were enrolled for the final analysis. The age-standardized prevalence of osteoporosis was estimated to be 33.49%(95%CI, 32.80-34.18%) in the middle-aged and elderly Chinese permanent residents, for men and women was 20.73% (95% CI, 19.58-21.87%) and 38.05% (95% CI, 37.22-38.89%), respectively. The serum concentrations of bone metabolic markers, and calcium and phosphorus metabolism were influenced by age, body mass index (BMI), gender, education level, regions, and bone mass status. Women, aged 60 or above, BMI lower than 18.5 kg/m 2 , low education level including middle school, primary school and no formal education as well as current regular smoking, a history of fracture were all significantly associated with a higher risk of osteoporosis and osteopenia in the middle-aged and elderly people., Conclusions: This study revealed dramatic regional differences in osteoporosis prevalence in China, and female, aged 60 or older, low BMI, low education level, current regular smoking, and a history of fracture were associated with a high risk of osteoporosis. More prevention and treatment resources should be invested into particular population exposed to these risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Shu, Tang, Li, Xie, Jiang, Jiang, Chen, Lin, Wei, Leng, Liao, Li, Zhang, Cui, Zhang, Lu, Shi and Wang.)

Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions can have local and systemic influence on drug activity., Competing Interests: SS, BR, CL, BH, OP, DW, AW, AM No competing interests declared, (© 2023, Sayin et al.)

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), and hepatitis B and C viruses. EBV, a member of the human gamma herpesvirus family, is a double-stranded DNA virus and the primary cause of infectious mononucleosis. Most EBV infections cause no long-term complications. However, it was reported that EBV infection is responsible for around 200,000 malignancies worldwide every year. Currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection. Recently, the gut microbiota has been investigated for its pivotal roles in pathogen protection and regulating metabolic, endocrine, and immune functions. Several studies have investigated the efficacy of antiviral agents, gut microbial metabolites, and natural products against EBV infection. In this review, we aim to summarise and analyse the reported molecular mechanistic and clinical studies on the activities of gut microbial metabolites and natural medicines against carcinogenic viruses, with a particular emphasis on EBV. Gut microbial metabolites such as short-chain fatty acids were reported to activate the EBV lytic cycle, while bacteriocins, produced by Enterococcus durans strains, have shown antiviral properties. Furthermore, several natural products and dietary bioactive compounds, such as curcumin, epigallocatechin gallate, resveratrol, moronic acid, and andrographolide, have shown antiviral activity against EBV. In this review, we proposed several exciting future directions for research on carcinogenic viruses.

Background: Since the current commonly used birth growth curves are unsuitable for neonates in high-altitude areas; this study aimed to establish birth growth curves for full-term neonates residing at 2,000-3,000 m., Methods: This cross-sectional study retrospectively analyzed the physical measurement data of 1,546 full-term neonates delivered at the Red Cross Hospital of Qinghai province, China, from July 2021 to April 2022. The percentile curves of birth weight, length, and head circumference of neonates of different gestational ages and genders were developed using curve fitting. The newly developed birth-weight percentile reference was compared with the INTERGROWTH-21st Neonatal Growth Curve (International Standard) and the Chinese Neonate Growth Curve (Chinese Standard)., Results: The median birth weight, length, and head circumference of the study population were 3,200 g, 52.0 cm, and 32.8 cm, respectively, except for the group with a gestational age of 37 weeks. The growth indicators of male infants in all groups were higher than those of the female infants ( P  < 0.05). We found differences between the newly developed birth-weight percentile curves in the high-altitude areas and the International and Chinese Standards., Conclusion: Establishing birth growth curves corresponding to altitude may be more suitable than the existing standards for local medical staff to conduct health assessments of neonates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Wang, Yao, Kang, Li, Zhang and Yu.)

Double-hit diffuse large B-cell lymphoma (DHL) is an uncommon subtype of lymphoma which poorly responds to current drug therapies and has low rates of long-term survival in the patients. Herein, we report a case of a 73-year-old Caucasian male who was diagnosed with DHL with double-hit mutations of rearrangement of both c-MYC and BCL2 in November 2013. He commenced the standard R-CHOP-14 chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) but changed to dose-adjusted DA-EPOCH-R protocol (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab) in the second and third cycles due to double-hit mutation. Because of intolerance to the intensive therapy, the patient decided to switch to Chinese medicine intervention. From March 2014 to December 2019, he was prescribed with a classical Chinese herbal formula- Sijunzi Decoction plus Prunella vulgaris based prescriptions. After 2 months of the Chinese herbal medicine intervention, the patient felt his right groin mass disappeared. Imaging follow-up showed no residual masses, and no lymphadenopathy was seen. During the period of Chinese herbal medicine treatment, his adherence and tolerability were well maintained with no adverse events. Imaging surveillances afterward found no evidence of lymphoma recurrence. His regular blood tests indicated that the patient's blood counts were normal and stable; no hematologic toxicity, hepatoxicity, or nephrotoxicity associated with Chinese herbal medicine were found. Follow-up visits until 2020 found that he had been living and enjoying a good quality of life for over 8 years post-diagnosis. This case study illustrates the potential values of Chinese herbal medicine in DHL treatment, alongside chemo-immunotherapy, and in maintaining long-term survival and satisfactory quality of life for DHL patients. The case report provides clinicians with preliminary evidence of the use of Chinese herbal medicine as a therapeutic strategy in the management of DHL.

Extensive research supported the therapeutic potential of curcumin, a naturally occurring compound, as a promising cytokinesuppressive anti-inflammatory drug. This study aimed to investigate the synergistic anti-inflammatory and anti-cytokine activities by combining 6-shogaol and 10-shogaol to curcumin, and associated mechanisms in modulating lipopolysaccharides and interferon-ɣ-induced proinflammatory signaling pathways. Our results showed that the combination of 6-shogaol-10-shogaol-curcumin synergistically reduced the production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor and interlukin-6 in lipopolysaccharides and interferon-γ-induced RAW 264.7 and THP-1 cells assessed by the combination index model. 6-shogaol-10-shogaol-curcumin also showed greater inhibition of cytokine profiling compared to that of 6-shogaol-10-shogaol or curcumin alone. The synergistic anti-inflammatory activity was associated with supressed NFκB translocation and downregulated TLR4-TRAF6-MAPK signaling pathway. In addition, SC also inhibited microRNA-155 expression which may be relevant to the inhibited NFκB translocation. Although 6-shogaol-10-shogaol-curcumin synergistically increased Nrf2 activity, the anti-inflammatory mechanism appeared to be independent from the induction of Nrf2. 6-shogaol-10-shogaol-curcumin provides a more potent therapeutic agent than curcumin alone in synergistically inhibiting lipopolysaccharides and interferon-γ induced proinflammatory mediators and cytokine array in macrophages. The action was mediated by the downregulation of TLR4/TRAF6/MAPK pathway and NFκB translocation.

Resveratrol has several functions, including protection of the heart and nervous system and exerts antidiabetic, anti-inflammatory, anti-aging, and antitumor effects. It is reported to impede the occurrence and development of tumors in cancer cell lines, animal models, and clinical studies. In vitro and in vivo experiments show that it exerts preventive or adjuvant therapeutic effects in pancreatic, colorectal, prostate, liver, and lung cancers. Mechanistic research reports show that resveratrol can induce tumor cell apoptosis and autophagy, inhibit cell cycle and angiogenesis, regulate nuclear factors and cyclooxygenase signal transduction pathways, and inhibit carcinogens' metabolic activation and alter tumor-related expression patterns; anti-oxidation affects tumor cell proliferation, metastasis, and apoptosis. However, the exact mechanism underlying its action remains unclear. This review highlights multiple aspects of the biological impacts and mechanisms underlying resveratrol action on the occurrence and development of lung cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Australian native plants have adapted themselves to harsh climatic conditions enabling them to produce unique and high levels of secondary metabolites. Native fruits and vegetables have been an integral part of the Indigenous Australian diet and Bush medicine for centuries. They have recently gained popularity owing to their rich dietary fiber, minerals, polyphenolic and antioxidant contents. This review presents a comprehensive summary and critical assessment of the studies performed in the last few decades to understand the phytochemical and nutritional profiles and therapeutic properties of Australian native fruits and vegetables. Furthermore, the potential of these fruits and vegetables as functional food ingredients and in the prevention and treatment of different diseases is discussed. Research on the nutritional and phytochemical profiles and therapeutic activity of Australian vegetables is limited with most studies focused on native fruits. These fruits have demonstrated promising antioxidant, anticancer, anti-inflammatory and antimicrobial activities mostly in in vitro models. More research to a) identify novel bioactive compounds, b) define optimal post-harvest and extraction methods, and c) understand molecular mechanisms of pharmacological activity through preclinical and clinical studies is prudent for the prospective and wider use of Australian native fruits and vegetables by the food, pharmaceutical, and nutraceutical industries.

The stability and grafting efficiency are important for polydopamine (pDA) coatings used as platforms for secondary grafting. In this work, polyethyleneimine (PEI) was co-deposited with dopamine on various materials (PP, PTFE and PVC), then immersed in a 1.0 M HCl solution or 1.0 M NaOH solution to investigate the detachment of the coatings using UV-vis spectroscopy, SEM, FTIR spectroscopy and XPS, and the effect of PEI molecular weight on the secondary grafting of heparin on the pDA/PEI coating was investigated through clotting time tests. The results showed that the detachment rates of the pDA/PEI coating (14.6%, 23.7%) co-deposited on PTFE in 1.0 M HCl or 1.0 M NaOH solutions were both lower than that of the pDA coating (35.0%, 74.6%), indicating that pDA/PEI coatings could better remain on substrates in a 1.0 M NaOH solution. Besides, pDA/PEI coatings on a PP membrane with both a higher deposition density and stability could be obtained when the mass ratio of DA/PEI was 2 : 1-1 : 1 and PEI molecular weight was 600 Da. After grafting heparin, it was found that the pDA/PEI coating with lower molecular weight (600 Da and 1800 Da) PEI could achieve a higher grafting density of heparin with a longer clotting time. Thus, the results provided better understanding about the stability of pDA/PEI coatings and efficiency of heparin grafting., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)