Modeling the effect of grazing on carbon and water use efficiencies in grasslands on the Qinghai-Tibet Plateau.

BACKGROUND: Carbon and water use efficiencies (CUE and WUE, respectively) are vital indicators of the adaptability of plants to environmental conditions. However, the effects of grazing and climate change on the spatiotemporal changes in CUE and WUE in Qinghai-Tibet Plateau grasslands (QTPG) are still unclear. RESULTS: Using the enhanced Biome-BGCMuSo model in combination with observed data, we estimated and analyzed the spatiotemporal variations in CUE and WUE and their responses to grazing in QTPG from 1979 to 2018. The mean annual CUE was 0.7066 in QTPG from 1979 to 2018 under the actual climate scenario. In general, the grassland CUE was low in the southeast and high in the northwest. Grazing generally decreased CUE in QTPG from 1979 to 2018, and there was an increasing trend in the difference in CUE between the grazing and nongrazing scenarios. The difference in CUE was generally greater in the northwest than in the southeast. The mean annual WUE was 0.5591 g C/kg H2O in QTPG from 1979 to 2018 under the actual climate scenario. After 2000, the grassland WUE exhibited a fluctuating upward trend. In general, the grassland WUE was greater in the southeast than in the northwest. Grazing generally decreased WUE in QTPG from 1979 to 2018, and there was an increasing trend in the difference in WUE between the grazing and nongrazing scenarios. The difference in WUE was generally greater in the northwest than in the southeast. CONCLUSIONS: The findings of this study suggested that the spatiotemporal changes in CUE and WUE in QTPG were closely related to changes in the natural environment and grazing management.

Predicting the potential distribution of 12 threatened medicinal plants on the Qinghai-Tibet Plateau, with a maximum entropy model.

Climate change is a vital driver of biodiversity patterns and species distributions, understanding how organisms respond to climate change will shed light on the conservation of endangered species. In this study, the MaxEnt model was used to predict the potential suitable area of 12 threatened medicinal plants in the QTP (Qinghai-Tibet Plateau) under the current and future (2050s, 2070s) three climate scenarios (RCP2.6, RCP4.5, RCP8.5). The results showed that the climatically suitable habitats for the threatened medicinal plants were primarily found in the eastern, southeast, southern, and some parts of the central regions on the QTP. Moreover, 25% of the threatened medicinal plants would have reduced suitable habitat areas within the next 30-50 years in the different future global warming scenarios. Among these medicinal plants, RT (Rheum tanguticum) would miss the most habitat (98.97%), while the RAN (Rhododendron anthopogonoides) would miss the least habitat (10.15%). Nevertheless, 33.3% of the threatened medicinal plants showed an increase in their future habitat area because of their physiological characteristics which are more adaptable to a wide range of climates. The climatic suitable habitat for 50% of the threatened medicinal plants would migrate to higher altitudes or higher latitudes regions. This study provides a data foundation for the conservation of biodiversity and wild medicinal plants on the QTP.

Diagnostic test accuracy of serum creatinine and cystatin C-based index for sarcopenia: a systematic review and meta-analysis.

BACKGROUND: Sarcopenia is an important prognostic factor, but its optimal screening methods remain challenging. Several new indices developed based on serum creatinine (Cr) and cystatin C (CysC) have been proposed to be diagnostic biomarkers for sarcopenia screening. OBJECTIVE: This review aimed to evaluate the diagnostic accuracy of serum Cr- and CysC-based indices for sarcopenia diagnosis. METHODS: We systematically searched MEDLINE, EMBASE, SCIE and SCOPUS from inception to 2 April 2023. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random-effects model was used to synthesise the pooled sensitivity, specificity and area under the curves of the summary receiver operating characteristic (SROC-AUC). RESULTS: We retrieved 936 publications and included 16 studies with 5,566 participants (mean age ranged: 51.0-78.4 years, 50.2% men). The prevalence of sarcopenia ranged from 7.8 to 69.5%. All included studies presented a moderate to high risk of bias. The serum Cr- and CysC-based indices showed moderate diagnostic accuracy for sarcopenia (pooled sensitivity: 0.67, 95% CI 0.57-0.75; pooled specificity: 076, 95% CI 0.67-0.83; pooled SROC-AUC: 0.78, 95% CI 0.74-0.81). The Cr/CysC ratio is the most widely studied index, followed by the Cr × eGFRcys index. Overall, both indicators had satisfactory and comparable performance in screening sarcopenia. CONCLUSION: Serum Cr- and CysC-based indices showed moderate diagnostic accuracy for sarcopenia. The most studied indices-the Cr/CysC ratio and Cr × eGFRcys index-had comparable diagnostic accuracy for evaluating sarcopenia and may serve as surrogate markers for sarcopenia. However, further validation is required to verify these findings.

hMSCs treatment attenuates murine herpesvirus-68 (MHV-68) pneumonia through altering innate immune response via ROS/NLRP3 signaling pathway.

Immunocompromised individuals are particularly vulnerable to viral infections and reactivation, especially endogenous herpes viruses such as Epstein-Barr virus (EBV), a member of oncogenic gamma-herpesviruses, which are commonly linked to pneumonia and consequently significant morbidity and mortality. In the study of human and animal oncogenic gammaherpesviruses, the murine gamma-herpesviruses-68 (MHV-68) model has been applied, as it can induce pneumonia in immunocompromised mice. Mesenchymal stem cell (MSC) treatment has demonstrated therapeutic potential for pneumonia, as well as other forms of acute lung injury, in preclinical models. In this study, we aim to investigate the therapeutic efficacy and underlying mechanisms of human bone marrow-derived MSC (hMSC) on MHV-68-induced pneumonia. We found that intravenous administration of hMSCs significantly reduced lung damages, diminished inflammatory mediators and somehow inhibited MHV-68 replication. Furthermore, hMSCs treatment can regulate innate immune response and induce macrophage polarization from M1 to M2 phenotype, could significantly alter leukocyte infiltration and reduce pulmonary fibrosis. Our findings with co-culture system indicated that hMSCs effectively reduced the secretion of of inflammation-related factors and induced a shift in macrophage polarization, consistent with in vivo results. Further investigations revealed that hMSCs treatment suppressed the activation of macrophage ROS/NLRP3 signaling pathway in vivo and in vitro. Moreover, administration of MCC950, a selective NLRP3 inhibitor has been shown to effectively reduce ROS production and subsequently alleviate inflammation induced by MHV-68. Taken together, our work has shown that hMSCs can effectively protect mice from lethal MHV-68 pneumonia, which may throw new light on strategy for combating human EBV-associated pneumonia.

Role of gender and age in features of Wilson's disease.

Background: Wilson's disease (WD) is a recessive genetic disorder characterized by copper metabolism dysfunction. It is difficult to obtain an accurate diagnosis due to its variable clinical presentation. This study aimed to describe the clinical characteristics and diagnostic particularities in a series of Chinese WD patients. Methods: The medical records of 371 patients with WD retrieved from January 2005 to December 2020 were retrospectively reviewed. Results: The incidence of WD has a male predominance in the adult population. However, the difference in sex distribution is not significant in the pediatric population. Females have an earlier symptom onset than males. The most common initial symptoms were neuropsychiatric manifestations both in the pediatric population (49.7%) and adult population (69.8%), and there was a male predominance (61.8%). Eighty-two percent of patients presented with more than two neurologic symptoms. Fifty-two (14%) patients presented with psychiatric symptoms. The most common WD phenotype was the neuropsychiatric form (48%). The age of onset occurred earlier in patients with the hepatic phenotype than in those with the neuropsychiatric phenotype. Moreover, there was a significant difference in sex distribution regarding phenotype. Females presented with a hepatic phenotype more often than males, and the neuropsychiatric phenotype occurred more frequently in males with an older onset age. Further study showed that the age at onset was a deciding factor for predicting the neuropsychiatric phenotype among the hepatic phenotype. However, sex did not correlate with the phenotype. Conclusion: Males seem to have a higher disease susceptibility, with symptom onset later than females. Males frequently present with a neuropsychiatric phenotype, while females present with a hepatic phenotype. Age at onset was a deciding factor for predicting the WD phenotype. Further studies focusing on the effect of estrogens on the pathology of WD are suggested.

A Novel Locking Buttress Plate Designed for Simultaneous Medial and Posterolateral Tibial Plateau Fractures: Concept and Comparative Finite Element Analysis.

OBJECTIVE: The complex tibial plateau fractures involving both medial and posterolateral columns are of frequent occurrence in clinics, but the existing fixation system cannot deal with medial and posterolateral fragments simultaneously. Therefore, a novel locking buttress plate named as medial and posterior column plate (MPCP) was designed in this study to fix the simultaneous medial and posterolateral tibial plateau fractures. Meanwhile, the comparative finite element analysis (FEA) was conducted to investigate the discrepancy between MPCP and traditional multiple plates (MP + PLP) in their biomechanical characteristics. METHODS: Two 3D finite element models of simultaneous medial and posterolateral tibial plateau fracture fixed with MPCP and MP + PLP system, respectively, was constructed. To imitate the axial stress of knee joint in ordinary life, diverse axial forces with 100, 500, 1000, and 1500 N were applied in the two fixation models, and then the equivalent displacement and stress nephograms and values were obtained. RESULTS: The similar trend of displacement and stress increasing with the loads was observed in the two fixation models. However, several heterogeneities of displacement and stress distribution were found in the two fixation models. The max displacement and von Mises stress values of plates, screws, and fragments in the MPCP fixation model were significantly smaller than that in the MP + PLP fixation model, except for the max-shear stress values. CONCLUSION: As a single locking buttress plate, the MPCP system showed the excellent benefit on improving the stability of the simultaneous medial and posterolateral tibial plateau fractures, compared with the traditional double plate fixation system. However, the excessive shear stress around screw holes should be paid attention to prevent trabecular microfracture and screw loosening.

The valuable role of dynamic 18F FDG PET/CT-derived kinetic parameter Ki in patients with nasopharyngeal carcinoma prior to radiotherapy: A prospective study.

BACKGROUND AND PURPOSE: Dynamic positron emission tomography/computed tomography (PET/CT) served the potential role of characterizing malignant foci. The main objective of this prospective study was to explore the advantage of dynamic PET/CT imaging in characterizing nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Patients with probable head and neck disease underwent a local dynamic PET/CT scan followed by a whole-body static scan. Patlak analysis was used to generate parametric influx rate constant (Ki) images from 48 frames obtained from a dynamic PET/CT scan. By delineating the volumes-of-interest (VOIs) of: primary tumor (PT), lymph node (LN), and normal nasopharyngeal tissues (N), we acquired the corresponding Ki mean and SUVmean of each site respectively to perform the quantitative statistical analysis. RESULTS: Qualified images of 71 patients with newly diagnosed NPC and 8 without nasopharyngeal malignant lesions were finally included. We found the correlations between Ki mean-PT and critical clinical features, including clinical stage (r = 0.368), T category (r = 0.643) and EBV-DNA copy status (r = 0.351), and Ki mean-PT differed within the group. SUVmean-PT showed correlations with clinical stage (r = 0.280) and T category (r = 0.472), but could hardly differ systematically within group of clinical features except T category. Ki mean-LN offered the positive correlations with N category (r = 0.294), M category (r = 0.238) and EBV-DNA copy status (r = 0.446), and differed within the group. In addition, Ki mean represented a sensitivity of 94.4 % and a specificity of 100 %, in distinguishing NPC from the non-NPC, when the cut-off was defined as 0.0106. When the cut-off of SUV being defined as 2.03, the sensitivity and specificity were both 100 %. CONCLUSION: Our research confirmed Ki compared favorably to SUV in characterizing NPC and found that Ki can serve as an effective imaging marker of NPC.

Pain as a risk factor for incident sarcopenia in community-dwelling older adults: A 1-year prospective cohort study.

BACKGROUND: Pain-related muscle disuse and inflammatory reactions may increase the risk of sarcopenia among older adults with pain. Although several studies have examined the association between pain and sarcopenia, the findings are mixed. In the present study, we examined the association of pain as well as pain intensity and location with incident sarcopenia among community-dwelling older adults and explored whether this association differed between men and women. METHODS: Pain characteristics, including the presence of pain, intensity (mild, moderate, and severe), and location (multisite, low back, joint, and chest), were self-reported at baseline. Sarcopenia was identified according to the consensus of the Asin Working Group for Sarcopenia 2019 at baseline and 1 year later. Multivariable Poisson regression was used to determine the association of pain status, intensity, and location with incident sarcopenia, respectively. RESULTS: Eight hundred seventy-three participants (67.1 ± 4.9 years, 524 female) who were free of sarcopenia at baseline were included, of which 64 (7.3%) developed sarcopenia in the follow-up. The presence of pain was significantly associated with an increased risk of incident sarcopenia in older adults (adjusted RR = 1.83, 95% CI = 1.16-2.89), with a significant risk accumulation in incident sarcopenia upon higher pain intensity. Older adults with multisite pain, low back pain, or joint pain were more likely to develop sarcopenia. Although older men reported a lower prevalence and intensity of pain, their risk of sarcopenia during follow-up was generally more pronounced than older women. CONCLUSIONS: Older adults with pain had a significantly higher risk of incident sarcopenia, with a significant risk accumulation in sarcopenia development upon higher pain intensity and specific pain location. Additional attention is needed to identify older adults with pain and to implement timely pain interventions to prevent sarcopenia. High-quality randomized controlled trials are warranted to verify the clinical significance of the present study.

Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): An open label, single-arm, phase Ib clinical trial.

BACKGROUND: Neoadjuvant programmed death receptor-1 (PD-1) inhibitors have drawn increasing attention in locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the safety and efficacy of gemcitabine and cisplatin (GP), combined with a PD-1 inhibitor, in patients with locally advanced HNSCC. MATERIALS AND METHODS: A total of 23 eligible patients were administered two cycles of toripalimab and GP followed by surgical resection. The primary endpoints were safety, treatment-related adverse events (TRAEs), and non-operation delay rates. The secondary endpoints consisted of pathological complete response (pCR) rate, major pathological response (MPR) rate, objective response rate (ORR), and R0 resection rate. RESULTS: The incidence of TRAEs from grades 1 to 4 was 43.5%, 34.8%, 13.0%, and 8.7%, respectively. Grade 3/4 TRAEs included neutropenia, fatigue, hyperglycemia, nausea and vomiting, decreased appetite, rash, and diarrhea. No treatment-related surgical delay was observed. The radiographic response rates were 5.0% (CR), 40.0% (PR), and 55.0% (SD). The ORR reached 45.0%. Eighteen patients underwent successful surgical resection. The R0 resection rate was 100%. The pathological response rates were 16.7% (pCR), 27.8% (MPR, two of five near-pCR), 16.7% (PPR), and 38.8% (NPR). CD4, CD8, CD20, and CD38 expression in the tumors significantly increased after neoadjuvant chemotherapy. The increase in CD20 levels after neoadjuvant treatment in patients with pCR/MPR was significantly higher than in patients with PPR/NPR. CONCLUSION: Triweekly neoadjuvant toripalimab-GP is feasible and achieves promising pCR and MPR rates in patients with resectable locally advanced HNSCC. TRIAL REGISTRATION: Chinese clinical trial registry, ChiCTR2100043743, Registered 27 Febrary 2021- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=120570.

Effects of establishing cultivated grassland on soil organic carbon fractions in a degraded alpine meadow on the Tibetan Plateau.

Background: The degradation of alpine meadows has induced substantial losses of soil organic carbon (SOC) on the Tibetan Plateau. A commonly-used method for rehabilitating degraded alpine meadows in this region is establishing cultivated grasslands through sowing seed mixtures, but its impact on the biochemical stability of SOC has remained inadequately explored. Methods: In this study, a total of 20 composited 0-20 cm soil samples were collected from a heavily degraded alpine meadow (DM) and three adjacent cultivated grasslands established for 3 years (CG3), 12 years (CG12), and 17 years (CG17) on the eastern Tibetan Plateau, and the SOC pool was separated into labile C pool I (LOC I), labile C pool II (LOC II), and recalcitrant C pool (ROC) in order to investigate changes in contents of SOC fractions that have different biochemical stabilities after the establishment of cultivated grassland. Results: Although the establishment of cultivated grasslands led to increases in soil total organic C content, the increase was only significant in samples with 17 years of cultivation. We found that the contents of the three SOC fractions were higher at CG3 and CG12 compared with those in the DM, and the differences were only significant for soil LOC II. By comparison, 17 years of cultivation led to significant increases in all of the SOC fraction contents. The results implied that different cultivation years had distinct impacts on SOC fractions in cultivated grasslands, and longer cultivation years contributed to accumulated soil ROC. The recalcitrance index of SOC in the DM was higher than that at CG3 and CG12, but lower than that at CG17. This was possibly due to the generally low litter quality of cultivated grasslands, which led to a slow release of complex compounds to soils. Moreover, it was observed that soil C:N ratio was a potential indicator of SOC biochemical stability because of their close correlation. Conclusions: Our findings suggest that the long-term establishment of cultivated grasslands on DM is a promising solution to recovering both the quantity and stability of SOC on the Tibetan Plateau.

Insight of a Metabolic Prognostic Model to Identify Tumor Environment and Drug Vulnerability for Lung Adenocarcinoma.

Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients' prognosis.

Artificial stem cells mediated inflammation-tropic delivery of antiviral drugs for pneumonia treatment.

BACKGROUND: Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity. METHODS: The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo. RESULTS: MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently. CONCLUSION: The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.

Tumor Microbiome in Nasopharyngeal Carcinoma and Its Association With Prognosis.

Introduction: Previous studies have reported a close relationship between cancer and microbes, particularly gut and tumor microbiota; however, the presence of tumor microbiome in nasopharyngeal carcinoma (NPC) and its role in the prognosis of NPC remain unclear. Methods: We collected 64 samples including tissues from 50 patients with NPC (NPC group) and 14 patients with chronic nasopharyngitis (control group) receiver operating characteristics and we applied 16S ribosome RNA gene sequencing of all samples to assess microbiome profiles and immunohistochemistry to detect tumor microbiome in NPC. Results: Patients in the control group harbored higher species diversity than those in the NPC group; however, the beta diversity was more distinct in the NPC group. In total, three genera with statistically significant differences between the two groups were identified. The area under the receiver operating characteristics (ROC) curve (AUC) was calculated using the relative abundance of these three significant genera, and a value of 0.842 was achieved. Furthermore, Turicibacter was confirmed as a potentially independent prognostic factor for NPC patients, and the progression-free survival (PFS) was markedly prolonged in patients with a low relative abundance of Turicibacter compared to patients with a high relative abundance of this genus (cutoff: 0.0046, hazard ratio: 5.10, 95% confidence interval: 2.04-12.77, p = 0.004). Conclusions: The present study provided strong evidence of a correlation between tumor microbiome and NPC; the tumor microbiome may be considered a biomarker for early NPC diagnosis. Turicibacter potentially served as a independently prognostic indicator for NPC patients.

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OBJECTIVES: To study the characteristics of amino acid metabolism in preterm infants in Guangxi, China. METHODS: A retrospective analysis was performed on the medical data of 30 757 neonates who underwent the screening for inherited metabolic diseases and had negative results in Guangxi Neonatal Disease Screening Center from 2018 to 2020. Among these neonates, there were 28 611 normal full-term infants (control group) and 2 146 preterm infants (preterm birth group). According to gestational age, the preterm infants were further divided into four groups: very preterm (n=209), moderately preterm (n=307), and late preterm group (n=1 630). According to birth weight, they were divided into three groups: very low birth weight group (n=161), low birth weight group (n=1 085), and normal birth weight group (n=900). According to blood collection time, they were divided into three groups: 3-7 days group (n=1 664), 8-14 days group (n=314) and 15-28 days group (n=168). Tandem mass spectrometry was performed to measure the levels of 11 amino acids in dried blood spots, which were then compared between groups. RESULTS: After adjustment for confounding factors, there were significant differences in the levels of 11 amino acids among different gestational age groups (P<0.05), and significant differences were observed in the levels of the 11 amino acids between the control group and the various preterm groups (except for citrulline and methionine in the late preterm group). There were significant differences in the levels of 11 amino acids among different birth weight groups (P<0.05). Except for ornithine, there were significant differences in the levels of other amino acids among the different blood collection time groups (P<0.05). CONCLUSIONS: Gestational age, birth weight and blood collection time all affect amino acid metabolism in preterm infants in Guangxi, China. This provides a basis for the laboratory to establish the reference standard and clinical interpretation of blood amino acid levels in preterm infants, and to improve the nutritional metabolism of preterm infants.

Black phosphorus nanoparticles for dual therapy of non-small cell lung cancer.

Lung cancer remains one of the leading causes of death in humans. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) commonly used to suppress tumour growth. However, constantly use of gefitinib results in drug-resistance, reduced efficacy and undesired side effects. To circumvent these drawbacks, targeted and photothermal therapies have emerged as effective strategies. Herein, we are first to adopt a black phosphorus (BP) nanoparticle-based novel delivering strategy by combining gefitinib and cancer cytomembrane to treat non-small cell lung cancer (NSCLC). In these gefitinib-containing nano-carriers, cyanine 5 (Cy5) biotin-labelled BP was incorporated with cancer membrane and then consists of a nanomaterial (BPGM), which enabled to deliver gefitinib to the tumours effectively. The combination of BPGM showed reinforcing effects to suppress NSCLC cells and xenograft tumours without apparent adverse effects both in vitro and in vivo. BPGM facilitated the delivery of gefitinib to tumour tissue and extended its retention time within tumours. These studies thus suggest that BP may serve as novel delivery strategy for lung cancer.

Disulfiram attenuates MCMV-Induced pneumonia by inhibition of NF-κB/NLRP3 signaling pathway in immunocompromised mice.

Cytomegalovirus (CMV) pneumonia in immunocompromised individuals is associated with damaging hyperinflammation and leads to high morbidity and mortality. It is urgently needed to develop new strategies to treat CMV-induced pneumonia. As disulfiram (DSF) reportedly inhibits inflammatory responses in different disease models, its therapeutic effects in CMV-induced pneumonia are proposed. In this study, we demonstrated that DSF effectively attenuated pulmonary injury and improved survival in murine CMV (MCMV) pneumonia model. DSF treatment inhibited lung inflammatory responses, e.g. reducing pro-inflammatory cytokines, upregulating anti-inflammatory cytokine, and lowering the accumulation of leukocytes in the lung. Similar to the in vivo results, DSF attenuated inflammatory responses and modulated NF-κB/NLRP3 inflammasome activation in MCMV-infected BMDMs. Furthermore, DSF reduced pulmonary fibrosis and viral loads in MCMV pneumonia mice and BMDMs. The mechanism of anti-inflammatory effects of DSF may due to its regulating NF-κB signaling and NLRP3 inflammasome activation. Collectively, our results suggest that DSF-mediated anti-hyperinflammatory effects have potentials for therapy of human CMV pneumonia.

Combination of Tumor Mutational Burden and Specific Gene Mutations Stratifies Outcome to Immunotherapy Across Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Purpose: To investigate the prognostic significance of tumor mutational burden (TMB) combined with specific prognosis-related gene mutations in immunotherapy for recurrent and metastatic head and neck squamous cell carcinoma (r/m HNSCC). Methods: One hundred thirty-two r/m HNSCC patients from the Morris and Allen cohorts had undergone immunotherapy. We constructed the immunotherapy-related gene prognostic index TP-PR combining TMB and PIK3CA, TP53, or ROS1 mutation. And we analyzed the differences in overall survival (OS) and immune cell infiltration between samples in different groups. The association of each signature's single-sample gene set enrichment analysis scores with TP-PR was tested using Spearman's correlation test. Results: The median OS of the patients with high TMB (TMB ≥10 mut/Mb) who received immunotherapy for r/m HNSCC was 2.5 times as long as that of the patients with low TMB (25 vs. 10 months). More importantly, the high TP-PR (TP-PR >0) group had better median OS (25 vs. 8 months) than the low TP-PR (TP-PR ≤0) group. CD8+ T cells and activated memory CD4+ T cells in the tissues of the patients with high TP-PR were higher than those in the patients with low TP-PR. Results showed that TP-PR stratification had a higher area under the curve (AUC) value (0.77, 95% CI 0.86-0.68) compared with TMB stratification (0.56, 95% CI 0.68-0.44). The differential gene expression in the high and low TP-PR groups mainly influenced metabolism-related signaling pathways. Conclusion: TP-PR was an effective predictor of immunotherapy outcome for r/m HNSCC, which might be better than TMB alone. Patients with high TP-PR had a better survival benefit than had the patients with low TP-PR.

Comparisons between Direct Anterior Approach and Lateral Approach for Primary Total Hip Arthroplasty in Postoperative Orthopaedic Complications: A Systematic Review and Meta-Analysis.

The direct anterior approach (DAA) are attracting increasing attention from orthopedic arthroplasty surgeons, due to the less blood loss, mild soft tissue invasion, rapid rehabilitation and shorter length of stay. However, the longer learning curve in DAA can give rise to several complications, such as intraoperative femoral fracture, lateral femoral cutaneous nerve injury, wound-healing problem, premature revision and so on. This meta-analysis was performed to compare the rate of postoperative orthopedic complications between the DAA and the lateral approach (LA). All studies involving the comparison of postoperative orthopedic complications after THA between the DAA and LA group were searched in 7 databases prior to October 2020. The odds ratio (OR) with the 95% confidence intervals (CI) for each outcome was calculated by using the RevMan 5.3. The methodological bias of included studies was evaluated and the potential heterogeneity sources were analyzed. Thirteen comparative studies including a total of 24853 hips (9575 hips in the DAA group and 15278 hips in the LA group) were eligible for this meta-analysis. There was no significant difference in the rate of surgical site infection [2.59% vs 2.14% (OR = 0.98; 95% CI: 0.59-1.61, P = 0.93)], heterotopic ossification [12.16% vs 26.47% (OR = 0.46; 95% CI: 0.20-1.07, P = 0.07)] and reoperation [2.70% and 2.11% respectively (OR = 0.93; 95% CI: 0.68-1.26, P = 0.64)] between the DAA and LA groups. Although a lower rate in prosthesis malposition [36.19% vs 54.86% (OR = 0.50; 95% CI: 0.35-0.73, P = 0.0003)], leg length discrepancy [1.87% vs 2.37% (OR = 2.35; 95% CI: 1.30-4.25, P = 0.005)] and Trendelenburg gait [1.68% vs 4.78% (OR = 0.29; 95% CI: 0.13-0.65, P = 0.003)] was observed in the DAA group, a higher rate in dislocation [0.77% vs 0.18% (OR = 3.73; 95% CI: 2.35-5.94, P< 0.00001)], periprosthetic fracture [1.05% vs 0.41% (OR = 2.38; 95% CI: 1.58-3.58, P< 0.0001)], prosthesis loosening [0.61% vs 0.37% (OR = 1.66; 95% CI: 1.05-2.62, P = 0.03)] and nerve injury [0.95% vs 0% (OR = 7.12; 95% CI: 1.66-30.48, P = 0.008)] was found in the DAA group. This meta-analysis demonstrated several evidences indicating that the DAA exhibited the advantages in the accurate prosthesis placement and less damage of surrounding hip musculature. However, a higher rate in dislocation, periprosthetic fracture, prosthesis loosening and nerve injury in the DAA group should be paid more attention, due to the limited exposure and a longer learning curve, compared to the LA.

The Antibacterial Effects of Supermolecular Nano-Carriers by Combination of Silver and Photodynamic Therapy.

The over-use of antibiotics has promoted multidrug resistance and decreased the efficacy of antibiotic therapy. Thus, it is still in great need to develop efficient treatment strategies to combat the bacteria infection. The antimicrobial photodynamic therapy (aPDT) and silver nanoparticles have been emerged as effective antibacterial methods. However, the silver therapy may induce serious damages to human cells at high concentrations and, the bare silver nanoparticles may rapidly aggregate, which would reduce the antibacterial efficacy. The encapsulation of sliver by nano-carrier is a promising way to avoid its aggregation and facilitates the co-delivery of drugs for combination therapy, which does not require high concentration of sliver to exert antibacterial efficacy. This work constructed a self-assembled supermolecular nano-carrier consisting of the photosensitizers (PSs), the anti-inflammatory agent and silver. The synthesized supermolecular nano-carrier produced reactive oxygen species (ROS) under the exposure of 620-nm laser. It exhibited satisfying biocompatibility in L02 cells. And, this nano-carrier showed excellent antibacterial efficacy in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as indicated by bacterial growth and colony formation. Its antibacterial performance is further validated by the bacteria morphology through the scanning electron microscope (SEM), showing severely damaged structures of bacteria. To summary, the supermolecular nano-carrier TCPP-MTX-Ag-NP combining the therapeutic effects of ROS and silver may serve as a novel strategy of treatment for bacterial infection.

Knockout of NOS2 Promotes Adipogenic Differentiation of Rat MSCs by Enhancing Activation of JAK/STAT3 Signaling.

Mesenchymal stromal cells (MSCs) are a heterogeneous population of cells that possess multilineage differentiation potential and extensive immunomodulatory properties. In mice and rats, MSCs produce nitric oxide (NO), as immunomodulatory effector molecule that exerts an antiproliferative effect on T cells, while the role of NO in differentiation was less clear. Here, we investigated the role of NO synthase 2 (NOS2) on adipogenic and osteogenic differentiation of rat MSCs. MSCs isolated from NOS2-null (NOS2-/-) and wild type (WT) Sprague-Dawley (SD) rats exhibited homogenous fibroblast-like morphology and characteristic phenotypes. However, after induction, adipogenic differentiation was found significantly promoted in NOS2-/- MSCs compared to WT MSCs, but not in osteogenic differentiation. Accordingly, qRT-PCR revealed that the adipogenesis-related genes PPAR-γ, C/EBP-α, LPL and FABP4 were markedly upregulated in NOS2-/- MSCs, but not for osteogenic transcription factors or marker genes. Further investigations revealed that the significant enhancement of adipogenic differentiation in NOS2-/- MSCs was due to overactivation of the STAT3 signaling pathway. Both AG490 and S3I-201, small molecule inhibitors that selectively inhibit STAT3 activation, reversed this adipogenic effect. Furthermore, after high-fat diet (HFD) feeding, knockout of NOS2 in rat MSCs resulted in significant obesity. In summary, NOS2 is involved in the regulation of rat MSC adipogenic differentiation via the STAT3 signaling pathway.