Alternative Linkage Chemistries in the Chemoenzymatic Synthesis of Microviridin-Based Cyclic Peptides.

Engineering biosynthetic pathways to ribosomally synthesized and post-translationally modified peptides (RiPPs) offers several advantages for both in vivo and in vitro applications. Here we probe the ability of peptide cyclases to generate trimacrocycle microviridin analogs with non-native cross-links. The results demonstrate that diverse chemistries are tolerated by macrocyclases in the ATP-grasp family and allow for the construction of unique cyclic peptide architectures that retain protease inhibition activity. In addition, cocomplex structures of analogs bound to a model protease were determined, illustrating how changes in functional groups maintain peptide conformation and target binding.

Comparative Mitogenomic Analyses of Darkling Beetles (Coleoptera: Tenebrionidae) Provide Evolutionary Insights into tRNA-like Sequences.

Tenebrionidae is widely recognized owing to its species diversity and economic importance. Here, we determined the mitochondrial genomes (mitogenomes) of three Tenebrionidae species (Melanesthes exilidentata, Anatolica potanini, and Myladina unguiculina) and performed a comparative mitogenomic analysis to characterize the evolutionary characteristics of the family. The tenebrionid mitogenomes were highly conserved with respect to genome size, gene arrangement, base composition, and codon usage. All protein-coding genes evolved under purifying selection. The largest non-coding region (i.e., control region) showed several unusual features, including several conserved repetitive fragments (e.g., A+T-rich regions, G+C-rich regions, Poly-T tracts, TATA repeat units, and longer repetitive fragments) and tRNA-like structures. These tRNA-like structures can bind to the appropriate anticodon to form a cloverleaf structure, although base-pairing is not complete. We summarized the quantity, types, and conservation of tRNA-like sequences and performed functional and evolutionary analyses of tRNA-like sequences with various anticodons. Phylogenetic analyses based on three mitogenomic datasets and two tree inference methods largely supported the monophyly of each of the three subfamilies (Stenochiinae, Pimeliinae, and Lagriinae), whereas both Tenebrioninae and Diaperinae were consistently recovered as polyphyletic. We obtained a tenebrionid mitogenomic phylogeny: (Lagriinae, (Pimeliinae, ((Tenebrioninae + Diaperinae), Stenochiinae))). Our results provide insights into the evolution and function of tRNA-like sequences in tenebrionid mitogenomes and contribute to our general understanding of the evolution of Tenebrionidae.

The effectiveness and safety of annulus closure device implantation in lumbar discectomy for patients with lumbar disc herniation: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to systematically estimate the effectiveness and safety of annulus closure device (ACD) implantation in discectomy for patients with lumbar disc herniation (LDH). METHODS: A systematic search was performed on PubMed, EMBASE and the Cochrane Library for randomized controlled trial (RCT) from inception until April 16, 2022. Trials which investigated comparisons between with and without ACD implantation in discectomy for LDH patients were identified. RESULTS: In total, five RCTs involving 2380 patients with LDH underwent discectomy were included. The included patients were divided into ACD group and control group (CTL). Significant differences were found in the rate of re-herniation (ACD: 7.40%, CTL: 17.58%), reoperation (ACD: 5.39%, CTL: 13.58%) and serious adverse event (ACD: 10.79%, CTL: 17.14%) between ACD group and CTL group. No significant difference was found in VAS-BACK, VAS-LEG, ODI and SF-12 PCS between ACD and CTL. The surgical time of ACD was longer than CTL with statistical significance. In subgroup analyses based on discectomy type, significant differences were found in the rate of re-herniation (ACD: 10.73%, CTL: 21.27%), reoperation (ACD: 4.96%, CTL: 13.82%) and serious adverse event (ACD: 7.59%, CTL: 16.89%) between ACD and CTL in limited lumbar discectomy (LLD). CONCLUSION: Discectomy either with or without ACD implantation is considered to achieve similar clinical outcomes. Whereas, the ACD implantation in LLD is associated with lower re-herniation and reoperation rate but prolonged surgical time for LDH patients. Researches on cost-effectiveness and effect of ACD implantation in different discectomy are needed in the future.

Global research productivity in the field of discectomy on lumbar disc herniation: A systematic bibliometric analysis.

Objective: To evaluate the global research productivity in the field of discectomy for lumbar disc herniation (LDH) through bibliometric analysis and mapping knowledge domains. Methods: A systematic literature search was performed on the Web of Science (WoS), including the Science Citation Index Expanded (SCIE) database and PubMed. The number of publications, countries of publications, journals of publications, total citation frequency, impact factors of journals, and Institutional sources were analyzed by Microsoft Excel 2019, the Online Analysis Platform of Bibliometrics, and VOSviewer. Hotspots were also analyzed and visualized based on VOSviewer. Results: A total of 2,066 papers were identified. The United States ranked first in the number of total citations (7,970). China ranked first in the number of publications (556, 26.9%), which has surpassed the United States in terms of the number of publications published annually since 2016. Wooridul Spine Hospital published the most papers (43). For journals, Spine has published the largest number of papers (289) in this field with the most citation frequencies (6,607). Hotspots could be divided into three clusters: surgery, lumbar disc herniation, and diagnoses. The most recent topic that appeared was symptomatic re-herniation. Conclusions: The United States is the most significant contributor to the development of discectomy for LDH. The current research focus of discectomy on LDH was the comparison between surgical approaches and evaluation of current minimally invasive discectomy. At present, minimally invasive techniques, such as endoscopic discectomy, cannot completely replace non-endoscopic discectomy (open discectomy and microdiscectomy) through bibliometric analysis and mapping knowledge domains.

Transcriptomic data recover a new superfamily-level phylogeny of Cucujiformia (Coleoptera, Polyphaga).

Cucujiformia, the largest taxon in the order Coleoptera, exhibits extraordinary morphological, ecological, and behavioral diversity. This infraorder is currently divided into seven superfamilies, but considerably incongruent relationships among superfamilies have been reported by recent phylogenomic studies. Here, we combined the 21 newly sequenced transcriptomes representing six superfamilies with nine previously published cucujiform genomes/transcriptomes to elucidate the phylogeny and evolution of Cucujiformia. The monophyly of each of five superfamilies were consistently supported by all phylogenetic analyses based on the twelve datasets (matrix occupancy, amino acid and nucleotide data) and the two analytical methods (maximum likelihood method and Bayesian inference). Both the amino acid datasets and the RY recoded nucleotide datasets recovered the monophyly of Cucujoidea. Topology test results statistically supported the following robust superfamily-level phylogeny in Cucujiformia: (Coccinelloidea, (Cleroidea, (Tenebrionoidea, (Cucujoidea, (Chrysomeloidea, Curculionoidea))))). Our divergence time analyses recovered a Permian origin of Cucujiformia and a Jurassic-Cretaceous origin of most superfamilies. The diversification of phytophagous beetles that occurred in the Cretaceous can be attributed to its co-evolution with angiosperms, supporting the hypothesis of a Cretaceous Terrestrial Revolution.

Tuberculosis-associated hemophagocytic lymphohistiocytosis misdiagnosed as systemic lupus erythematosus: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with rapid progression and high mortality. HLH occurs mostly due to infection, malignant tumors, and immune disorders. Among infections that cause HLH, viral infections, especially Epstein-Barr virus infections, are common, whereas tuberculosis is rare. Tuberculosis-associated HLH has a wide range of serological and clinical manifestations that are similar to those of systemic lupus erythematosus (SLE). CASE SUMMARY: This study describes a case of tuberculosis-associated HLH misdiagnosed as SLE because of antinuclear antibody (ANA), Smith (Sm) antibody and lupus anticoagulant positivity; leukopenia; thrombocytopenia; pleural effusion; decreased C3, quantitatively increased 24 h urinary protein and fever. The patient was initially treated with glucocorticoids, which resulted in peripheral blood cytopenia and symptom recurrence. Then, caseating granulomas and hemophagocytosis were observed in her bone marrow. She was successfully treated with conventional category 1 antituberculous drugs. In addition, we reviewed the literature on tuberculosis-associated HLH documented in PubMed, including all full-text articles published in English from December 2009 to December 2019, and summarized the key points, including the epidemiology, clinical manifestations, diagnosis, and treatment of tuberculosis-associated HLH and the differences of the present case from previous reports. CONCLUSION: Tuberculosis should be considered in patients with fever or respiratory symptoms. Antituberculous drugs are important for treating tuberculosis-associated HLH.

Mitochondrial phylogenomics provides insights into the phylogeny and evolution of spiders (Arthropoda: Araneae).

Spiders are among the most varied terrestrial predators, with highly diverse morphology, ecology, and behavior. Morphological and molecular data have greatly contributed to advances in the phylogeny and evolutionary dynamics of spiders. Here, we performed comprehensive mitochondrial phylogenomics analysis on 78 mitochondrial genomes (mitogenomes) representing 29 families; of these, 23 species from eight families were newly generated. Mesothelae retained the same gene arrangement as the arthropod ancestor ( Limulus polyphemus), while Opisthothelae showed extensive rearrangement, with 12 rearrangement types in transfer RNAs (tRNAs) and control region. Most spider tRNAs were extremely truncated and lacked typical dihydrouridine or TΨC arms, showing high tRNA structural diversity; in particular, trnS1 exhibited anticodon diversity across the phylogeny. The evolutionary rates of mitochondrial genes were potentially associated with gene rearrangement or truncated tRNAs. Both mitogenomic sequences and rearrangements possessed phylogenetic characteristics, providing a robust backbone for spider phylogeny, as previously reported. The monophyly of suborder, infraorder, retrolateral tibial apophysis clade, and families (except for Pisauridae) was separately supported, and high-level relationships were resolved as (Mesothelae, (Mygalomorphae, (Entelegynae, (Synspermiata, Hypochilidae)))). The phylogenetic positions of several families were also resolved (e.g., Eresidae, Oecobiidae and Titanoecidae). Two reconstructions of ancestral web type obtained almost identical results, indicating that the common ancestor of spiders likely foraged using a silk-lined burrow. This study, the largest mitochondrial phylogenomics analysis of spiders to date, highlights the usefulness of mitogenomic data not only for providing efficient phylogenetic signals for spider phylogeny, but also for characterizing trait diversification in spider evolution.

Global Research Trends in Robotic Applications in Spinal Medicine: A Systematic Bibliometric Analysis.

OBJECTIVE: We systematically evaluated the global research trends in robotic application on the spine through bibliometric analysis and mapping knowledge domains. METHODS: A systematic literature search was performed of the PubMed and Web of Science, including the Science Citation Index Expanded, databases. The number, countries, journals, and authors of the publications, total citations, average publication year, and institution sources were analyzed using Microsoft Excel, the Online Analysis Platform of Bibliometrics, and VOSviewer. The hotspots were analyzed and visualized using VOSviewer. RESULTS: We identified a total of 2135 publications. The United States ranked first in the number of publications (n = 824; 38.63%) and frequency of citations (n = 29,075). Northwestern University had the highest number of publications (n = 67) and Harvard University the highest number of citations (n = 4198). The Journal of NeuroEngineering and Rehabilitation published the largest number of reports (n = 73), and the most frequently cited journal was Nature (n = 3844 citations). The research hotspots were divided into 3 categories analyzed by VOSviewer: rehabilitation, basic science, and surgery. According to the average publication year, the most recent hotspot was radiation exposure, and the earliest hotspot was radiosurgery. CONCLUSIONS: The number of studies of robotic application on the spine has continued to increase. The United States was the greatest contributor to robotic applications on the spine. Robot-assisted rehabilitation for neurological and orthopedic lesions is still a major research hotspot. The range of robotic applications on the spine has expanded from assisted rehabilitation to assisted rehabilitation and surgery.

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA.

BACKGROUND: Cancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial. RESULTS: In this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro. CONCLUSIONS: Affinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist, providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy.

Cinnamaldehyde and Doxorubicin Co-Loaded Graphene Oxide Wrapped Mesoporous Silica Nanoparticles for Enhanced MCF-7 Cell Apoptosis.

BACKGROUND: Combined chemotherapy is often affected by the different physicochemical properties of chemotherapeutic drugs, which should be improved by the reasonable design of co-loaded preparations. PURPOSE: A kind of simple but practical graphene oxide (GO) wrapped mesoporous silica nanoparticles (MSN) modified with hyaluronic acid (MSN@GO-HA) were developed for the co-delivery of cinnamaldehyde (CA) and doxorubicin (DOX), in order to enhance their combined treatment on tumor cells and reduce their application defects. METHODS: The MSNCA@GODOX-HA was constructed by MSNCA (loading CA via physical diffusion) and GODOX-HA (modified with HA and loading DOX via π-π stacking) through the electrostatic adsorption, followed by the physicochemical characterization, serum stability and in vitro release study. Cytotoxicity on different cells was detected, followed by the tumor cell uptake tests. The intracellular reactive oxygen species (ROS) changes, mitochondrial functions and activities of caspase-3/-9 in MCF-7 cells were also evaluated, respectively. RESULTS: The MSNCA@GODOX-HA nanoparticles kept stable in FBS solution and achieved pH-responsive release behavior, which was beneficial to increase the accumulation of CA and DOX in tumor cells to enhance the treatment. MSNCA@GODOX-HA exerted higher cytotoxicity to MCF-7 human breast cancer cells than H9c2 cardiac myocyte cells, which were not only attributed to the active targeting to tumor cells by HA, but also related with the activation of intrinsic apoptotic pathway in MCF-7 cells induced by CA, which was mediated by the specific ROS signal amplification and the interference with mitochondrial function. Moreover, the efficacy of DOX was also enhanced by the above process. CONCLUSION: The establishment of the MSNCA@GODOX-HA nanoparticles played a role in promoting strengths and restricting shortcomings of CA and DOX, thereby exerting their function and achieving efficient treatment against cancer.

Recent advances: peptides and self-assembled peptide-nanosystems for antimicrobial therapy and diagnosis.

Bacterial infections, especially the refractory treatment of drug-resistant bacteria, are one of the greatest threats to human health. During the past decades, biomedical nanomaterials have been developed in an increasing number of fields, which significantly contribute to our public healthcare systems. Peptide-based drugs, such as antimicrobial peptides, cyclopeptides, and glycopeptides, play important roles in the treatment of drug-resistant bacterial infections, due to their unique lower resistance antibacterial mechanism. Among them, biomimetic nanostructures fabricated by self-assembled peptide nanomaterials have received considerable development in surface protection, tissue engineering, bactericides, etc. Besides, bacterial diagnostic reagents based on self-assembled peptide materials also provide strong support for early detection and infection imaging of bacterial infections. In this review, we have systematically discussed peptide-based self-assembled nanomaterials, including their sequences, subunits, secondary structures, assembled nanostructures, and biomedical applications for antibacterial therapy and diagnosis. We have reviewed and discussed the structure-function relationship, molecular design strategy, and structure effect of antimicrobial peptides. The sequence design of self-assembled peptides and the application of self-assembled peptide nanomaterials in the diagnosis and treatment of bacterial infections are emphasized. Also, we analyzed and summarized the design and development of smart materials, reviewed the innovative "in vivo self-assembly" nanotechnology, and proposed the future design and prospect of smart self-assembly nanomaterials based on peptides in the biological antibacterial field.

Effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery: A randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a complication of central nervous system in patients after surgery. Edaravone as a brain-protective agent may have protective effect on postoperative cognitive function. The study was designed to explore the effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery and potential mechanism. PATIENTS AND METHODS: Patients undergoing hip joint replacement surgery were randomly allocated into 2 groups: the edaravone group (group E) and the control group (group C). Group E received intravenous edaravone at a dose of 0.5 mg/kg after induction of anesthesia, while group C received normal saline. The cognitive function was evaluated with the Mini-Mental State Examination (MMSE) 1day before surgery,3 days and the 7 days after surgery. Patients' plasma samples were collected to detect the levels of S100ß protein (S100ß), interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), superoxide dismutase (SOD) and malondialdehyde (MDA) before the induction of anesthesia, at the end of surgery and on postoperative day 3. RESULTS: The MMSE scores in group E were higher than those of group C 3 days after surgery (25.98 ± 1.99 vs 24.86 ± 1.86, p = 0.003). There were remarkable rises (p < 0.05) in plasma IL-6, S100ßand MMP-9 levels at the end of surgery and on postoperative day 3 in the two groups, however, edaravone pretreatment could reduce these levels to a certain extent compared with group C (p < 0.05).In group E, the SOD concentration was higher at the end of surgery (16.03 ± 2.46U/ml vs. 13.65 ± 2.53U/ml, p = 0.0001), while the MDA level was lower on postoperative day 3 than those in group C (7.01 ± 2.37 nmol/ml vs. 11.34 ± 3.18 nmol/ml, p = 0.0001). CONCLUSION: The results indicated that preoperative intervention with edaravone may improve the postoperative cognitive function in elderly patients undergoing hip joint replacement surgery.

[Expression Level of TGFß1 and VEGF Gene in Acute Myeloid Patients and Its Clinical Prognostic Value].

OBJECTIVE: To study the expression level of TGFß1 and VEGF gene in patients with acute myeloid leukemia (AML) and its clinical prognostic value. METHODS: Seventy-eight AML patients treated in our hospital from July 2016 to September 2018 were selected. After isolation of bone marrow mononuclear cells from the patients, the levels of TGFß1 and VEGF genes were detected by RT-PCR, and the correlation of TGFß1 with VEGF genes and clinical characteristics of AML patients was analyzed. OS and EFS of the patients were evaluated by Kaplan-Meier, and Cox risk ratio model was used to analyze the prognostic risk factors of AML patients. RESULTS: The relative expression level of TGFß1 gene in AML patients was 0.32±0.04, which was significantly lower than that in control group (P<005). The relative expression level of vascular endothelial growth factor(VEGF) gene in the patients was 2.65±0.15, which was significantly higher than that in the control group (P<0.05). The levels of TGFß1 and VEGF genes significantly correlated with leukocyte count, hemoglobin, platelet and peripheral blast levels in AML patients (P<0.05). The level of TGFß1 in AML patients with complete remission was higher than that in patients with partial remission or non-remission (P<0.05). The level of TGFß1 in AML patients with partial remission was significantly higher than that in patients with non-remission (P<0.05). The level of VEGF in AML patients with complete remission was lower than at in patients with partial remission or non-remission (P<0.05). The level of VEGF in AML patients with partial remission was significantly lower than that in patients with non-remission (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in AML patients with high expression of TGFß1 were better than those in patients with low expression of TGFß1 (P<0.05), OS and DFS in AML patients with low expression of VEGF were better than those in patients with high expression of VEGF (P<0.05). Multivariate Cox regression analysis showed that platelet, TGFß1 and VEGF gene were independent influencing factors of OS (P<0.05). Leukocyte, TGFß1 and VEGF gene were independent influencing factors of DFS (P<0.05). CONCLUSION: Decreased expression of TGFß1 and increased expression of VEGF gene in AML patients closely relate to the poor prognosis of AML patients, which can provide reference for improving clinical efficacy of AML patients.

Galectin-3 and TRIM16 coregulate osteogenic differentiation of human bone marrow-derived mesenchymal stem cells at least partly via enhancing autophagy.

BACKGROUND: The osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) is critical for bone homeostasis. Here, we investigated the regulation of Galectin-3 and tripartite motif protein 16 (TRIM16) on osteogenic differentiation of hBMSCs through autophagy. METHODS: Quantitative PCR (qPCR) and western blot were performed to determine the expression of osteogenic markers, autophagic markers, Galectin-3 and TRIM16. Short-hairpin RNAs (shRNAs) and overexpression plasmids were used to manipulate the expression of Galectin-3, TRIM16 and Unc-51 like autophagy activating kinase 1 (ULK1). Alkaline phosphatase (ALP) activity was measured by ALP staining assay. Calcium deposition in differentiated hBMSCs was assessed by Alizarin Red S staining. LC3 puncta formation was monitored by immunofluorescence staining. The interaction between indicated proteins was confirmed by co-immunoprecipitation (Co-IP) assay. RESULTS: Either Galectin-3 or TRIM16 knockdown led to impaired ALP activity, reduced calcium deposition, down-regulation of pro-osteogenic markers as well as restrained autophagy in osteogenic-induced hBMSCs. However, overexpression of Galectin-3 or TRIM16 promoted osteogenic differentiation of hBMSCs, which was then compromised by autophagy inhibition. Co-IP experiment demonstrated that TRIM16 associated with Galectin-3 through ULK1. Meanwhile, osteogenic induction enhanced the association between TRIM16 and ULK1 or coiled-coil myosin-like BCL2-interacting protein (Beclin1), and TRIM16 increased the stability of ULK1 and Beclin1. Moreover, either TRIM16 or ULK1 knockdown dampened the pro-osteogenic effect of Galectin-3, which elucidated that Galectin-3 mediated osteogenic differentiation was at least partly dependent on TRIM16 and ULK1. CONCLUSION: In summary, the present study revealed Galectin-3 and TRIM16 co-regulated osteogenic differentiation of hBMSCs at least partly via enhancing autophagy, which might provide a promising approach for osteoporosis treatment in future.

A tumour-selective cascade activatable self-detained system for drug delivery and cancer imaging.

Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders.

[Value of MYC, BCL-2 and BCL-6 for Evaluation of Prognosis in Patients with Diffuse Large B Cell Lymphoma].

OBJECTIVE: To analyze the prognostic value of BCL-2, BCL-6 and MYC in patients with diffuse large B cell lymphoma (DLBCL). METHODS: One hundred and sixty three cases of DLBCL in our hospital from March 2012 to March 2015 were selected. The specimens of lymphoma tissue of patients were collected. The expression of BCL-2, BCL-6 and MYC was detected by immunohistochemical method. The fusion of IGH/BCL-2, the gene breakage of BCL-6 and MYC were detected by interphase fluorescence in situ hybridization. The correlation of the expression levels of BCL-2, BCL-6 and MYC with the clinicopathological features and prognosis in the patients with DLBCL was further analyzed. RESULTS: MYC, BCL-2 and BCL-6 showed pale brown or reddish brown positive signals, among them MYC mainly positively expressed on the cell membrane, and BCL-2 mainly expressed on the cytoplasm and local cell membrane, and BCL-6 mainly expressed in the nucleus. The expression level of BCL-2 in ECOG physical status score 2 was higher than that in patients with ＜2 scores, and the expression level of BCL-2 in CD5+ and germinal center B-cell-like (GCB) was significantly higher than that in patients with non-GCB (P＜0.05), and the international prognostic index (IPI) for 3-5 scores at the MYC expression level was significantly higher than that of the 0-2 score (P＜0.05); the expression level of BCL-6 in immune subtype CD5+ and GCB was significantly lower than that in non-GCB (P＜0.05). The results of Cox multivariate analysis showed that the expression level of BCL-2, BCL-6 and MYC significant correlate with the overall survival and progression-free survival (P＜0.05) of the patients with DLBCL. CONCLUSION: BCL-2, BCL-6 and MYC as important molecular markers are of high value for evaluating the prognosis of patients with DLBCL.

Cytotoxic Nitrogenous Terpenoids from Two South China Sea Nudibranchs Phyllidiella pustulosa, Phyllidia coelestis, and Their Sponge-Prey Acanthella cavernosa.

A detailed chemical investigation of two South China Sea nudibranchs Phyllidiella pustulosa and Phyllidia coelestis, as well as their possible sponge-prey Acanthella cavernosa, led to the isolation of one new nitrogenous cadinane-type sesquiterpenoid xidaoisocyanate A (1), one new naturally occurring nitrogen-containing kalihinane-type diterpenoid bisformamidokalihinol A (16), along with 17 known nitrogenous terpenoids (2⁻15, 17⁻19). The structures of all the isolates were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported axiriabiline A (5) was determined by X-ray diffraction (XRD) analysis. In a bioassay, the bisabolane-type sesquiterpenoids 8, 10, and 11 exhibited cytotoxicity against several human cancer cell lines.

Effects of perioperative transcutaneous electrical acupoint stimulation on monocytic HLA-DR expression in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass: study protocol for a double-blind randomized controlled trial.

BACKGROUND: Cardiac surgery involving cardiopulmonary bypass (CPB) is known to be associated with a transient postoperative immunosuppression. When severe and persistent, this immune dysfunction predisposes patients to infectious complications, which contributes to a prolonged stay in the intensive care unit (ICU), and even mortality. Effective prevention and treatment methods are still lacking. Recent studies revealed that acupuncture-related techniques, such as electroacupuncture and transcutaneous electrical acupoint stimulation (TEAS), are able to produce effective cardioprotection and immunomodulation in adult and pediatric patients undergoing cardiac surgery with CPB, which leads to enhanced recovery. However, whether perioperative application of TEAS, a non-invasive technique, is able to improve immunosuppression of the patients with post-cardiosurgical conditions is unknown. Thus, as a preliminary study, the main objective is to evaluate the effects of TEAS on the postoperative expression of monocytic human leukocyte antigen (-D related) (mHLA-DR), a standardized "global" biomarker of injury or sepsis-associated immunosuppression, in patients receiving on-pump coronary artery bypass grafting (CABG). METHODS: This study is a single-center clinical trial. The 88 patients scheduled to receive CABG under CPB will be randomized into two groups: the group receiving TEAS, and the group receiving transcutaneous acupoint pseudo-electric stimulation (Sham TEAS). Expression of mHLA-DR serves as a primary endpoint, and other laboratory parameters (e.g., interleukin [IL]-6, IL-10) and clinical outcomes (e.g., postoperative infectious complications, ICU stay time, and mortality) as the secondary endpoints. In addition, immune indicators, such as high mobility group box 1 protein and regulatory T cells will also be measured. DISCUSSION: The current study is a preliminary monocentric clinical trial with a non-clinical primary endpoint, expression of mHLA-DR, aiming at determining whether perioperative application of TEAS has a potential to reverse CABG-associated immunosuppression. Although the immediate clinical impact of this study is limited, its results would inform further large-sample clinical trials using relevant patient-centered clinical outcomes as primary endpoints. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02933996. Registered on 13 October 2016.

Graphene Quantum Dots-Mediated Theranostic Penetrative Delivery of Drug and Photolytics in Deep Tumors by Targeted Biomimetic Nanosponges.

Dual-targeted delivery of drugs and energy by nanohybrids can potentially alleviate side effects and improve the unique features required for precision medicine. To realize this aim, however, the hybrids which are often rapidly removed from circulation and the piled up tumors periphery near the blood vessels must address the difficulties in low blood half-lives and tumor penetration. In this study, a sponge-inspired carbon composites-supported red blood cell (RBC) membrane that doubles as a stealth agent and photolytic carrier that transports tumor-penetrative agents (graphene quantum dots and docetaxel (GQD-D)) and heat with irradiation was developed. The RBC-membrane enveloped nanosponge (RBC@NS) integrated to a targeted protein that accumulates in tumor spheroids via high lateral bilayer fluidity exhibits an 8-fold increase in accumulation compared to the NS. Penetrative delivery of GQDs to tumor sites is actuated by near-infrared irradiation through a one-atom-thick structure, facilitating penetration and drug delivery deep into the tumor tissue. The synergy of chemotherapy and photolytic effects was delivered by the theranostic GQDs deep into tumors, which effectively damaged and inhibited the tumor in 21 days when treated with a single irradiation. This targeted RBC@GQD-D/NS with the capabilities of enhanced tumor targeting, NIR-induced drug penetration into tumors, and thermal ablation for photolytic therapy promotes tumor suppression and exhibits potential for other biomedical applications.

Two new cytotoxic steroids from the Chinese soft coral Sinularia sp.

Two new steroids, ximaosteroid E (1) and ximaosteroid F (2), along with two known related compounds (3 and 4), were isolated from the Chinese soft coral Sinularia sp. Notably, 1 possesses an uncommon dihydrofuran group. Their structures were established from extensive spectroscopic analyses and comparisons of their spectral data with those reported in the literature. The absolute configuration of 2 was determined by applying the modified Mosher's method. In bioassay, compounds 1, 2, and 4 showed significant cytotoxicity against the HL-60 tumor cell line with IC50 values of 1.79, 4.03 and 0.69 µM, respectively.