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Problem: Does sildenafil have an effect on pregnancy outcomes in patients with poor endometrial development?Methods: This study included 472 infertility patients who underwent in vitro fertilization/intracytoplasmatic sperm injection and frozen-thawed embryo transfer (IVF/ICSI-FET) and suffered from poor endometrial development in the hormone replacement cycle (HRC) from April 2017 to July 2019. The patients were divided into two groups: the sildenafil group(n=88) and the control group(n=384). Endometrial thicknesses and types on endometrial transformation day, as well as pregnancy outcomes after FET (biochemical pregnancy, clinical pregnancy, early abortion, late abortion, and live birth rates) between two groups were analyzed. Results: No significant differences were observed in endometrial thicknesses and types on endometrial transformation day between the sildenafil group and the control group. There were also no statistically significant differences in pregnancy outcomes between the two groups. After adjusting for confounding factors, the application of sildenafil could not improve endometrial thickness and type of the day of endometrial transformation and the growth of endometrial thickness. Moreover, the sildenafil was not closely related to clinical pregnancy outcomes.Conclusions: Sildenafil could not better endometrial development and pregnancy outcomes in patients with poor endometrial development.

Neuroinflammation is an important secondary aggravating factor in spinal cord injury (SCI). Inhibition of the inflammatory response is critical for SCI treatment. Glycyrrhizic acid (GA) is an anti-inflammatory drug, but its utility for SCI is unclear. This study aimed to evaluate the effects of GA on inflammation after SCI and the underlying mechanism.Cell counting kit-8 assays were performed to assess the viability of highly aggressively proliferating immortalized cells that had been treated with lipopolysaccharide (LPS) and/or GA. Reverse transcription quantitative polymerase chain reaction and Western blotting were performed to assess expression of high mobility group box-1 protein (HMGB1), ionized calcium binding adaptor molecule 1, and inflammatory factors in vitro and in vivo. GA (100 mg/kg) was intraperitoneally injected into rats. Anti-inflammatory effects of GA were analyzed in SCI tissues. p38/Jun N-terminal kinase signaling pathway proteins were analyzed by Western blotting.Cell counting kit-8 assay results showed that treatment with 100 ng/mL LPS for 12 hours was optimal. After LPS treatment, highly aggressively proliferating immortalized cells were activated; messenger RNA expression levels of HMGB1 and inflammatory factors were increased. GA significantly inhibited LPS-induced HMGB1 expression and inflammatory responses, as determined by reverse transcription quantitative polymerase chain reaction and Western blotting. Transfection with an HMGB1-overexpression plasmid reversed the anti-inflammatory effects of GA. In addition, intraperitoneal injection of GA (100 mg/kg) into rats for 3 days significantly reduced expression levels of HMGB1 and inflammatory factors after SCI in vivo. GA reduced phosphorylation, but not levels, of p38 and Jun N-terminal kinase proteins.GA attenuates the inflammatory response after SCI by inhibiting HMGB1 through the p38/JNK signaling pathway and thus has therapeutic potential for SCI.

NG2 cells are highly proliferative glial cells that can self-renew or differentiate into oligodendrocytes, promoting remyelination. Following demyelination, the proliferative and differentiation potentials of NG2 cells increase rapidly, enhancing their differentiation into functional myelinating cells. Levels of the transcription factors Olig1 and Olig2 increase during the differentiation of NG2 cells and play important roles in the development and repair of oligodendrocytes. However, the ability to generate new oligodendrocytes is hampered by injury-related factors (e.g., myelin fragments, Wnt and Notch signaling components), leading to failed differentiation and maturation of NG2 cells into oligodendrocytes. Here, we review Notch signaling as a negative regulator of oligodendrocyte differentiation and discuss the extracellular ligands, intracellular pathways, and key transcription factors involved.

Background. After radical hysterectomy for cervical cancer, the most common complication is lower urinary tract symptoms. Post-operatively, bladder capacity can alter bladder function for a prolonged period. This study aimed to identify factors affecting bladder storage function. Methods. A multicenter, retrospective cohort study was conducted. Information of patients with stages IA2 to IIB cervical cancer with urodynamic study results were retrospectively collected from nine hospitals between June 2013 and June 2018 according to the inclusion criteria. Demographic, surgical, and oncological data were collected. The univariate and multivariate logistic regression was used to identify clinical factors associated with bladder storage function. Results. Two hundred and three patients with cervical cancer had urodynamic testing post-operatively. Ninety-five (46.8%) patients were diagnosed with stress urinary incontinence (SUI). The incidence of low bladder compliance (LBC) was 23.2%. Twenty-seven (13.3%) patients showed detrusor overactivity (DO). Fifty-seven patients (28.1%) presented with a decreased maximum cystometric capacity (DMCC). The probability of composite bladder storage dysfunction was 68.0%. Multivariate analysis confirmed that laparoscopy represents a protective factor for SUI with an odds ratio of 0.498 (P = 0.034). Patients who underwent a nerve-sparing procedure were less odds to experience SUI (P = 0.014). A significant positive correlation between LBC and DO was observed (P

Effects of microwave power on the sensory properties (taste and aroma), chemical composition (catechins, caffeine, crude protein, and amino acid), active composition (flavones, triterpene, polysaccharide, and ergosterol) and antioxidant properties (superoxide free radical and hydroxyl radical scavenging abilities, reducing power) of Ganoderma lucidum fermented sea-buckthorn tea were investigated. G. lucidum fermented sea-buckthorn tea was dehydrated using microwaves at three power settings: 125, 250, and 500. After microwave treatment, a statistically significant difference in the chemical composition, active composition and antioxidant capacity (p

The continuing emergence of viral pathogens and their rapid spread into heavily populated areas around the world underscore the urgency for development of highly effective vaccines to generate protective antiviral Ab responses. Many established and newly emerging viral pathogens, including HIV and Ebola viruses, are most prevalent in regions of the world in which Mycobacterium tuberculosis infection remains endemic and vaccination at birth with M. bovis bacille Calmette–Guérin (BCG) is widely used. We have investigated the potential for using CD4+ T cells arising in response to BCG as a source of help for driving Ab responses against viral vaccines. To test this approach, we designed vaccines comprised of protein immunogens fused to an immunodominant CD4+ T cell epitope of the secreted Ag 85B protein of BCG. Proof-of-concept experiments showed that the presence of BCG-specific Th cells in previously BCG-vaccinated mice had a dose-sparing effect for subsequent vaccination with fusion proteins containing the Ag 85B epitope and consistently induced isotype switching to the IgG2c subclass. Studies using an Ebola virus glycoprotein fused to the Ag 85B epitope showed that prior BCG vaccination promoted high-affinity IgG1 responses that neutralized viral infection. The design of fusion protein vaccines with the ability to recruit BCG-specific CD4+ Th cells may be a useful and broadly applicable approach to generating improved vaccines against a range of established and newly emergent viral pathogens.

MEG8 is involved in ischemia stroke, however, its role in ischemia stroke remains unknown. The current research aimed to investigate the effects and mechanisms of MEG8 in ischemic stroke. Mouse brain microvascular endothelial cells (BMECs) were treated by oxygen-glucose deprivation (OGD). Then, the expressions of MEG8 and miR-130a-5p were detected by quantitative reverse transcription-polymerase chain reaction (q-PCR). Cell counting kit-8 (CCK-8), wound-healing, tube formation, Western blot, and q-PCR assays were performed to detect the effects of MEG8 and miR-130a-5p on cell viability, migration, and angiogenesis and VEGFA expression. Bioinformatics, dual-luciferase reporter assay, and RNA immunoprecipitation analysis were carried out to investigate the targeting relationship between MEG8 and miR-130a-5p, and between miR-130a-5p and VEGFA. Then, rat middle cerebral artery occlusion (MCAO) model and MEG8 overexpression MCAO model were established, and neurological deficit and infarct volume of the model rats were evaluated. Finally, Western blot and q-PCR were carried out to detect the expressions of MEG8, miR-130a-5p, and VEGFA. MEG8 was upregulated and miR-130a-5p was downregulated in OGD-treated BMECs. MiR-130a-5p was found to be a target of MEG8, and VEGFA was predicted to be a potential target of miR-130a-5p. Downregulation of MEG8 inhibited the cell viability, migration, and angiogenesis and the expression of VEGFA via negatively regulating miR-130a-5p of BMECs treated by OGD/non-OGD. In addition, MEG8 reduced cerebral ischemia, neurological score and miR-130a-5p expression, and increased VEGFA expression of MCAO rat. Our findings proved that MEG8 regulates angiogenesis and attenuates cerebral ischemia after ischemic stroke via miR-130a-5p/VEGFA signaling.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

Background Sternal tumors are difficult to diagnose, and usually need to be differentiated from other diseases such as tuberculosis, osteosarcoma, intrathoracic thyroid and thymoma. The sternum is a rare site of Hodgkin's lymphoma, which is often misdiagnosed as tuberculosis on routine histopathology. Case summary We reported a 47-year-old female patient with chest pain in the upper sternum for 1 mo. Chest computed tomography found a mass in the upper sternum. Pathology and immunohistochemistry of the biopsy confirmed the diagnosis of typical Hodgkin's lymphoma (mixed cellularity subtype). Patient was diagnosed with primary sternal Hodgkin's lymphoma and administered 6 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy. Patient had no tumor recurrence and progression at a follow-up visit 2 years later. Conclusion This study highlights the rarity of primary sternal Hodgkin's lymphoma and the challenges of its diagnosis. A PubMed and Web of Science search revealed 10 reported cases of sternal involvement in Hodgkin's lymphoma.

Background Lung cancer (LC) is one of the most common types of malignant tumors and is the most prominent cause of tumor-related death worldwide. LC is a heterogeneous disease caused by somatic cell mutations and dysregulation in several signaling pathways. Understanding these pathways provides the basis for detecting LC. LC screening and diagnosis in current clinic still rely on computed tomography (CT), but its high false positive rates and cost may prevent it from being a routine screening method. Therefore, the discovery of new non-invasive and more valuable biomarkers may present an improved diagnostic approach for LC, and potentially provide more useful information for the prognosis and treatment of LC in patients. This study investigated the potential of detecting serum autoantibodies produced against human epididymis secretory protein 4 (HE4) for LC diagnosis in high-risk groups. Methods Serum samples from 61 patients with LC were included in this study, and another 53 serum samples from healthy donors or benign lung diseases (BLD) patients were collected as the control group. The samples were analyzed with enzyme-linked immunosorbent assays (ELISA). Results ELISA results showed significantly higher levels of serum autoantibodies against HE4 in samples from LC patients compared to the control group (P

Circular RNAs are an increasingly important topic in non-coding RNA biology, drawing considerable attention in recent years. Accumulating evidence suggests a critical role for circular RNAs in both early and latent stages of disease pathogenesis. Circular RNAs are abundantly expressed in brain tissue, with significant implications for neural development and disease progression. Disruption of these processes, including those seen in response to brain injury, can have serious consequences such as hemiplegia, aphasia, coma, and death. In this review, we describe the role of circular RNAs in the context of brain injury and explore the potential connection between circular RNAs, brain hypoxic ischemic injury, ischemia-reperfusion injury, and traumatic injury.

The proverbial “nine lives” of cats are attributed to the capacity of the felines to withstand jumps and falls from a high-rise without being fatally wounded, and this is due in large part to their impact-resistant paw pads. The pads possess a complex architecture of multiscale collagen fiber networks and adipose mass chambers. We propose in this paper the concept of a hierarchical composite made of porous polyurethane (PU) main network skeletons coated with graphene oxide (GO)/multiwalled carbon nanotubes (MWCNTs), freeze-dry constructed secondary membrane network configurations with GO/MWCNTs, and embedded in a polyborondimethylsiloxane (PBDMS) matrix. The design of the composite is inspired by the architectures of collagens present in the cat paw and the composites provide significant creep resistance, load bearing, shape recovery and also stiffness tailoring. More importantly, the hierarchical composites possess remarkable high energy dissipations during quasi-static cyclic compression and dynamic mechanical loadings as vibration (damping capacity: 160% increase compared to the pure matrix) and impact (impacting energy absorption: ∼100%). The multiscale deformation mechanisms are analyzed and discussed with the support of finite element simulations. The main fibrous and secondary membranous networks generated during the manufacturing of the composite act as multiscale confinements to the lipid-like matrix, so that the matrix with reversible B-O bonds can significantly contribute to the unusual energy dissipation characteristics. Similar to the cat paws, the hierarchical composites are also soft, flexible and show significant potential for safety wearing devices in sport and broad engineering applications.

Background. The small molecule inhibitor XAV939 could inhibit the proliferation and promote the apoptosis of non-small cell lung cancer (NSCLC) cells. This study was conducted to identify the key circular RNAs (circRNAs) and microRNAs (miRNAs) in XAV939-treated NSCLC cells. Methods. After grouping, the NCL-H1299 cells in the treatment group were treated by 10 μM XAV939 for 12 h. RNA-sequencing was performed, and then the differentially expressed circRNAs (DE-circRNAs) were analyzed by the edgeR package. Using the clusterprofiler package, enrichment analysis for the hosting genes of the DE-circRNAs was performed. Using Cytoscape software, the miRNA-circRNA regulatory network was built for the disease-associated miRNAs and the DE-circRNAs. The DE-circRNAs that could translate into proteins were predicted using circBank database and IRESfinder tool. Finally, the transcription factor (TF)-circRNA regulatory network was built by Cytoscape software. In addition, A549 and HCC-827 cell treatment with XAV939 were used to verify the relative expression levels of key DE-circRNAs. Results. There were 106 DE-circRNAs (including 61 upregulated circRNAs and 45 downregulated circRNAs) between treatment and control groups. Enrichment analysis for the hosting genes of the DE-circRNAs showed that ATF2 was enriched in the TNF signaling pathway. Disease association analysis indicated that 8 circRNAs (including circ_MDM2_000139, circ_ATF2_001418, circ_CDC25C_002079, and circ_BIRC6_001271) were correlated with NSCLC. In the miRNA-circRNA regulatory network, let-7 family members⟶circ_MDM2_000139, miR-16-5p/miR-134-5p⟶circ_ATF2_001418, miR-133b⟶circ_BIRC6_001271, and miR-221-3p/miR-222-3p⟶circ_CDC25C_002079 regulatory pairs were involved. A total of 47 DE-circRNAs could translate into proteins. Additionally, circ_MDM2_000139 was targeted by the TF POLR2A. The verification test showed that the relative expression levels of circ_MDM2_000139, circ_CDC25C_002079, circ_ATF2_001418, and circ_DICER1_000834 in A549 and HCC-827 cell treatment with XAV939 were downregulated comparing with the control. Conclusions. Let-7 family members and POLR2A targeting circ_MDM2_000139, miR-16-5p/miR-134-5p targeting circ_ATF2_001418, miR-133b targeting circ_BIRC6_001271, and miR-221-3p/miR-222-3p targeting circ_CDC25C_002079 might be related to the mechanism in the treatment of NSCLC by XAV939.

A balanced ratio of fatty acids n-6 to n-3 in chicken eggs is important for health and to help prevent and manage obesity and other diseases. Traditionally, fish oil or flax seed has been utilized as feed additives to decrease the ratio of n-6 to n-3(n-6:n-3) fatty acids in eggs. The hull of spina date seed(HSDS) is a common agricultural waste product in China, from which wood vinegar(HSDSWV) may be derived. This study evaluated HSDSWV as a sup-plement in hen feeds to improve the quality of eggs and decrease the ratio of fatty acids n-6:n-3. HSDSWV was obtained via carbonization, and refined. Six concentrations(nil to 0.5%) of HSDSWV were prepared and fed to 6 hen groups, respectively, for 50 d. The fatty acids of the hen’s egg yolks were analyzed by gas chromatography/electron ionization-mass spectrometry(GC/EI-MS) in the selected ion monitoring(SIM) mode. The 0.2% HSDSWV resulted in the best egg yolk quality, with a lower percentage of linoleic acid(C18:2n6) and higher percentages of cis-5,8,11,14,17-eicosapentaenoic acid(C20:5n3) and cis-4,7,10,13,16,19-docosahexaenoic acid(C22:6n3), and thus a lower n-6:n-3 ratio compared with the other HSDSWV concentrations. In addition, the eggs contained higher levels of yolk fat and egg yolk than the controls did. In conclusion, to modify the fatty acid composition of hens’ eggs and obtain a balanced ratio of n-6:n-3, 0.2% HSDSWV may be considered suitable as a dietary supplement in hens’ feed.

The present study aimed to develop and evaluate a nomogram for predicting the overall survival (OS) of patients with low-grade glioma (LGG).Patients with LGG diagnosed from 1973 to 2013 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. A total of 3732 patients were randomly divided into a training set (n = 2612) and a validation set (n = 1120). Univariate and multivariate Cox regression analyses of the clinical variables were performed to screen for significant prognostic factors. Next, a nomogram that included significant prognostic variables was formulated to predict for LGG. Harrell's concordance index (C-index) and calibration plots were formulated to evaluate the reliability and accuracy of the nomogram using bootstrapping according to the internal (training set) and external (validation set) validity.A nomogram was developed to predict the 5- and 9-year OS rates using 7 variables in the training set: age, tumor site, sex, marital status, histological type, tumor size, and surgery (P0.05). The C-index for internal validation, which the nomogram used to predict OS according to the training set, was 0.777 (range, 0.763-0.791), and the C-index for external validation (validation set) was 0.776 (range, 0.754-0.797). The results of the calibration plots showed that the actual observation and prediction values obtained by the nomogram had good consistency between the 2 sets.We have developed a ready-to-use nomogram model that includes clinical characteristics to predict OS. The nomogram might provide consultation and risk assessments for subsequent treatment of patients with LGG.

Purpose Glioblastoma multiforme (GBM) is a highly malignant tumor of the central nervous system. Although primary GBM patients receive extensive therapies, tumors may recur within months, and there is no objective and scientific method to predict prognosis. Adoptive immunotherapy holds great promise for GBM treatment. However, the expression profiles of the tumor-associated antigens (TAAs) and tumor immune microenvironment (TME) genes used in immunotherapy of GBM patients have not been fully described. The present study aimed to develop a predictive tool to evaluate patient survival based on full analysis of the expression levels of TAAs and TME genes. Methods Expression profiles of a panel of 87 TAAs and 8 TME genes significantly correlated with poor prognosis were evaluated in 44 GBM patients and 10 normal brain tissues using quantitative real-time polymerase chain reaction (qRT-PCR). A linear formula (the LASSO algorithm based in the R package) weighted by regression coefficients was used to develop a multi-element expression score to predict prognosis; this formula was cross-validated by the leave-one-out method in different GBM cohorts. Results After analysis of gene expression, clinical features, and overall survival (OS), a total of 8 TAAs (CHI3L1, EZH2, TRIOBP, PCNA, PIK3R1, PRKDC, SART3 and EPCAM), 1 TME gene (FOXP3) and 4 clinical features (neutrophil-to-lymphocyte (NLR), number of basophils (BAS), age and treatment with standard radiotherapy and chemotherapy) were included in the formula. There were significant differences between high and low scoring groups identified using the formula in different GBM cohorts (TCGA (n=732) and GEO databases (n=84)), implying poor and good prognosis, respectively. Conclusion The multi-element expression score was significantly associated with OS of GBM patients. The improve understanding of TAAs and TMEs and well-defined formula could be implemented in immunotherapy for GBM to provide better care.

A novel Gram-stain-positive, non-motile, rod-shaped, non-spore-forming bacterium, designated HLT2-9T, was isolated from the ice tongue surface of Hailuogou Glacier in Sichuan Province, PR China. Colonies of cells were cream yellow, convex and round. Growth occurred at 0–27 °C (optimum, 20 °C), pH 7.0–10.0 (pH 7.0) and in the presence of 0–2.0 % (w/v) NaCl (0 %). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain HLT2-9T belonged to the genus Nocardioides . The highest level of sequence similarities were found to Nocardioides glacieisoli CGMCC1.11097T (99.24 %), Nocardioides oleivorans CGMCC 4.6882T (98.54 %) and Nocardioides ganghwensis CGMCC 4.6875T (98.54 %). However, the low average nucleotide identity (85.6–87.9 %) and digital DNA–DNA hybridization values (26.4–30.2 %) of strain HLT2-9T to its three closest relatives demonstrated that it represents a novel species of the genus Nocardioides . The major cellular fatty acids of strain HLT2-9T were C17 : 1 ω8c and iso-C16 : 0. Strain HLT2-9T contained ll-2,6-diaminopimelic acid as the diamino acid in the cell-wall peptidoglycan. The predominant menaquinone is MK-8(H4). The G+C content of the genomic DNA was 70.65 mol%. Based on evidence collected from the phenotypic, genotypic and phylogenetic analyses, a novel species Nocardioides zhouii sp. nov. is proposed, with HLT2-9T (=CGMCC 1.11084T=NBRC 109783T) as the type strain.

Background: People with agrammatism have profound deficits in producing functional categories. The Tree Pruning Hypothesis proposes that these deficits are attributed to the reduced ability...

BACKGROUND Paragangliomas in the mediastinum are rare, accounting for only 1%-2% of all paragangliomas and < 0.3% of all mediastinal tumors. Most paragangliomas are nonfunctional, therefore, asymptomatic functional paragangliomas in the left posterior mediastinum are extremely rare. Perioperative management including preoperative preparation, careful intraoperative procedures, and strict postoperative care is important, and one-stage surgical resection should be performed only after appropriate perioperative measures are undertaken. Because those tumors are rare, it is necessary to report known cases to raise awareness regarding them. CASE SUMMARY We report the case of a 47-year-old male who was admitted to our hospital with the chief complaints of intermittent tearing pain on the left side of the chest and back for more than 10 mo. A chest contrast-enhanced computed tomography scan revealed a round, solid mass in the left posterior mediastinum, with low-density cystic lesions in the middle, and no enlarged lymph nodes in the hilum or mediastinum (Figure 1). After the diagnosis of paraganglioma, the patient was preoperatively given an oral adrenoceptor blocking drug (phenoxybenzamine), and intravenous fluid resuscitation for two weeks, subsequently the patient underwent a one-stage resection of lesions via left thoracotomy. The patient’s blood pressure increased to 220/120 mmHg when the tumor was touched, which could be relieved by symptomatic treatment such as accelerating liquid transfusion or other intervention to lower blood pressure. The patient recovered uneventfully after surgery, with no abnormal blood pressure or recurrence during one year of follow-up visits. CONCLUSION Surgical resection is the preferred treatment for asymptomatic functional paragangliomas.

Background: To evaluate the value of interleukin (IL)-27 measured in serum and bronchoalveolar lavage fluid (BALF) for the diagnosis of smear-negative pulmonary tuberculosis (TB). Methods: This was a prospective study of patients planned to undergo bronchoscopy at Wuxi No.5 People's Hospital between January 2017 and September 2018. The patients were grouped as the TB and control groups. BALF and serum IL-27 were measured by ELISA. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value and calculate the optimal cutoff values. Results: There were 40 patients in the control group and 87 in the TB group. In the TB group, 20 had positive sputum smear results and 67 were negative. The area under the ROC curve (AUC) of BALF IL-27 for pulmonary TB was 0.897 (95% CI: 0.830–0.944) (P

Central nervous system (CNS) lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption. Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been shown. Herein, abundant deposition of the blood coagulation protein fibrinogen around B-cell lymphoma was detected in CNS lymphoma patients and in the CNS parenchyma in an orthotopic mouse model. Functional enrichment analysis of unbiased cerebrospinal fluid proteomics of CNS B-cell lymphoma patients showed that coagulation protein networks were highly connected with tumor-associated biological signaling pathways. Invivo two-photon imaging demonstrated that lymphoma growth was associated with BBB disruption, and invitro experiments identified a role for fibrinogen in promoting lymphoma cell adhesion. Overall, these results identify perivascular lymphoma clustering at sites of fibrinogen deposition, and suggest that fibrinogen may be a target for pharmacologic intervention in metastatic B-cell lymphoma associated with BBB disruption.

Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome are life threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high-value targets, including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development.

Glioblastoma is the most common and aggressive type of brain tumor. Although treatments for glioblastoma have been improved recently, patients still suffer from local recurrence in addition to poor prognosis. Previous studies have indicated that the efficacy of chemotherapeutic or bioactive agents is severely compromised by the blood-brain barrier and the inherent drug resistance of glioblastoma. The present study developed a delivery system to improve the efficiency of delivering therapeutic agents into glioblastoma cells. The anticancer drug paclitaxel (PTX) was packed into nanoparticles that were composed of amphiphilic poly (γ-glutamic-acid-maleimide-co-L-lactide)-1,2-dipalmitoylsn-glycero-3-phosphoethanolaminecopolymer conjugated with targeting moiety transferrin (Tf). The Tf nanoparticles (Tf-NPs) may enter glioblastoma cells via transferrin receptor-mediated endocytosis. MTT assay and flow cytometry were used to explore the cytotoxic effects, cellular uptake and cellular distribution of paclitaxel-loaded nanoparticles. The results indicated that both PTX and PTX-Tf-NPs inhibited the viability of rat glioblastoma C6 cells in a dose-dependent manner, but the PTX-Tf-NPs exhibited a greater inhibitory effect compared with PTX, even at higher concentrations (0.4, 2 and 10 µg/ml). However, both PTX and PTX-Tf-NPs exhibited a reduced inhibitory effect on the viability of mouse hippocampal neuronal HT22 cells compared with that on C6 cells. Additionally, in contrast to PTX alone, PTX-Tf-NPs treatment of C6 cells at lower concentrations (0.0032, 0.0160 and 0.0800 µg/ml) induced increased G2/M arrest, although this difference did not occur at a higher drug concentration (0.4 µg/ml). It was observed that FITC-labeled PTX-Tf-NPs were endocytosed by C6 cells within 4 h. Furthermore, FITC-labeled PTX-Tf-NPs or Tf-NPs co-localized with a lysosomal tracker, Lysotracker Red DND-99. These results of the present study indicated that Tf-NPs enhanced the cytotoxicity of PTX in glioblastoma C6 cells, suggesting that PTX-Tf-NPs should be further explored in animal models of glioblastoma.

Over the years, lung cancer remains the leading cause of cancer deaths in worldwide. In view of this, increasingly importance has been attached to the further optimization and improvement of its treatment. Reactive oxygen species (ROS) play a key role in regulating tumor development and anti-cancer treatment. Recently, the development of nanomaterials provides new platforms for ROS-based cancer treatment methods, which can help to reduce side effects and enhance anti-cancer effects. In recent years, a variety of lung cancer treatment models have been reported, such as chemodynamic therapy (CDT), photodynamic therapy (PDT), radiation therapy (RT) and controlled drug release (CDR). In this review, we are going to discuss the possible mechanism of action and current research status of ROS-based nanomaterials in the treatment of lung cancer in order to provide constructive ideas for relative research and expect this work could inspire the future development of novel lung cancer treatments.

HCMV enters cells primarily through glycoprotein B (gB)-mediated membrane fusion. Several neutralizing antibodies against different epitopes of gB have been isolated. Here, we report neoepitopes on antigenic domain I (AD-5) of gB revealed by study of a group of novel potent neutralizing monoclonal antibodies (mAbs). Electron micrographs and site-directed mutagenesis demonstrated that residues (N208, L213 and Y226) are the key sites for neoepitopes, which localize to the fusion subdomain of AD-5, spatially close to the fusion loops of gB. Glycosylation studies showed that these mAbs binding is independent of the glycans of gB protein. Functionally, these mAbs mainly interfere with viral membrane fusion rather than viral adhesion to cell. Moreover, sera from gBAD-5-immunized mice exhibited better antiviral efficacy than gBECD-immunization sera. Overall, our results reconstruct the antigenic profile of AD-5 and provide scientific basis for the optimal design of gB-based vaccine, especially those that focus the immune response on AD-5.

Two Gram-stain-negative, aerobic, rod-shaped, non-motile, bacterial strains, designated as ZB1P21T and ZT4R22T, were isolated from ice and cryoconite samples collected from Zepu glacier on the Tibetan Plateau, PR China. The phylogenetic analysis of 16S rRNA gene showed that the two strains belong to the genus Mucilaginibacter . Strain ZB1P21T showed the highest similarity to Mucilaginibacter rigui WPCB133T (97.35 %), while strain ZT4R22T showed the highest similarity to Mucilaginibacter gilvus F01003T (99.11 %). The average nucleotide identity values between the two novel strains and their closest relatives were 79.42 and 85.72 % respectively. The two novel strains contained MK-7 as the major menaquinone, and summed feature 3 (comprising C16 : 1 ω7c and/or C16 : 1 ω6c), iso-C15:0, iso-C17 : 03-OH and C16 : 1 ω5c as the major fatty acids. The major polar lipid of the two novel strains were phosphatidylethanolamine. Based on these data, we propose two novel species, Mucilaginibacter glaciei sp. nov. (ZB1P21T=CGMCC 1.23981T=NBRC 113932T) and Mucilaginibacter pankratovii sp. nov. (ZT4R22T=CGMCC 1.23487T=NBRC 113931T).

BACKGROUND: Previous study suggested that Chinese Herbal Medicine (CHM) Formula Huashibaidu granule might shorten disease course of Corona Virus Disease 2019 (COVID-19) patients. Our research aims to investigate the early treatment effect of Huashibaidu granule in mild COVID-19 patients under well clinical management. METHODS: An unblended cluster-randomized clinical trial was conducted at the Dongxihu FangCang hospital. 2 cabins were randomly allocated to CHM or control group, with 204 randomly sampled mild COVID-19 patients in each cabin. All participants received a 7-day conventional treatment, and CHM group cabin used additional Huashibaidu granule 10g twice daily. Participants were followed up until they met clinical endpoint. The primary outcome was patient become worsening before clinical endpoint occurred. The secondary outcomes was discharge with cure before clinical endpoint occurred and relief of composite symptoms after 7 days treatment. FINDINGS: All 408 participants were followed up to meet clinical endpoint and included in statistical analysis. The baseline characteristics were comparable between 2 groups. The number of worsening patients in the CHM group was 5 (2.5%), and that in the control group was 16 (7.8%). There was a significant difference between groups (P=0.014). 8 foreseeable mild adverse events occurred without statistical difference between groups. INTERPRETATION: 7-day early treatment with Huashibaidu granule reduced worsening conversion of mild COVID-19 patients. Our study supports Huashibaidu Granule as an active option for early treatment of mild COVID-19 in similar medical locations with well management. TRIAL REGISTRATION: The Chinese Clinical Trial Registry: ChiCTR2000029763. FUNDING: This study was supported by “National Key R&D Program of China” (No.2020YFC0841500). DECLARATION OF INTERESTS: The authors guaranteed that there existed no competing interest in this paper. ETHICS APPROVAL STATEMENT: Ethics Review Committee of Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences Approval of Ethical Review Acceptance Number: S2020-001; Approval Number: P20001/PJ01.

Although human antibodies elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-reactive antibodies. Herein, we isolated and profiled a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery coronavirus disease-19 (COVID-19) convalescent patient who had dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS-CoV-2 spike (S) protein. The complex structure of the N protein RNA binding domain with the mAb with the highest binding affinity (nCoV396) revealed changes in the epitopes and antigen’s allosteric regulation. Functionally, a virus-free complement hyper-activation analysis demonstrated that nCoV396 specifically compromises the N protein-induced complement hyper-activation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.

Although human antibodies elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-reactive antibodies. Herein, we isolate and profile a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery coronavirus disease-19 (COVID-19) convalescent patient who has dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS-CoV-2 spike (S) protein. The complex structure of the N protein RNA binding domain with the highest binding affinity mAb (nCoV396) reveals changes in the epitopes and antigen’s allosteric regulation. Functionally, a virus-free complement hyperactivation analysis demonstrates that nCoV396 specifically compromises the N protein-induced complement hyperactivation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.

Summary Four potent native human monoclonal antibodies (mAbs) targeting distinct epitopes on tetanus toxin (TeNT) are isolated with neutralization potency ranging from approximately 17 mg to 6 mg each that are equivalent to 250 IU of human anti-TeNT immunoglobulin. TT0170 binds fragment B, and TT0069 and TT0155 bind fragment AB. mAb TT0067 binds fragment C and blocks the binding of TeNT to gangliosides. The co-crystal structure of TT0067 with fragment C of TeNT at a 2.0-A resolution demonstrates that mAb TT0067 directly occupies the W pocket of one of the receptor binding sites on TeNT, resulting in blocking the binding of TeNT to ganglioside on the surface of host cells. This study reveals at the atomic level the mechanism of action by the TeNT neutralizing antibody. The key neutralization epitope on the fragment C of TeNT identified in our work provides the critical information for the development of fragment C of TeNT as a better and safer tetanus vaccine.

Aims & Objective: Coronavirus Disease 2019 (COVID-19) caused by the human coronavirus 2019 (HCoV-19, also known as SARS-CoV-2) infection is currently in a global outbreak. COVID-19 has posed a huge threat to public health and economic stability worldwide. CR3022, a human monoclonal neutralizing antibody isolated from a Severe Acute Respiratory Syndrome (SARS) recovery patient, was confirmed to be able to bind the S protein of HCoV-19 with a certain degree of neutralizing activity. Crystal structural information indicated that CR3022 could bind to the epitope on the receptor binding domain (RBD) of HCoV-19, whose epitope consists of 28 amino acids, and 24 of them are conserved in SARS-CoV of SARS. However, the crystal structure is only a static conformation at a certain moment in time, and it cannot provide dynamic details of the interaction between antigen and antibody. Methods: In this study, molecular dynamics (MD) simulation combined with MM/PBSA and CAS methods were performed to investigate the mechanism of binding of CR3022 against SARS-CoVRBD and HCoV-19-RBD in order to determine their holographic dynamic information. Results: It was found that the CR3022-SARS-CoV-RBD complex was more stable during 100ns MD run than that of the CR3022-HCoV-19-RBD system. There were common conservative amino acids on the β2 sheet of RBD, including Tyr369, Phe377, Lys378, Tyr380, Gly381, Lys386, Leu390 and others. These conservative amino acids play significant roles in the binding process of CR3022 antibody against SARS-CoV-RBD and HCoV-19-RBD. It was also found that the binding mode of CR3022 to its native target SARS-CoV-RBD is more comprehensive and uniform. Moreover, the β2 sheet residue Thr385 and non-β2 sheet residues Arg408 and Asp428 of the CR3022-SARS-CoV-RBD system were found to be crucial for their binding affinities, thus forming a special conformational epitope. However, these key amino acids are not present in the CR3022-HCoV-19-RBD system. The binding mode of CR3022 and HCoV-19-RBD is similar to that of SARS-CoV-RBD, but the deficiency of crucial hydrogen-bonds and salt-bridges. Therefore, the binding of CR3022 and HCoV-19-RBD only draws on the partial mode of the binding of CR3022 and SARS-CoV-RBD, so there is a loss of affinity. Conclusion: Thus, in order to better fight the epidemic of COVID-19 with the CR3022 antibody, this antibody needs to further improve the neutralization efficiency of HCoV-19 through mutation of it’s CDR region.

BACKGROUND Tumor-derived exosomes have been used as diagnostic biomarkers to discriminate between tumor patients and healthy people. This study explored the roles of exosomal miRNAs in lung adenocarcinoma metastasis by microarray and developed a novel method for diagnosis of lung adenocarcinoma. MATERIAL AND METHODS Four lung adenocarcinoma patients' peripheral blood, including 2 metastasis and 2 N-metastasis, were used for exosomes miRNA microarray analysis. Exosomes were extracted by ultracentrifugation and identified by transmission electron microscopy. All the raw data were normalized by R software with limma packet. qRT-PCR was used to validate the microarray results. A549 cells were used to identify the functions of miR-4448. Western blot, qRT-PCR, RNAi, CCK8, and transwell invasion assay were used to verify the metastasis and proliferation abilities. RESULTS miR-4436a and miR-4687-5p were upregulated between the metastasis and N-metastasis group, while miR-22-3p, miR-3666, miR-4448, miR-4449, miR-6751-5p and miR-92a-3p were downregulated. miR-4448 was also downregulated between the metastasis and control group, whereas there was no significant difference between the N-metastasis group and control group. qRT-PCR confirmed the downregulation of miR-4448 in exosomes from lung adenocarcinoma patients compared with N-metastasis patients and healthy people. CCK8 and transwell invasion assay showed that A549 cells transfected with miR-4448 inhibitor had higher proliferation and metastasis ability. qRT-PCR and Western blot confirmed the high expression of MMP2 and MMP9 in A549 cells transfected with miR-4448 inhibitor. CONCLUSIONS miR-4448 can inhibit A549 cell proliferation and metastasis. miR-4448 in exosomes has the potential to serve as a diagnostic marker of patients with adenocarcinoma metastasis.

The present study aimed to develop an effective nomogram for predicting the overall survival (OS) of patients with cerebral anaplastic glioma (AG). This study included 1939 patients diagnosed with AG between 1973 and 2013 who were identified using the Surveillance, Epidemiology, and End Results database. A multivariate Cox regression analysis revealed that age, histology, tumor site, marital status, radiotherapy, and surgery were independent prognostic factors and, thus, these factors were selected to build a clinical nomogram. Harrell's concordance index (C-index) and a calibration curve were formulated to evaluate the discrimination and calibration of the nomogram using bootstrapping. A nomogram was developed to predict 5- and 9-year OS rates based on 6 independent prognostic factors identified in the training set: age, tumor site, marital status, histology, radiotherapy, and surgery (P

A goal of HIV vaccine development is to elicit antibodies with neutralizing breadth. Broadly neutralizing antibodies (bNAbs) to HIV often have unusual sequences with long heavy-chain complementarity-determining region loops, high somatic mutation rates and polyreactivity. A subset of HIV-infected individuals develops such antibodies, but it is unclear whether this reflects systematic differences in their antibody repertoires or is a consequence of rare stochastic events involving individual clones. We sequenced antibody heavy-chain repertoires in a large cohort of HIV-infected individuals with bNAb responses or no neutralization breadth and uninfected controls, identifying consistent features of bNAb repertoires, encompassing thousands of B cell clones per individual, with correlated T cell phenotypes. These repertoire features were not observed during chronic cytomegalovirus infection in an independent cohort. Our data indicate that the development of numerous B cell lineages with antibody features associated with autoreactivity may be a key aspect in the development of HIV neutralizing antibody breadth., A subset of HIV-infected individuals can develop broadly neutralizing antibodies. Boyd and colleagues studied such HIV-infected individuals and found significant perturbations in their antibody repertoires, including increased frequencies of B cells expressing antibodies with features associated with autoreactivity.

Four potent native human mAbs targeting distinct epitopes on TeNT were isolated with neutralization potency ranging from approximately 17 mg to 6 mg each equivalent to 250IU of human anti-TeNT immunoglobulin. TT0170 binds fragment B, TT0069 and TT0155 bind fragment AB. MAb TT0067 binds fragment C and blocks the binding of TeNT to gangliosides, Co-crystal structure of TT0067 with fragment C of TeNT at 2.01 A resolution demonstrated that mAb TT0067 directly occupies the W pocket of one of the receptor binding sites on TeNT, resulting in blocking the binding of TeNT to ganglioside on the surface of host cells to neutralize TeNT, and revealed at the first time at atomic level the mechanism of action by TeNT neutralizing antibody and the key neutralization epitope on the fragment C of TeNT, and provided the critical information for development of fragment C of TeNT as a better and safer tetanus vaccine.

MicroRNA are significant regulators of neuropathic pain development. Neuroinflammation contributes a lot to the progression of neuropathic pain. miR-381 is involved in various pathological processes. However, the role of miR-381 in neuropathic pain development remains barely understood. Therefore, in our study, we aimed to investigate the effects of miR-381 on the process of neuropathic pain progression by establishing a rat model using chronic sciatic nerve injury (CCI). Here, we observed that miR-381 was dramatically decreased in CCI rats. Up-regulation of miR-381 strongly reduced neuropathic pain behaviors including mechanical and thermal hyperalgesia. In addition, inflammatory cytokine expression, including IL-6, IL-10 and TNF-α were significantly repressed by overexpression of miR-381. High mobility group box 1 protein (HMGB1) and Chemokine CXC receptor 4 (CXCR4) participate in neuropathic pain development. In our present study, HMGB1 and CXCR4 were predicted as direct targets of miR-381 by employing bioinformatics analysis. Overexpression of miR-381 was able to restrain the expression of HMGB1 and CXCR4 greatly. The direct correlation between HMGB1 and CXCR4 and miR-381 was confirmed in our research. Furthermore, we found that HMGB1 and CXCR4 were increased in CCI rats time-dependently. Moreover, it was demonstrated that silence of HMGB1 and CXCR4 in CCI rats depressed neuropathic pain progression greatly. In conclusion, it was indicated that miR-381could inhibit neuropathic pain development through targeting HMGB1 and CXCR4.

BACKGROUND Before tyrosine kinase inhibitor (TKI) therapy can be administered in patients with advanced non-small cell lung cancer (NSCLC), EGFR mutation testing is required. However, few studies have evaluated the extent of EGFR testing in real-world practice in China. METHODS A multicenter, observational study of EGFR testing in NSCLC patients in North China was conducted. Treatment-naive patients or those with postoperative recurrent stage IIIB/IV NSCLC were enrolled. The primary objective was EGFR testing rate. Secondary objectives included EGFR mutation status, EGFR testing methods and specimens, factors associated with EGFR testing, and overall survival with or without EGFR testing. RESULTS Overall, 2809 patients with stage IIIB/IV NSCLC were enrolled; 90.78% had adenocarcinoma. The EGFR screening rate was 42.54%. EGFR testing rates were higher in tumor samples obtained by lymph node puncture, and in patients with urban medical insurance, adenocarcinoma, non-smokers, or those located in developed cities (all P < 0.001). The EGFR mutation rate was 46.44%. The most commonly used specimens for EGFR testing were biopsy tumor samples (67.53%). PCR-based methods (72.05%), Sanger sequencing (5.36%), and Luminex liquid chip (5.10%) were the most frequently used testing platforms. Similar positive EGFR mutation rates were achieved with different platforms. TKI therapy was the first-line treatment administered to most EGFR-positive patients (56.22%), and chemotherapy in EGFR-negative patients (84.88%). Overall survival was higher in EGFR-tested than in untested patients (27.50 vs. 19.73 months; P = 0.007). CONCLUSION Real-world EGFR testing rates for NSCLC in North China were relatively low because of clinical and social factors, including medical insurance coverage.

Cervical spine diseases lead to a heavy economic burden to the individuals and societies. Moreover, frequent post-operative complications mean a higher risk of neck pain and revision. At present, controversy still exists for the etiology of spinal diseases and their associated complications. Knowledge of in vivo cervical spinal loading pattern is proposed to be the key to answer these questions. However, direct acquisition of in vivo cervical spinal loading remains challenging. In this study, a previously developed cervical spine musculoskeletal multi-body dynamics model was utilized for spinal loading prediction. The in vivo dynamic segmental contributions to head motion and the out-of-plane coupled motion were both taken into account. First, model validation and sensitivity analysis of different segmental contributions to head motion were performed. For model validation, the predicted intervertebral disk compressive forces were converted into the intradiskal pressures and compared with the published experimental measurements. Significant correlations were found between the predicted values and the experimental results. Thus, the reliability and capability of the cervical spine model was ensured. Meanwhile, the sensitivity analysis indicated that cervical spinal loading is sensitive to different segmental contributions to head motion. Second, the compressive, shear and facet joint forces at C3–C6 disk levels were predicted, during the head flexion/extension, lateral bending and axial rotation. Under the head flexion/extension movement, asymmetric loading patterns of the intervertebral disk were obtained. In comparison, symmetrical typed loading patterns were found for the head lateral bending and axial rotation movements. However, the shear forces were dramatically increased during the head excessive extension and lateral bending. Besides, a nonlinear correlation was seen between the facet joint force and the angular displacement. In conclusion, dynamic cervical spinal loading was both intervertebral disk angle-dependent and level-dependent. Cervical spine musculoskeletal multi-body dynamics model provides an attempt to comprehend the in vivo biomechanical surrounding of the human head-neck system.

Pardi and colleagues report on a vaccine platform in which purified, antigen-encoding, nucleoside-modified mRNA is encapsulated in lipid nanoparticles. Immunization with this vaccine elicits potent T follicular helper cell, germinal center B cell, and protective, neutralizing antibody responses., T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.

Detailed knowledge of the in vivo loading and kinematics in the knee joint is essential to understand its normal functions and the aetiology of osteoarthritis. Computer models provide a viable non-invasive solution for estimating joint loading and kinematics during different physiological activities. However, the joint loading and kinematics of the tibiofemoral and patellofemoral joints during a gait cycle were not typically investigated concurrently in previous computational simulations. In this study, a natural knee architecture was incorporated into a lower extremity musculoskeletal multibody dynamics model based on a force-dependent kinematics approach to investigate the contact mechanics and kinematics of a natural knee joint during a walking cycle. Specifically, the contact forces between the femoral/tibial articular cartilages and menisci and between the femoral and tibial/patellar articular cartilages were quantified. The contact forces and kinematics of the tibiofemoral and patellofemoral joints and the muscle activations and ligament forces were predicted simultaneously with a reasonable level of accuracy. The developed musculoskeletal multibody dynamics model with a natural knee architecture can serve as a potential platform for assisting clinical decision-making and postoperative rehabilitation planning.

Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

We have previously indicated that CXCL3 was upregulated in the tissues of prostate cancer, and exogenous administration of CXCL3 played a predominant role in the tumorigenicity of prostate cancer cells. In the present study, we further explored the role and the underlying mechanism of CXCL3 overexpression in the oncogenic potential of prostate cancer in an autocrine/paracrine fashion. CXCL3-overexpressing prostate cancer cell line PC-3 and immortalized prostate stromal cell line WPMY-1 were established by gene transfection. CCK-8, transwell assays and growth of tumor xenografts were conducted to characterize the effects of CXCL3 on PC-3 cells’ proliferation and migration. Western blotting was conducted to test whether CXCL3 could affect the expression of tumorigenesis-associated genes. The results showed that CXCL3 overexpression in PC-3 cells and the PC-3 cells treated with the supernatants of CXCL3-transfected WPMY-1 cells stimulated the proliferation and migration of PC-3 cells in vitro and in a nude mouse xenograft model. Western blotting revealed higher levels of p-ERK, Akt and Bcl-2 and lower levels of Bax in the tumor xenografts transplanted with CXCL3-transfected PC-3 cells. Moreover, the tumor xenografts derived from the PC-3 cells treated with supernatants of CXCL3-transfected WPMY-1 cells showed higher expression of ERK, Akt and Bcl-2 and lower expression of Bax. These findings suggest that CXCL3 autocrine/paracrine pathways are involved in the development of prostate cancer by regulating the expression of the target genes that are related to the progression of malignancies.