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Background The detection of islet autoantibodies is essential for the accurate classification and diagnosis of diabetes mellitus (DM). The islet autoantibody distribution varies by age. However, screening strategies for DM patients with different onset ages remain lacking. Methods This cross-sectional study included 17 536 DM patients from 46 medical centers across China. The seroprevalence of glutamic acid decarboxylase autoantibody (GADA), insulinoma-associated-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A) and insulin autoantibody (IAA) was determined in younger and older patients with type 1 DM (T1DM) (n=287 and 285, respectively), younger and older patients with latent autoimmune diabetes (LAD) (n=140 and 121, respectively), and younger and older patients with type 2 DM (T2DM) (n=200 in each group). Results The cutoff age between younger and older patients was 35 years using restricted cubic spline method (n = 17 536, adjusted R2 = 0.97, residual standard error = 1.32; P < 0.001). The seroprevalence rates of four islet autoantibodies were higher in patients aged 15-35 years than in those ≥ 35 years (GADA: 17% vs. 5.6%, IA-2A: 8.5% vs. 1.3%, ZnT8A: 6.3% vs. 2.3%, IAA: 2.2% vs. 1.0%). The prevalence of ZnT8A was higher in LAD patients than in T1DM patients, especially in older LAD patients. The results indicated that ZnT8A detection can increase the detection rate of older LAD patients from 70.2% (based on GADA detection alone) to 91.7%. Conclusions In patients stratified according to the cutoff age of 35 years, the optimal detection sequence should be GADA, IA-2A, and ZnT8A in younger patients and GADA, ZnT8A, and IA-2A in older patients, so as to reduce the screening cost while improving the detection rate. Particularly, the ZnT8A test is recommended in older patients to avoid a missed LAD diagnosis.

Background Prenatal stress (PS) can cause brain retardation, reduce the learning and memory ability of the offspring and significantly increase the incidence of depression in offspring. Paeoniflorin (PF), a kind of monoterpenoid glycoside, is one of the main active ingredients of Chinese Medicine Paeonia lactiflora Pall, has anti-inflammation and potential neuroprotective effects. However, few reports have shown that the neuroprotective effects of PF are exerted through ameliorating Glutamate toxicity in vivo and in vitro. Methods Here, we used a prenatal restraint stress model and Glu-induced excitotoxic neurotoxicity in SH-SY5Y cells to study the effects of PF. Results Our results showed that PF can ameliorate learning and memory impairments and increases the density of hippocampal neurons, typical Golgi-positive pyramidal cells, and neuronal Neurogranin (Ng) expression in PS rat offspring. Furthermore, PF can significantly up-regulate the decrease of Glu-induced SH-SY5Y cell viability. At the same time, PF can significantly reduce apoptosis, ROS, NO levels, and intracellular Ca2+ concentration, and significantly inhibit the increase of mitochondrial membrane potential. Besides, PF significantly increased the expression of Nrf2 and iNOS, decreased p-JNK/JNK, p-P38/P38, Bax/Bcl-2, active-caspase-3, and active-caspase-9. Conclusions Our results demonstrate that PF may be an effective treatment in preventing the development of PS-induced learning and memory impairment and have therapeutic potential in Glu-related neurological diseases.

Background Computed tomography (CT)‐detected extramural venous invasion (EMVI) has been identified as an independent factor that can be used for risk stratification and prediction of prognosis in patients with gastric cancer (GC). Overall survival (OS) is identified as the most important prognostic indicator for GC patients. However, the molecular mechanism of EMVI development and its potential relationship with OS in GC are not fully understood. In this radiogenomics‐based study, we sought to investigate the molecular mechanism underlying CT‐detected EMVI in patients with GC, and aimed to construct a genomic signature based on EMVI‐related genes with the goal of using this signature to predict the OS. Materials and Methods Whole mRNA genome sequencing of frozen tumor samples from 13 locally advanced GC patients was performed to identify EMVI‐related genes. EMVI‐prognostic hub genes were selected based on overlapping EMVI‐related differentially expressed genes and OS‐related genes, using a training cohort of 176 GC patients who were included in The Cancer Genome Atlas database. Another 174 GC patients from this database comprised the external validation cohort. A risk stratification model using a seven‐gene signature was constructed through the use of a least absolute shrinkage and selection operator Cox regression model. Results Patients with high risk score showed significantly reduced OS (training cohort, p = 1.143e‐04; validation cohort, p = 2.429e‐02). Risk score was an independent predictor of OS in multivariate Cox regression analyses (training cohort, HR = 2.758; 95% CI: 1.825–4.169; validation cohort, HR = 2.173; 95% CI: 1.347–3.505; p, Imaging feature of computed tomography‐detected extramural venous invasion (EMVI) has been identified as an independent risk factor of gastric cancer (GC). We aimed to investigate the molecular mechanism of EMVI based on whole mRNA genome sequencing of frozen cancerous samples from 13 locally advanced GC. Then using TCGA database, we constructed an EMVI‐related gene model and found it could predict the prognosis in patients with GC.

PURPOSE To assess liver necroinflammation in HCV patients undergone antiviral therapy by Gd-EOB-DTPA-enhanced MRI with histopathologic analyses as reference. METHODS HCV patients were enrolled in this prospective study before antiviral treatment between 09-2016 and 07-2017. Unenhanced MR, Gd-EOB-DTPA-enhanced MR, and liver biopsy were performed before and 24 weeks after treatment of daclatasvir with asunaprevir (DAA). DWI was obtained using a breath-hold single-shot echo planar spin-echo sequence. Twenty minutes after administration of Gd-EOB-DTPA, the relative enhancement (RE) and the contrast enhancement index (CEI) were recorded. Liver necroinflammatory activity grades (G0-18) were categorized on the Ishak Scoring systems. CEI, RE, and DWI of baseline and 24 weeks after treatment were compared by paired t test. Relationship between MR parameters and histologic scores was evaluated by Pearson's correlation. Receiver operating characteristic analysis evaluated the measurements' diagnostic performance. MRI variability between two readers was assessed using the intraclass correlation coefficient.Results RESULTS: A decrease of liver necroinflammatory activity grade (p

Androgenetic complete hydatidiform moles (CHMs) are associated with an increased risk of gestational trophoblastic neoplasia. P57KIP2 expression in hydatidiform moles is thought to be a powerful marker for differentiating CHMs from partial hydatidiform moles (PHMs). However, since there are so few such families clinically, very few studies have addressed the importance of p57KIP2-positive in the diagnosis and prognosis of CHM. This study aimed to emphasize the significance of the accurate diagnosis of rare CHM and careful follow-up. The classification of the hydatidiform mole was based on morphologic examination and p57KIP2 expression was determined by p57KIP2 immunohistochemical staining. Copy number variation sequencing was used to determine the genetic make-up of the mole tissues. In addition, the short tandem repeat polymorphism analysis was used to establish the parental origin of the moles. Finally, whole-exome sequencing was performed to identify the causal genetic variants associated with this case. In one Chinese family, the proband had numerous miscarriages throughout her two marriages. Morphologic evaluation and molecular genotyping accurately sub-classified two molar specimens as uniparental disomy CHM of androgenetic origin. Furthermore, p57KIP2 expression was found in cytotrophoblasts and villous stromal cells. In the tissue, there were hyperplasia trophoblastic cells and heteromorphic nuclei. In this family, no deleterious variant genes associated with recurrent CHM were detected. It is important to evaluate the prognostic value of p57KIP2 expression in androgenetic recurrent CHM. This knowledge may help to minimize erroneous diagnosis of CHMs as PHMs, as well as making us aware of the need to manage potential gestational trophoblastic neoplasia.

Pseudomonas aeruginosa DN1 can efficiently utilize fluoranthene as its sole carbon source, and the initial reaction in the biodegradation process is catalyzed by a ring-hydroxylating dioxygenase (RHD). To clarify the binding interaction of RHD with fluoranthene in the strain DN1, the genes encoding alpha subunit (RS30940) and beta subunit (RS05115) of RHD were functionally characterized through multi-technique combination such as gene knockout and homology modeling as well as molecular docking analysis. The results showed that the mutants lacking the characteristic alpha subunit and/or beta subunit failed to degrade fluoranthene effectively. Based on the translated protein sequence and Ramachandran plot, 96.5% of the primary amino-acid sequences of the alpha subunit in the modeled structure of the RHD were in the permitted region, 2.3% in the allowed region, but 1.2% in the disallowed area. The catalytic mechanism mediated by key residues was proposed by the simulations of molecular docking, wherein the active site of alpha subunit constituted a triangle structure of the mononuclear iron atom and the two oxygen atoms coupled with the predicted catalytic ternary of His217-His222-Asp372 for the dihydroxylation reaction with fluoranthene. Those amino acid residues adjacent to fluoranthene were nonpolar groups, and the C7-C8 positions on the fluoranthene ring were estimated to be the best oxidation sites. The distance of C7-O and C8-O was 3.77 Å and 3.04 Å respectively, and both of them were parallel. The results of synchronous fluorescence and site-directed mutagenesis confirmed the roles of the predicted residues during catalysis. This binding interaction could enhance our understanding of the catalytic mechanism of RHDs and provide a solid foundation for further enzymatic modification.

Background: The best type of autograft for anterior cruciate ligament (ACL) reconstruction remains debatable. Hypothesis: Compared with bone–patellar tendon–bone (BPTB) and hamstring tendon (HT) autografts, the quadriceps tendon (QT) autograft has comparable graft survival as well as clinical function and pain outcomes. Study Design: Meta-analysis; Level of evidence, 4. Methods: A systematic literature search was conducted in PubMed, Embase, Scopus, and the Cochrane Library to July 2020. Randomized controlled trials (RCTs) and observational studies reporting comparisons of QT versus BPTB or HT autografts for ACL reconstruction were included. All analyses were stratified according to study design: RCTs or observational studies. Results: A total of 24 studies were included: 7 RCTs and 17 observational studies. The 7 RCTs included 388 patients, and the 17 observational studies included 19,196 patients. No significant differences in graft failure ( P = .36), the International Knee Documentation Committee (IKDC) subjective score ( P = .39), or the side-to-side difference in stability ( P = .60) were noted between QT and BPTB autografts. However, a significant reduction in donor site morbidity was noted in the QT group compared with the BPTB group (risk ratio [RR], 0.17 [95% CI, 0.09-0.33]; P < .001). No significant differences in graft failure ( P = .57), the IKDC subjective score ( P = .25), or the side-to-side stability difference ( P = .98) were noted between QT and HT autografts. However, the QT autograft was associated with a significantly lower rate of donor site morbidity than the HT autograft (RR, 0.60 [95% CI, 0.39-0.93]; P = .02). A similar graft failure rate between the QT and control groups was observed after both early and late full weightbearing, after early and late full range of motion, and after using the QT autograft with a bone plug and all soft tissue QT grafts. However, a significantly lower rate of donor site morbidity was observed in the QT group compared with the control group after both early and late full weightbearing, after early and late full range of motion, and after using the QT autograft with a bone plug and all soft tissue QT grafts. No difference in effect estimates was seen between RCTs and observational studies. Conclusion: The QT autograft had comparable graft survival, functional outcomes, and stability outcomes compared with BPTB and HT autografts. However, donor site morbidity was significantly lower with the QT autograft than with BPTB and HT autografts.

Introduction and Aims: Elevated plasma levels of C-reactive protein (CRP) are closely associated with progressive renal injury in patients with chronic kidney disease (CKD). Here, we tested a hypothesis that CRP may promote renal fibrosis and inflammation via a TGF-β/Smad3-dependent mechanism. Methods: Role and mechanisms of TGF-β/Smad3 in CRP-induced renal fibrosis and inflammation were examined in a mouse model of unilateral ureteral obstruction (UUO) induced in CRP Tg/Smad3 KO mice and in a rat tubular epithelial cell line in which Smad3 gene is stably knocked down (S3KD-NRK52E). Results: We found that mice overexpressing the human CRP gene were largely promoted renal inflammation and fibrosis as evidenced by increasing IL-1β, TNF-α, MCP-1 expression, F4/80+ macrophages infiltration, and marked accumulation of α-smooth muscle actin (α-SMA), collagen I and fibronectin in the UUO kidney, which were blunted when Smad3 gene was deleted in CRPtg-Smad3KO. Mechanistically, we found that the protection of renal inflammation and fibrosis in the UUO kidney of CRPtg-Smad3KO mice was associated with the inactivation of CD32-NF-κB and TGF-β/Smad3 signaling. Conclusion: In conclusion, Smad3 deficiency protects against CRP-mediated renal inflammation and fibrosis in the UUO kidney by inactivating CD32-NF-κB and TGF-β/Smad3 signaling.

Sepsis is a serious complication after infection, whose further development may lead to multiple organ dysfunction syndrome and so on. It is an important cause of death in critically ill patients who suffered an infection. Sepsis cardiomyopathy is a common complication that exacerbates the prognosis of patients. At present, though the pathogenesis of sepsis cardiomyopathy is not completely clear, in-depth study of the pathogenesis of sepsis cardiomyopathy and the discovery of its potential therapeutic targets may decrease the mortality of sepsis patients and bring clinical benefits. This article reviews mitochondrial dysfunction, mitophagy, oxidation stress, and other mechanisms in sepsis cardiomyopathy.

Background The primary aim of this systematic review and meta-analysis was to compare postoperative pain, analgesic consumption, and complications after fascia iliaca block (FIB) versus control for patients undergoing primary total hip arthroplasty (THA). Second, we compared the outcomes of FIB versus placebo. Finally, we sought to evaluate pain and analgesic consumption after preoperative and postoperative FIB. Methods We performed a systematic literature search in MEDLINE, Embase, Scopus, Web of Science, Google Scholar, ClinicalTrials.gov, and CENTRAL through February 2021 to identify randomized controlled trials (RCTs) that evaluated the efficacy of FIB versus control for patients undergoing primary THA. All analyses were conducted on intent-to-treat data with a random-effects model. Results Twelve RCTs with a total of 815 patients were included. There was no difference in postoperative pain (P = 0.64), analgesic consumption (P = 0.14), or complication rate (P = 0.99) between FIB and control groups. Moreover, no difference in postoperative pain (P = 0.26), analgesic consumption (P = 0.06), or complication rate (P = 0.71) was found between FIB and placebo. Moreover, sensitivity analysis suggested that no significant difference in postoperative pain, analgesic consumption, or complication rate was present between FIB and control in studies that used preoperative and postoperative FIB. Conclusion FIB was not found to be superior to placebo or various anesthetic techniques for patients undergoing primary THA, as measured by postoperative pain, analgesic consumption, and complications.

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19., COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.

Characterizing the structural basis of ligand recognition of adenosine A2A receptor (AA2AR) will facilitate its rational design and development of small molecules with high affinity and selectivity, as well as optimal therapeutic effects for pain, cancers, drug abuse disorders, etc. In the present work, we applied our reported algorithm, molecular complex characterizing system (MCCS), to characterize the binding features of AA2AR based on its reported 3D structures of protein-ligand complexes. First, we compared the binding score to the reported experimental binding affinities of each compound. Then, we calculated an output example of residue energy contribution using MCCS and compared the results with data obtained from MM/GBSA. The consistency in results indicated that MCCS is a powerful, fast, and accurate method. Sequentially, using a receptor-ligand data set of 57 crystallized structures of AA2ARs, we characterized the binding features of the binding pockets in AA2AR, summarized the key residues that distinguish antagonist from agonist, produced heatmaps of residue energy contribution for clustering various statuses of AA2ARs, explored the selectivity between AA2AR and AA1AR, etc. All the information provided new insights into the protein features of AA2AR and will facilitate its rational drug design.

Direct implantation of mesenchymal stem cells (MSCs) for cartilage and bone tissue engineering faces challenges, such as immune rejection and loss of cellular viability or functionality. As nanoscale natural particles, exosomes or small extracellular vesicles (EVs) of MSCs have potential to circumvent these problems. It is significant to investigate the impact of the tissue origin of MSCs on the therapeutic bioactivity of their corresponding EVs for cartilage and bone regeneration. Here, rat MSCs isolated from the adipose, bone marrow, and synovium are cultured to obtain their corresponding EVs (ADSC-EVs, BMSC-EVs, and SMSC-EVs, respectively). The ADSC-EVs stimulate the migration, proliferation, and chondrogenic and osteogenic differentiation of BMSCs in vitro as well as cartilage and bone regeneration in a mouse model more than the BMSC-EVs or SMSC-EVs. Proteomics analysis reveals that the tissue origin contributes to the distinct protein profiles among the three types of EVs, which induced cartilage and bone regenerative capacities by potential mechanisms of regulating signaling pathways including focal adhesion, ECM-receptor interaction, actin cytoskeleton, cAMP, and PI3K-Akt signaling pathways. Consequently, these findings provide insight that the adipose may be a superior candidate in EV-based nanomedicine for cartilage and bone regeneration. STATEMENT OF SIGNIFICANCE: Extracelluar vesicles (EVs) of mesenchymal stem cells (MSCs) have been considered as a promising approach in cartilage and bone tissue engineering. In this study, for the first time, we investigated the tissue origin effect of EVs on chondrogenesis and osteogenesis of MSCs in vitro and in vivo. The results demonstrated that EVs of adipose-derived MSCs showed the most efficiency. Meanwhile, protein proteomics revealed the potential mechanisms. We provide a novel evidence that the adipose is a superior reservoir in EV-based nanotechnologies and biomaterials for cartilage and bone regeneration.

Accumulating evidence has suggested that mechanical stimuli play a crucial role in regulating the lineage-specific differentiation of stem cells through fine-tuning redox balance. We aimed to investigate the effects of cyclic tensile strain (CTS) on the expression of antioxidant enzymes and cardiac-specific genes in P19 cells, a widely characterized tool for cardiac differentiation research. A stretching device was applied to generate different magnitude and duration of cyclic strains on P19 cells. The messenger RNA and protein levels of targeted genes were determined by real-time polymerase chain reaction and Western blot assays, respectively. Proper magnitude and duration of cognitive stimulation therapy (CST) stimulation substantially enhanced the expression of both antioxidant enzymes and cardiac-specific genes in P19 cells. Sirtuin 1 (SIRT1) played an essential role in the CTS-induced cardiomyogenic differentiation of P19, as evidenced by changes in the expression of antioxidant enzymes and cardiac-specific genes. Mechanical loading promoted the cardiomyogenic differentiation of P19 cells. SIRT1 was involved in CST-mediated P19 differentiation, implying that SIRT1 might serve as an important target for developing methods to promote cardiomyogenic differentiation of stem cells.

Pesticides are widely used in the world for agriculture and industry. A lot of pesticide residues are observed in our air, soil, and water, which has been regarded as serious environmental contaminations. More and more researches begin to pay attention to the potential toxic effects of pesticides on human health. Till now, it has been confirmed that pesticides exposures are associated with carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. Pesticides exposure might play an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. In this review, we focused on the relationship between the main commonly used pesticides and dopaminergic neurodegeneration. The main mechanism of neurotoxicity induced by pesticides exposure were also discussed. Additionally, it is known that the main histological hallmark of dopamine neurodegeneration is the presence of α-synuclein aggregates called Lewy bodies. Therefore, we also discussed the linkages between pesticide exposure and synuclein protein aggregation, which would be helpful to understand the etiology of neurodegeneration.

Tumor repopulation occurs when residual tumor cells surviving therapies tenaciously proliferate and re‐establish the tumor. The cellular and molecular mechanisms underlying this process remain poorly understood. In this study, we propose that polyploid giant cancer cells (PGCCs) are involved in tumor repopulation via neosis following radiotherapy. We found that although the majority of PGCCs induced by irradiation underwent cell death, some PGCCs exhibited proliferative capacity. Utilizing time‐lapse microscopy and single‐cell cloning assays, we observed that proliferating PGCCs underwent neosis, thereby contributing to tumor cell repopulation after irradiation. Notably, HMGB1 released from dying tumor cells rather than intracellular HMGB1 could promote neosis‐based tumor repopulation, and the latter could be suppressed by the use of HMGB1 inhibitors. Taken together, our results indicate that PGCC can initiate tumor repopulation via neosis following radiation therapy., In this study, we propose that polyploid giant cancer cells (PGCCs) are involved in tumor repopulation following radiotherapy. Although the majority of PGCCs induced by irradiation underwent cell death, some PGCCs exhibited proliferative capacity, identified as neosis. HMGB1 released from dying tumor cells rather than intracellular HMGB1 could promote neosis‐based tumor repopulation.

Chiral assemblies by combining natural biomolecules with plasmonic nanostructures hold great promise for plasmonic enhanced sensing, imaging, and catalytic applications. Herein, we demonstrate that human serum albumin (HSA) and porcine serum albumin (PSA) can guide the chiral assembly of gold nanorods (GNRs) with left-handed chiroptical responses opposite to those by a series of other homologous animal serum albumins (SAs) due to the difference of their surface charge distributions. Under physiological pH conditions, the assembly of HSA or PSA with GNRs yielded left-handed twisted aggregates, while bovine serum albumin (BSA), sheep serum albumin, and equine serum albumin behaved on the contrary. The driving force for the chiral assembly is mainly attributed to electrostatic interaction. The opposite chiroptical signals acquired are correlated with the chiral surface charge distributions of the tertiary structures of SAs. Moreover, the chirality of the assembly induced by both HSA and BSA can be enhanced or reversed by adjusting the pH values. This work provides new insights into the modulation of protein-induced chiral assemblies and promotes their applications.

Aims Very limited data are available concerning the clinicopathological and molecular features of early subungual melanoma (SM), especially with regard to the Asian population. The aim of this study was to investigate the clinical, histological, immunohistochemical and chromosomal features of early SM. Methods and results Fifty-two in-situ and 13 thin (Breslow thickness ≤1.0 mm) SM cases were retrospectively reviewed. All patients presented with longitudinal melanonychia involving a single digit, and the thumb was the most affected digit (35 of 65, 53.8%). Microscopically, most cases showed small to medium nuclear enlargement (58 of 65) and mild to moderate nuclear atypia (57 of 65). Hyperchromatism and irregular contours of nuclei were persistent features in all cases. The variation of melanocyte count (the number of melanocytes per mm dermal-epithelial junction) ranged from 31 to 255. Intra-epithelial mitoses were identified in 34 cases (52.3%). Statistically, features of in-situ lesions including higher melanocyte count (>70), presence of multinucleated melanocytes, inflammatory infiltrate and cutaneous adnexal extension, were associated with early invasion. Melan-A, human melanoma B (HMB)45, mouse monoclonal melanoma antibody (PNL2) and SOX10 antibodies (>95.0%) showed superior diagnostic sensitivity to S-100 protein (83.1%). Fluorescence in-situ hybridisation (FISH) results were positive in 15 of 23 successfully analysed cases. Conclusions To the best of our knowledge, this is the largest single-institution study of early SM in an Asian population, and the largest cohort tested by FISH. Early SM mainly showed small to medium nuclear enlargement and mild to moderate nuclear atypia. High melanocyte count, hyperchromatism and irregular contours of nuclei and intra-epithelial mitoses are crucial diagnostic parameters. Immunohistochemistry, especially SOX10 staining, and FISH analysis are valuable in the diagnosis of SM.

Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

Radiotherapy is an effective treatment for non-small cell lung cancer (NSCLC). However, irradiated, dying tumor cells generate potent growth stimulatory signals during radiotherapy that promote the repopulation of adjacent surviving tumor cells to cause tumor recurrence. We investigated the function of caspase-3 in NSCLC repopulation after radiotherapy. We found that radiotherapy induced a DNA damage response (DDR), activated caspase-3, and promoted tumor repopulation in NSCLC cells. Unexpectedly, caspase-3 knockout attenuated the ataxia-telangiectasia mutated (ATM)/p53-initiated DDR by decreasing nuclear migration of endonuclease G (EndoG), thereby reducing the growth-promoting effect of irradiated, dying tumor cells. We also identified p53 as a regulator of the Cox-2/PGE2 axis and its involvement in caspase-3-induced tumor repopulation after radiotherapy. In addition, injection of caspase-3 knockout NSCLC cells impaired tumor growth in a nude mouse model. Our findings reveal that caspase-3 promotes tumor repopulation in NSCLC cells by activating DDR and the downstream Cox-2/PGE2 axis. Thus, caspase-3-induced ATM/p53/Cox-2/PGE2 signaling pathway could provide potential therapeutic targets to reduce NSCLC recurrence after radiotherapy.

Articular cartilage has a highly organized structure, responsible for supporting tremendous mechanical loads. How to repair defected articular cartilage has become a great challenge as the avascular nature of cartilage limits its regenerative ability. Aiming to facilitate chondrogenic differentiation and cartilage regeneration, we recently explored a novel combination therapy using soluble poly-l-lysine/Kartogenin (L-K) nanoparticles and a poly(lactic-co-glycolic acid) PLGA/methacrylated hyaluronic acid (PLHA) complex scaffold. The potential use for joint cartilage reconstruction was investigated through L-K nanoparticles stimulating adipose-derived stem cells (ADSCs) on PLHA scaffolding, which ultimately differentiated into cartilage in vivo. In this study, on one hand, an effective method was established for obtaining uniform L-K nanoparticles by self-assembly. They were further proved to be biocompatible to ADSCs via cytotoxicity assays in vitro and to accelerate ADSCs secreting type 2 collagen in a dose-dependent manner by immunofluorescence. On the other hand, the porous PLHA scaffold was manufactured by the combination of coprecipitation and ultraviolet (UV) cross-linking. Nanoindentation technology-verified PLHA had an appropriate stiffness close to actual cartilage tissue. Additional microscopic observation confirmed that the PLHA platform supported proliferation and chondrogenesis for ADSCs in vitro. In the presence of ADSCs, a 12-week osteochondral defect regeneration by the combination therapy showed that smooth and intact cartilage tissue successfully regenerated. Furthermore, the results of combination therapy were superior to those of phosphate-buffered saline (PBS) only, KGN, or KGN/PLHA treatment. The results of magnetic resonance imaging (MRI) and histological assessment indicated that the renascent tissue gradually regenerated while the PLHA scaffold degraded. In conclusion, we have developed a novel multidimensional combination therapy of cartilage defect repair that facilitated cartilage regeneration. This strategy has a great clinical translational potential for articular cartilage repair in the near future.

In vivo and vitro evidence indicates that ornithine and its related metabolic products play a role in tumor development. Whether ornithine is associated with breast cancer in humans is still unclear. We examined the association between circulating ornithine levels and breast cancer in females. This 1:1 age-matched case–control study identified 735 female breast cancer cases and 735 female controls without breast cancer. All cases had a pathological test to ascertain a breast cancer diagnosis. The controls were ascertained using pathologic testing, clinical examinations, and/or other tests. Fasting blood samples were used to measure ornithine levels. The average age for cases and controls were 49.6 years (standard deviation [SD] 8.7 years) and 48.9 years (SD 8.7 years), respectively. Each SD increase in ornithine levels was associated with a 12% reduction of breast cancer risk (adjusted odds ratio [OR] 0.88; 95% confidence interval [CI] 0.79–0.97). The association between ornithine and breast cancer did not differ by pathological stages of diagnosis or tumor grades (all P for trend > 0.1). We observed no effect measure modification by molecular subtypes (P for interaction = 0.889). In conclusion, higher ornithine levels were associated with lower breast cancer risk in females.

Longitudinal melanonychia in paediatric patients often represents a difficult diagnostic challenge, and studies emphasising its clinical and histopathological features are limited due to its low incidence in childhood.We retrospectively analysed 35 paediatric cases identified by excision specimens on their clinicopathological features, and performed fluorescence in-situ hybridisation on 13 available cases. Fingernails (77.1%) were more likely to be affected. Total melanonychia and Hutchinson's sign were observed in 10 (28.6%) and 14 (40.0%) cases, respectively. Nail dystrophy at diagnosis was present in five cases. After complete excision of the lesions, four patients relapsed during follow-up (mean = 38 months). Seventeen cases were diagnosed as lentigines and 18 as naevi, among which 11 cases were categorised as lentigines/naevi with atypical melanocytic hyperplasia. Mild-to-moderate nuclear atypia, confluency of melanocytes, focal pagetoid spread and peri-ungual skin involvement were found in 25.7% (9 of 35), 40.0% (14 of 35), 40.0% (14 of 35) and 40.0% (14 of 35) of cases, respectively. Thirteen cases tested by fluorescence in-situ hybridisation showed no copy number aberration at the probed loci. There was a statistically significant difference in the following features between patients aged less and more than 10 years (P 0.05): cytomorphology, mild-to-moderate nuclear atypia, confluency of melanocytes, focal pagetoid spread and melanocyte count.Some concerning clinicopathological characteristics, which are signs indicative of melanoma in adults, are not uncommon in paediatric longitudinal melanonychia, especially in patients aged ≤ 10 years. Owing to the extremely low incidence of melanoma in paediatric longitudinal melanonychia, in most circumstances a more conservative clinical management strategy should be adopted.

Available safety evaluations regarding mesoporous silica nanoparticles (mSiNPs) are based on the assumption of a relatively high exposure concentration, which makes the findings less valuable in a realistic environment. In this study, we employed Caenorhabditis elegans (C. elegans) as a model to assess the neuronal damage caused by mSiNPs at the predicted environmentally relevant concentrations. After nematodes were acute and prolonged exposed to mSiNPs at concentrations over 300 μg/L, locomotion degeneration, shrinking behavior, and abnormal foraging behavior were observed, which were associated with the deficits in the development of GABAergic neurons, including D-type and RME motor neurons. Furthermore, the oxidative stress evidenced by excessive ROS generation might contribute to the mechanism of mSiNPs damaging neurons. Although the neurotoxicity of mSiNPs was weaker than (nonmesoporous) SiNPs, it is still necessary for researchers to pay attention to the adverse effects caused by mSiNPs in the environmental animals, especially with the rapid increase in mSiNPs application. Considering the conserved property of GABAergic neurons during evolution, these findings will shed light on our understanding of the potential eco-risks of NPs to the nervous system of other animal models.

Objective: To assess the efficacy of bronchoscopic interventional therapy for benign tracheal stenosis by combination of intelligent imaging analysis system and immunohistochemistry. Methods: The therapeutic effect was evaluated by Computed Tomography (CT) image changes, and the effects of thermofrequency and glucocorticoids were analyzed by animal experiments. Eighteen patients with benign tracheal stenosis who were enrolled in 2017.06–2019.06 were enrolled, and the thickness, diameter and lumen area of the most narrow tracheal tube before and after bronchoscopy and 1 month after bronchoscopy were measured using intelligent image analysis software. Thirty male SD rats were randomly divided into three groups (Radiofrequency group, Glucocorticoids+Radiofrequency group and control group). At the 5th, and 28th day the comparisons were made on the pathological changes of rats skin,the average optical density value of TGF-β1 and the collagen density after the damage by Radiofrequency, Glucocorticoids+Radiofrequency. Results: The thickness, diameter and lumen area of the wall before and after bronchoscopy are: 3.17 ± 1.01 mm versus 1.60 ± 0.23 mm; 3.61 ± 1.23 mm versus 9.04 ± 1.00 mm; 11.19 ± 5.32 versus 67.34 ± 13.80 mm2. The scar healing was observed in Radiofrequency group, but in the Glucocorticoids+Radiofrequency group the rats’ skin were healed incompletely. The results showed significant statistical differences among three groups on TGF-β1 comparisons: 988.41 ± 111.91, 730.19 ± 109.52 and 437.37 ± 60.48 (P < 0.05). The same results of comparisons on the collagen density showed: 96540.58 ± 29909.51, 43768.16 ± 6264.72 and 34521.15 ± 4636.19 (P < 0.05). Conclusions: After bronchoscopy intervention, the wall thickness of benign tracheal stenosis can be reduced, and the lumen diameter and area can be increased. The results can be analyzed using CT. Locally injected Betamethasone can alleviate the cicatricial tissue hyperblastosis induced by radiofrequency.

Diabetes is associated with a high risk of developing cognitive impairment, but the underlying mechanism remains unclear. Recent studies have found that gut microbiota may be involved in the progression of diabetes-associated cognitive impairment.To analyze the diversity of gut microbiota in type 2 diabetes with or without cognitive impairment METHODS: 16S rRNA sequencing was used to detect the gut microbiota composition in 154 type 2 diabetes (T2DM) subjects RESULTS: Among 154 elderly T2DM participants included in our study, 73 with normal and 81 with impaired cognition. Lower levels of hemoglobin and HDL were observed in subjects with cognitive impairment. Patients with cognitive impairment had a lower abundance of Tenericutes. Comparison at the genus level revealed that T2DM patients with cognitive impairment had a decreased abundance of Bifidobacterium and unranked-RF39 and an increased abundance of Peptococcus and unranked-Leuconostocaceae. Additionally, the relative abundance of Veillonella and Pediococcus were decreased in subjects with cognitive impairment. Furthermore, the relative abundance of 7 sub-functions was significantly changed in the group with cognitive impairment. Calcium signaling pathways and the Renin-angiotensin system were upregulated in the cognitive impairment group while GnRH signaling, Fc gamma R-mediated phagocytosis, endocytosis, isoflavonoid biosynthesis, and cytochrome P450 were deregulated.Bifidobacterium may be associated with cognition in T2DM. Calcium signaling and renin-angiotensin system were shown to be associated with diabetes-associated cognitive impairment through gut microbiota.

BackgroundLongitudinal evidence on change of serum urate level with mortality risk is limited as prior studies have a measurement of serum urate at a single time point. Further, the combined effect of serum urate and systemic inflammation on mortality is unknown.MethodsWe conducted a prospective cohort study of 152,358 participants (122,045 men and 30,313 women) with repeated measurements of serum urate in 2006, 2008, 2010, and 2012 (107,751 participants had all four measurements of serum urate). We used the Cox proportional hazard model to examine the association between cumulative average and changes in serum urate with mortality. The combined effect of serum urate and systemic inflammation was determined by testing the interaction of serum urate and high-sensitive C-reactive protein (hs-CRP) in relation to mortality risk.ResultsDuring a median follow-up of 8.7 (interquartile range 6.3–9.2) years, we identified 7564 all-cause deaths, 1763 CVD deaths, 1706 cancer deaths, and 1572 other deaths. We observed U-shaped relationships of cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with stable serum urate, those with greater increases in serum urate had a 1.7-fold elevated mortality (hazard ratio (HR) = 1.66, 95% confidence interval (CI) = 1.49–1.84), and those with decreased serum urate had a 2-fold elevated mortality risk (HR = 2.14, 95% CI 1.93–2.37). Participants with both hyperuricemia and hs-CRP had 1.6 times higher mortality, compared with those with low serum urate and hs-CRP levels (HR = 1.56, 95% CI 1.37–1.76).ConclusionsWe observed a U-shaped relationship of long-term cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with relatively stable serum urate levels, a greater increase or decrease in serum urate was associated with elevated mortality. Participants with both hyperuricemia and high systemic inflammation had the greatest mortality risk compared with those with low serum urate and low hs-CRP levels.

Mesenchymal stem cells (MSCs)-derived exosomes are being increasingly focused as the new biological pro-regenerative therapeutic agents for various types of tissue injury. Here, we explored the potential of a novel exosome-based therapeutic application combined with a local fibrin delivery strategy for tendon repair. After discovering that bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) promoted the proliferation, migration and tenogenic differentiation of tendon stem/progenitor cells (TSPCs) in vitro, we embedded BMSCs-exos in fibrin and injected it into the defect area of rat patellar tendon, and the results showed that the exosomes could be controlled-released from the fibrin, retained within the defect area, and internalized by TSPCs. BMSCs-exos embedded in fibrin significantly improved the histological scores, enhanced the expression of mohawk, tenomodulin, and type I collagen, as well as the mechanical properties of neotendon, and also promoted the proliferation of local TSPCs in vivo. Overall, we demonstrated the beneficial role of BMSCs-exos in tendon regeneration, and that fibrin-exosomes delivery system represents a successful local treatment strategy of exosomes. This study brings prospects in the potential application of exosomes in novel therapies for tendon injury. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells have been identified as a preferred approach in tissue regeneration. In this study, we reported bone marrow mesenchymal stem cells (BMSCs) promote the proliferation and migration of tendon stem/progenitor cells (TSPCs) via the paracrine signaling effect of the nanoscale exosomes. We also demonstrated that the application of BMSCs-derived exosomes might be a promising approach to activate the regenerative potential of endogenous TSPCs in tendon injured region, and fibrin-exosomes delivery system represents a successful local treatment strategy of exosomes.