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Background: The effectiveness of platelet-rich plasma (PRP) injections for knee osteoarthritis and the effects of leukocyte-poor PRP (LP-PRP) versus leukocyte-rich PRP (LR-PRP) are still controversial. Purpose: To assess the effectiveness of different PRP injections through a direct and indirect meta-analysis of randomized controlled trials. Study Design: Systematic review; Level of evidence, 1. Methods: A systematic literature search of electronic databases (PubMed, Cochrane Library, and EMBASE) was performed to locate randomized controlled trials published through March 2019 that compared PRP with control treatment. A random-effects meta-analysis was conducted to synthesize the evidence, and meta-regression analyses were conducted to determine the influence of trial characteristics. An indirect comparison was performed to assess the effects of LP-PRP and LR-PRP compared with hyaluronic acid (HA). Results: A total of 21 trials were included. A clinically important benefit for pain relief was seen for intra-articular PRP compared with intra-articular saline (standardized mean difference [SMD] = –1.38 [95% CI, –2.07 to –0.70]; P < .0001; I 2 = 37%) and corticosteroid solution injection (SMD = –2.47 [95% CI, –3.34 to –1.61]; P < .00001; I 2 = 47%). As a result of heterogeneity (I 2 = 89%), there was no conclusive effect compared with HA, even though the pooling effect provided clinically relevant pain relief (SMD = –0.59 [95% CI, –0.97 to –0.21]; P = .003). Indirect meta-analysis showed that there was no significant difference between LR-PRP and LP-PRP. Conclusion: PRP injections are beneficial for pain relief and functional improvement in knee osteoarthritis. Larger, randomized high-quality studies are needed to compare the effects of LP-PRP and LR-PRP.

Immune checkpoint inhibitors (ICI) benefit some cancer patients but de novo resistance remains poorly understood. Analyzing transcriptional data from two clinical trial cohorts, GO30140 and IMbrave150, we find B cell lymphoma 9 (BCL9), a Wnt/β-catenin co-factor, associated with resistance. We develop a BCL9-targeting peptide, hsBCL9 Z96 , which suppresses tumor growth in combination with anti-PD-L1 ab in preclinical hepatocellular carcinoma (HCC) mouse models. Multi-omics analyses implicate targeting BCL9 inhibits BMP4 secretion and downregulates CD24 on tumor cells, reprogramming macrophages toward a tumor-suppressive phenotype and promoting macrophage phagocytosis. This in turn rejuvenates T cell immunity via enhanced macrophage-mediated antigen presentation. Our data extend our understanding of how tumor-derived Wnt/β-catenin signaling impedes the innate and adaptive immune responses in the tumor microenvironment and provide preliminary evidence that targeting BCL9 is a promising preclinical strategy to mitigate ICI resistance in HCC. Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

The CRISPR/Cas9 system is an efficient gene-editing method, but the majority of gene-edited animals showed mosaicism, with editing occurring only in a portion of cells. Here we show that single gene or multiple genes can be completely knocked out in mouse and monkey embryos by zygotic injection of Cas9 mRNA and multiple adjacent single-guide RNAs （spaced 10-200 bp apart） that target only a single key exon of each gene. Phenotypic analysis of F0 mice following targeted deletion of eight genes on the Y chromosome individually demonstrated the robustness of this approach in generating knockout mice. Importantly, this approach delivers complete gene knockout at high efficien- cies （100% on Arnt[ and 91% on Prrt2） in monkey embryos. Finally, we could generate a complete Prrt2 knockout monkey in a single step, demonstrating the usefulness of this approach in rapidly establishing gene-edited monkey models.

Background Sustained activation of hepatocyte growth factor (HGF)/c-MET signaling is a major driver of hepatocellular carcinoma (HCC) progression, but underlying mechanism is unclear. ArfGAP With SH3 Domain, Ankyrin Repeat And PH Domain 2 (ASAP2) can reportedly activate GTPases and promote receptor tyrosine kinase signaling. However, the exact role of ASAP2 in HCC, especially for c-MET activation, also remains elusive. Methods ASAP2 expression levels in HCC tissues and cells were quantified using qRT-PCR, western blot (WB) analysis, and immunohistochemistry staining. Cell counting kit-8 (CCK-8) and colony formation assays were performed to evaluate cell proliferation rates. Flow cytometry assays were conducted to assess apoptosis rates. Wound healing and Transwell assays were performed to determine cell migration and invasion capacities. Epithelial-mesenchymal transition (EMT)-related marker expression levels were also examined. Subcutaneous implantation and tail vein injection models were applied for in vivo growth and metastasis evaluations, respectively. Bioinformatics analyses of The Cancer Genome Atlas and STRING datasets were performed to explore ASAP2 downstream signaling. Co-immunoprecipitation and Cycloheximide chasing experiments were performed to assess protein–protein interactions and protein half-life, respectively. Results ASAP2 had higher expression levels in HCC tissues than in normal liver, and also predicted poor prognosis. Knocking down ASAP2 significantly impaired cell proliferation, migration, and invasion capacities, but promoted apoptosis in HCC cells in vitro. However, overexpression of ASAP2 achieved the opposite effects. In vivo experiments confirmed that ASAP2 could promote HCC cell growth and facilitate lung metastasis. Interestingly, ASAP2 was essential for triggering EMT. Gene Set Enrichment Analysis demonstrated that c-MET signaling was greatly enriched in ASAP2-high HCC cases. Additionally, c-MET signaling activity was significantly decreased following ASAP knockdown, evidenced by reduced c-MET, p-AKT, and p-ERK1/2 protein levels. Importantly, ASAP2 knockdown effectively attenuated HGF/c-MET signaling-induced malignant phenotypes. c-MET and ASAP2 expression levels were positively correlated in our cohort. Mechanistically, ASAP2 can directly bind to CIN85, thereby disrupting its interaction with c-MET, and can thus antagonize CIN85-induced c-MET internalization and lysosome-mediated degradation. Notably, knocking down CIN85 can rescue the observed inhibitory effects caused by ASAP2 knockdown. Conclusions This study highlights the importance of ASAP2 in sustaining c-MET signaling, which can facilitate HCC progression.

Targeted integration of transgenes can be achieved by strategies based on homologous recombination （HR）, mi- crohomology-mediated end joining （MMEJ） or non-homologous end joining （NHEJ）. The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining （HMEJ）-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and -800 bp of homology arms, and the targeted genome. We found no significant improve- ment of the targeting efficiency by the HMEJ-based method in either mouse embryonic stem cells or the neuroblas- toma cell line, N2a, compared to the HR-based method. However, the HMEJ-based method yielded a higher knock- in efficiency in HEK293T cells, primary astrocytes and neurons. More importantly, this approach achieved transgene integration in mouse and monkey embryos, as well as in hepatocytes and neurons in vivo, with an efficiency much greater than HR-, NHEJ- and MMEJ-based strategies. Thus, the HMEJ-based strategy may be useful for a variety of applications, including gene editing to generate animal models and for targeted gene therapies.

Identification of new nasopharyngeal carcinoma (NPC) biomarkers is of great clinical value for the diagnosis and treatment of NPC. HOTAIR, a cancer‐related long non‐coding RNA, was tested and its prognostic value for NPC was evaluated. As determined using in situ hybridization (ISH), 91 of 160 (56.87%) paraffin‐embedded NPC biopsies showed high expression levels of HOTAIR (staining index score ≥ 6). HOTAIR was upregulated in tumors with a large size (P = 0.021), more advanced clinical stage (P = 0.012) and increased lymph node tumor burden (P = 0.005). Quantified using real‐time PCR, HOTAIR expression levels in fresh tissue and paraffin‐embedded samples were 5.2 ~ 48.4‐fold higher compared with non‐cancer tissue samples. Moreover, HOTAIR expression levels increased with clinical stage progression, which was consistent with ISH findings in the paraffin‐embedded tissue. Most importantly, NPC patients with higher HOTAIR levels had a poor prognosis for overall survival using univariate and multivariate analysis. In addition, HOTAIR mediated the migration, invasion and proliferation of NPC cells in vitro. HOTAIR is a potential biomarker for the prognosis of NPC, and dysregulation of HOTAIR might play an important role in NPC progression.

This article investigates corporate social responsibility (CSR) practices while taking into account their product substitutability and environmental responsibility. CSR firms, integrating environmental and social concerns into its business operations, are introduced. The effects of the firms' social concerns, environmental responsibility, and product substitutability are all captured. First, firms' social concerns improve both outputs and CSR firms' objective function value, while reducing the profit maximization firm's profits. Second, environmental responsibility has the contrary effects. Both the outputs and the objective function values of both firms decrease with their product substitutability. Finally, social concern effects on CSR firms' performance are uncertain.

Systemic sclerosis (SSc) is a remarkably systemic heterogeneous connective tissue disease with many organs involved. The heart is one of the major organs involved, carrying the threat of sudden cardiac death, especially in diffuse cutaneous SSc. This review summarizes the pathophysiology, types, new diagnostic approaches, and imaging and novel therapies of primary cardiac complications while underlining the effects of recently developed non-contrast cardiovascular magnetic resonance (CMR) in early diagnosis. Medline and Embase were searched for articles published up to July 2019. A combination of Medical Subject Headings (MeSH) terms and keywords pertaining to SSc (\"Scleroderma, Systemic\" OR \"Systemic sclerosis\" OR' SSc\"), AND cardiology (\"cardiology\" OR \"heart\" OR \"cardiac\") were applied to the search strategies. Literature was mainly printed in English and Chinese about cardiac complications in systemic sclerosis. After selected simply on the title and abstract, the articles were included for the full text. Article type was not limited. Relevant cardiac manifestations are complex, including arrhythmias, pericardial effusion, myocardial dysfunction, and valvular diseases. Even though the symptoms of cardiac complications are well known, unfortunately, they appear to be poor prognostic factors. As systemic sclerosis with cardiac complications has a high mortality rate and patients might have a poor quality of life, it is essential to promote early diagnosis and treatment. With the advent of non-invasive imaging techniques, such as CMR, early diagnosis of cardiac complications in SSc is becoming more effective. Cardiac complications play an essential role in SSc and carry the threat of sudden cardiac death. More basic and clinical studies are warranted to develop better management of cardiac involvement in patients with SSc.

Dear Editor, Germ cell transplantation and testicular tissue grafting have been developed for male fertility restoration. The testis tissue from young mammals, including mice and monkeys, is capable of undergoing complete spermatogenesis in xenografts, and sperms obtained from monkey testicular tissue xenografts have yielded monkey blastocysts after intracytoplasmic sperm injection （ICSI）,

Breast cancer is one of the most common cancer in women and a proportion of patients experiences brain metastases with poor prognosis. The study aimed to construct a novel predictive clinical model to evaluate the overall survival (OS) of patients with postoperative brain metastasis of breast cancer (BCBM) and validate its effectiveness. From 2010 to 2020, a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University, and they were randomly assigned to the training cohort and the validation cohort. Data of another 173 BCBM patients were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database as an external validation cohort. In the training cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS. The model capability was assessed using receiver operating characteristic, C-index, and calibration curves. Kaplan-Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model. The accuracy and prediction capability of the model were verified using the validation and SEER cohorts. LASSO Cox regression analysis revealed that lymph node metastasis, molecular subtype, tumor size, chemotherapy, radiotherapy, and lung metastasis were statistically significantly correlated with BCBM. The C-indexes of the survival nomogram in the training, validation, and SEER cohorts were 0.714, 0.710, and 0.670, respectively, which showed good prediction capability. The calibration curves demonstrated that the nomogram had great forecast precision, and a dynamic diagram was drawn to increase the maneuverability of the results. The Risk Stratification System showed that the OS of low-risk patients was considerably better than that of high-risk patients ( P < 0.001). The nomogram prediction model constructed in this study has a good predictive value, which can effectively evaluate the survival rate of patients with postoperative BCBM.