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ABSTRACTMesenchymal stem cells (MSCs) with multipotential differentiation ability are main cell source for cartilage tissue engineering, but its application is restricted by the difficulty in regulating committed chondrogenic differentiation. Study revealed that certain substrate topographic structure can enhance the chondrogenic differentiation of MSCs. This study prepared silk fibroin (SF) films with gradient microscopic surface patterns based on P280-P7000 type specification sandpapers, and investigated the adhesion, proliferation and chondrogenic differentiation of human adipose-derived stem cells (hADSCs) on the SF films. The results showed that the SF films surface had convex dots with diameter of 3–50 μm, and hADSCs could adhere and proliferate well on the film. Transcriptomics analysis indicated that hADSCs tend to differentiate differently on the SF films, among which hADSCs on P1000 SF films had higher expression of chondrogenic markers Sox-9 and Col-II, with activated yes associated protein (YAP) and restricted F-actin. In vitro co-culture of human OA knee cartilage with hADSCs seeded SF films found satisfactory cartilage protection effect in P1000 group. Overall, this study preliminarily revealed the microscopic surface pattern of SF films may induce chondrogenic differentiation of hADSCs through extracellular matrix mediated Hippo/Yap pathway, and provided a new strategy for cartilage repair.

Antibiotic resistance genes (ARGs) are critical emerging pollutants that have attracted considerable attention. Deoxynivalenol (DON) is one of the most prevalent mycotoxins in cereal crops worldwide, arising severe health hazards to both humans and animals. Even if numerous researches argue in favor of a notorious influence of DON on the gut, the effects of dietary DON exposure on the ARG profile in poultry intestine remain obscure. In this study, two separate feeding experiments using Jing Tint 6 laying hens exposed to 4.5 or 9.0 mg/kg DON were performed to explore the impact of dietary DON exposure on the microbial community structure and the profiles of ARGs in the intestine via 16S rDNA sequencing and metagenomics sequencing, respectively. In addition, growth performance and intestinal barrier function were also determined to assess the feasibility of using DON-contaminated feedstuffs inappropriate for pigs’ consumption in laying hens. Chronic ingestion of DON at 9.0 mg/kg did not alter zootechnical parameters. However, histomorphological impairments were observed in liver and jejunum. Additionally, metagenomic sequencing revealed that dietary DON exposure at 9.0 mg/kg level dramatically changed the gut microbial structure and shifted the ARG profile. The abundance of tetracycline ARG subtype in the layer cecum was decreased, whereas the abundance of vancomycin ARG subtype was increased upon DON exposure. Co-occurrence network analysis identified that Prevotella was the major ARG host in the intestine of laying hens. In summary, our findings demonstrated that DON-contaminated feedstuffs inappropriate for pigs’ consumption should be prudently used in hen production, and shed new light on the interactions between mycotoxins and ARGs in the poultry intestine.

Abstract Philadelphia chromosome (Ph)‐like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high‐risk subset of Ph‐like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph‐like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling (CRLF2/EPOR/JAK2 rearrangements or p‐CRKL/p‐STAT5 high expression) had the worst outcome (3‐year overall survival [OS] of 28.8% vs. 80.1% for others, p

Abstract Background Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal and multi-directional differentiation potential and possess the functions of immunomodulation, regulation of cell growth, and repair of damage. Over recent years, MSCs have been found to regulate the secretion of inflammatory factors and to exert regulatory effects on various lymphocytes in inflammatory states, and on the subsequent repair of tissue damage caused by inflammation. In the present study, we analyzed the effects of tissue inflammation on the characteristics of MSCs. Methods Human fat derived from the infrapatellar fat pad (IPFP) of knees with differing degrees of inflammation was extracted from specimens derived from total knee arthroplasties. HE and immunohistochemical staining was performed to directly observe the evidence and degree of inflammation in human infrapatellar fat pad tissue in order to classify MSCs cells, by their origin, into highly inflamed and lowly inflamed groups, and to study the effect of tissue inflammation on cell acquisition rates via cellular counting data. Flow cytometry assays were performed to investigate the effect of tissue inflammation on MSC surface marker expression. Trilineage differentiation, including osteogenesis, adipogenesis, and chondrogenesis, was performed to assess the effect of tissue inflammation on the ability of MSCs to undergo directed differentiation. The effect of tissue inflammation on the ability of MSCs to proliferate was investigated via clone formation studies. RNA-sequencing was performed to evaluate the transcriptomes of MSCs derived from different areas of inflammation. The effect of tissue inflammation on tissue repair capacity and safety of MSCs was investigated via a murine model of acute liver injury. Results The results of cell count data indicate that a high degree of tissue inflammation significantly decreases the acquisition rate of MSCs, and the proportion of CD34+ and CD146+ cells. The results of our trilineage differentiation assay show that a higher degree of inflammation decreases osteogenic differentiation and enhances adipogenic and chondrogenic differentiation of MSCs. However, these differences were not statistically significant. Clone formation assays indicate that the degree of tissue inflammation at the MSC source does not significantly affect the proliferative capacity of MSCs. The transcriptomes of MSCs remain relatively stable in fat pad tissues derived from both highly and lowly inflamed samples. The results of acute liver injury investigations in mice indicate that MSCs of high and low inflammatory tissue origin have no significant difference in their tissue repair capability. Conclusions High tissue inflammation at the source of MSCs reduces the acquisition rate of MSCs and the percentage of CD34+ and CD146+ cells acquisition. However, source tissue inflammation may not significantly affect trilineage differentiation potential and proliferative capacity of MSCs. Also, MSCs obtained from differing source degrees of inflammation retain stable and similar transcriptomic profile and are both safe and efficacious for tissue repair/regeneration without detectable differences. Graphical Abstract

Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUS::ERG at our center. Thirty-six AML patients harboring FUS::ERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK–RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUS::ERG AML compared to RUNX1::RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUS::ERG AML was 11.9 (95% confidence interval [CI]: 9.0–not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4–NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK–RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.

Background: Osteoarthritis (OA) is a debilitating degenerative joint disease, leading to significant pain and disability. Despite advancements, current regenerative therapies, such as mesenchymal stem cells (MSCs), face challenges in clinical efficacy and ethical considerations. This study aimed to evaluate the therapeutic potential of stromal vascular fraction gel (SVF-gel) in comparison to available treatments like hyaluronic acid (HA) and adipose-derived stem cells (ADSCs) and to assess the enhancement of this potential by incorporating tropoelastin (TE).Methods: We conducted a comparative laboratory study, establishing an indirect co-culture system using a Transwell assay to test the effects of HA, ADSCs, SVF-gel, and TE-SVF-gel on osteoarthritic articular chondrocytes (OACs). Chondrogenic and hypertrophic markers were assessed after a 72-hour co-culture. SVF-gel was harvested from rat subcutaneous abdominal adipose tissue, with its mechanical properties characterized. Cell viability was specifically analyzed for SVF-gel and TE-SVF-gel. The in vivo therapeutic effectiveness was further investigated in a rat model of OA, examining MSCs tracking, effects on cartilage matrix synthesis, osteophyte formation, and muscle weight changes.Results: Cell viability assays revealed that TE-SVF-gel maintained higher cell survival rates than SVF-gel. In comparison to the control, HA, and ADSCs groups, SVF-gel and TE-SVF-gel significantly upregulated the expression of chondrogenic markers COL 2, SOX-9, and ACAN and downregulated the hypertrophic marker COL 10 in OACs. The TE-SVF-gel showed further improved expression of chondrogenic markers and a greater decrease in COL 10 expression compared to SVF-gel alone. Notably, the TE-SVF-gel treated group in the in vivo OA model exhibited the most MSCs on the synovial surface, superior cartilage matrix synthesis, increased COL 2 expression, and better muscle weight recovery, despite the presence of fewer stem cells than other treatments.Discussion: The findings suggest that SVF-gel, particularly when combined with TE, provides a more effective regenerative treatment for OA by enhancing the therapeutic potential of MSCs. This combination could represent an innovative strategy that overcomes limitations of current therapies, offering a new avenue for patient treatment. Further research is warranted to explore the long-term benefits and potential clinical applications of this combined approach.

In order to extend the shelf life of Pleurotus eryngii in nanofilm vacuum packaging, the fresh postharvest Pleurotus eryngii was placed in TiO2 and SiO2 composite nanofilm fresh-keeping bags, the sample was precooled to below 4 ℃ under 0.07 MPa and then stored at 2 ℃. In order to evaluate the dynamic changes of flavor qualities during storage, the free amino acids and the volatile flavor compounds were analyzed at 0, 20, and 40 days. The results showed that 17 free amino acids were detected, including 7 essential amino acids. The total amount of amino acids was 1196.15 mg/100 g, 1425.26 and 1629.77 mg/100 g on day 0, 20 and 40, and the content of delicious amino acids increased with storage time. A total of 36 volatile compounds were detected. The alcohols and esters were the two main components, which accounting for about 90% of the total volatile compounds content. The Venn diagram of volatile compounds, the heat diagram of relative content, and the PCA load diagram of key volatile substances revealed that the types and contents of volatile flavor compounds of Pleurotus eryngii changed significantly (P

Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.

Methotrexate (MTX) has an antitumor effect when used for the treatment of acute lymphoblastic leukemia (ALL). This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX. Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay. The serum MTX concentration was determined using homogeneous enzyme immunoassay. MTX-related toxicities were also evaluated. Renal toxicity was significantly associated with higher serum MTX concentrations at 24, 48, and 72 hours, and MTX elimination delay (P = 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively), whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours, and MTX elimination delay in candidate polymorphisms (P = 0.014, P = 0.019, and P = 0.007, respectively). SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours (P = 0.016, P = 0.043, respectively). MTRR rs1801394 was associated with serum MTX concentrations at 72 hours (P = 0.045). Neutropenia was related to SLC19A1 rs4149056 (odds ratio [OR]: 3.172, 95% confidence interval [CI]: 1.310–7.681, P = 0.011). Hepatotoxicity was associated with ABCC2 rs2273697 (OR: 3.494, 95% CI: 1.236–9.873, P = 0.018) and MTRR rs1801394 (OR: 0.231, 95% CI: 0.084–0.632, P = 0.004). Polymorphisms of SLCO1B1, SLC19A1, ABCC2, and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.

Background Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). For years, RARA, RARB and RARG rearrangement were found in resembling APL continually. The confirmed partner genes of RARG rearrangement included CPSF6, NUP98, NPM1, PML, and HNRNPC. These patients were a group of resembling APL with rare molecular genetic abnormality and unfavorable prognosis. They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy.Case presentation We reported a 25-year-old female patient with a novel fusion gene RARG-HNRNPM (RARG chr12:53606869: –; HNRNPM chr19: 8527413: + based on GRCh37/hg19 Assembly) through RNA-seq as resembling APL. The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse.Discussion and conclusions RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.

Anterior cruciate ligament (ACL) rupture is one of the most common knee injuries. Due to the limited self-healing capacity, complex structure, and mechanical environment, the regeneration of ACL remains a challenge. To achieve fast recovery and long-term ACL regeneration, biodegradable scaffolds with excellent initial mechanical support and cell recruitment ability have gained increasing research interest. The aptamer-functionalized silk fiber was fabricated by embedding silk fiber into morpholinoethanesulfonic/1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride, N-hydroxysuccinimide buffer with aptamer 19s (Apt19s) and characterized in vitro. The clinically size-matched silk ligament was braided utilizing commercial methodology (polyethylene terephthalate ligament), and the tensile strength was analyzed. A total of 18 rabbits were used to test the early mesenchymal stem cell (MSC) recruitment of Apt19s-functionalized silk ligaments. Macroscopic analysis and hematoxylin and eosin and immunohistochemistry stainings were applied at 3, 5, and 7 days post-implantation. The ultimate strength of silk fiber was lower than that of PET fibers. However, the prepared silk ligament had comparable mechanical strength to the native ACL. In vitro, the Apt19s-functionalized fiber recruited bone marrow-derived MSCs. In vivo, Apt19s-functionalized silk ligament enhanced early MSCs recruitment after implantation in comparison with the aptamer-free ligament. The Apt19s-functionalized scaffold silk ligament exhibited comparable mechanical strength with native ACL and enhanced endogenous MSC homing.

Abstract Due to radiation resistance and the immunosuppressive microenvironment of metastatic osteosarcoma, novel radiosensitizers that can sensitize radiotherapy (RT) and antitumor immunity synchronously urgently needed. Here, the authors developed a nanoscale metal–organic framework (MOF, named TZM) by co‐doping high‐atomic elements Ta and Zr as metal nodes and porphyrinic molecules (tetrakis(4‐carboxyphenyl)porphyrin (TCPP)) as a photosensitizing ligand. Given the 3D arrays of ultra‐small heavy metals, porous TZM serves as an efficient attenuator absorbing X‐ray energy and sensitizing hydroxyl radical generation for RT. Ta–Zr co‐doping narrowed the highest occupied molecular orbital‐lowest unoccupied molecular orbital (HOMO–LUMO) energy gap and exhibited close energy levels between the singlet and triplet photoexcited states, facilitating TZM transfer energy to the photosensitizer TCPP to sensitize singlet oxygen (1O2) generation for radiodynamic therapy (RDT). The sensitized RT–RDT effects of TZM elicit a robust antitumor immune response by inducing immunogenic cell death, promoting dendritic cell maturation, and upregulating programmed cell death protein 1 (PD‐L1) expression via the cGAS–STING pathway. Furthermore, a combination of TZM, X‐ray, and anti‐PD‐L1 treatments amplify antitumor immunotherapy and efficiently arrest osteosarcoma growth and metastasis. These results indicate that TZM is a promising radiosensitizer for the synergistic RT and immunotherapy of metastatic osteosarcoma.

BackgroundSeveral studies have shown that colorectal adenomas are the most important precancerous lesions. The colonoscopic identification of groups with the high risk of malignant colorectal adenomas remains a controversial issue for clinicians.AimsTo evaluate the basic characteristics of colorectal adenomas with malignancy risk using high-grade dysplasia (HGD) as an alternative marker for malignant transformation.MethodsData from Shanghai General Hospital between January 2017 and December 2021 were retrospectively analyzed. The primary outcome was the incidence of HGD in adenomas, which was used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the HGD rate in adenomas were analyzed in relation to adenoma-related factors.ResultsA total of 9,646 patients identified with polyps during 57,445 screening colonoscopies were included in the study. Patients with flat polyps, sessile polyps, and pedunculated polyps represented 27.3% (N = 2,638), 42.7% (N = 4,114), and 30.0% (N = 2,894) of the total number, respectively. HGD was found in 2.41% (N = 97), 0.92% (N = 24), and 3.51% (N = 98) of sessile adenomas, flat adenomas, and pedunculated adenomas, respectively (P < 0.001). Multivariable logistic regression showed that polyp size (P < 0.001) but not shape (P > 0.8), was an independent predictor of HGD. Contrast to the diameter ≤1 cm, the OR value for diameters 1–2, 2–3, and >3 cm was 13.9, 49.3, and 161.6, respectively. The HGD incidence also increased in multiple adenomas (>3 vs. >1, ORs 1.582) and distal adenomas (distal vs. proximal adenomas, OR 2.252). Adenoma morphology (pedunculated vs. flat) was statistically significant in univariate analysis but not when size was included in the multivariate analysis. Besides, the incidence of HGD was also significantly higher in older patients (>64 vs.

Intra-articular injection of mesenchymal stem cells (MSCs) is a promising strategy for osteoarthritis (OA) treatment. However, more and more studies reveal that the injected MSCs have poor adhesion, migration, and survival in the joint cavity. A recent study shows that tropoelastin (TE) regulates adhesion, proliferation and phenotypic maintenance of MSCs as a soluble additive, indicating that TE could promote MSCs-homing in regenerative medicine. In this study, we used TE as injection medium, and compared it with classic media in MSCs intra-articular injection such as normal saline (NS), hyaluronic acid (HA), and platelet-rich plasma (PRP). We found that TE could effectively improve adhesion, migration, chondrogenic differentiation of infrapatellar fat pad MSCs (IPFP-MSCs) and enhance matrix synthesis of osteoarthritic chondrocytes (OACs) in indirect-coculture system. Moreover, TE could significantly enhance IPFP-MSCs adhesion via activation of integrin β1, ERK1/2 and vinculin (VCL) in vitro. In addition, intra-articular injection of TE-IPFP MSCs suspension resulted in a short-term increase in survival rate of IPFP-MSCs and better histology scores of rat joint tissues. Inhibition of integrin β1 or ERK1/2 attenuated the protective effect of TE-IPFP MSCs suspension in vivo. In conclusion, TE promotes performance of IPFP-MSCs and protects knee cartilage from damage in OA through enhancement of cell adhesion and activation of integrin β1/ERK/VCL pathway. Our findings may provide new insights in MSCs intra-articular injection for OA treatment.

Abstract Very few reports elucidate the prognosis of patients with TP53 aberrations using both measurable residual disease (MRD) and the status of having undergone allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, aberrations of TP53 were analyzed using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) in patients with Philadelphia chromosome-negative (Ph−) ALL enrolled in a prospective single-arm clinical trial at our leukemia center. We analyzed the survival of the patients grouped according to the MRD level at the third month and whether or not received allo-SCT. We found that allo-SCT could improve the OS in patients with TP53 aberrations; Patients having negative MRD at the third month still showed worse 3-year OS and 3-year DFS without undergoing allo-SCT, which is different from previous studies, moreover, the prognostic significance of TP53 deletions was as important as TP53 mutations, the importance of screening both TP53 deletions and mutations in adult Ph− ALL at diagnosis should be emphasized.

Introduction:. Mature plasmacytoid dendritic cells (pDCs) proliferation associated with myeloid neoplasms (MPDMN) are recognized as a neoplasm related to fully differentiated pDCs. Although it has been reported for many years, the genomic landscape of MPDMN is poorly understood. Methods:. We reported two patients who developed acute myeloid leukemia (French-American-British M5 subtype) coexisted with immunophenotypically mature pDCs proliferation, which fit the diagnosis of MPDMN. We sorted pDCs from myeloid blasts by flow cytometry and performed whole-exome sequencing and RNA sequencing of the two cell populations, respectively. Results:. The immunophenotypes of pDCs in both patients were positive for CD123bri, HLA-DR, CD4, CD303, CD304, and negative for CD56, CD34, CD117, and TdT. The variant allele frequency of gene mutations in myeloid blasts and pDCs were similar. The expression data showed myeloid blasts clustered tightly with hematopoietic stem cells, and pDCs from patients clustered tightly with granulocyte-monocyte progenitors/common myeloid progenitor, rather than with pDCs from the GEO platform. Conclusion:. Our study suggested that pDCs derived from the leukemic clone, evidenced by a shared mutation profile and similar transcriptional signatures between pDCs and concurrent myeloid blasts.

Recent studies highlight the vital role of oxidative stress and reactive oxygen species (ROS) during progression of osteoarthritis (OA). Attenuating oxidative stress and reducing reactive oxygen species generation in joints represent reasonable strategies for the treatment of osteoarthritis. To address the potential question for clinical translation, and improve the biocompatibility and long-term performance of current antioxidants, the present study provided high biocompatible small positively charged tantalum nanoparticles (Ta-NH2 NPs) with sustained intra-articular catalase activity and first applied to osteoarthritis intervention. Our in vitro results showed that Ta-NH2 NPs were stable with good biocompatibility, and protected viability and hyaline-like phenotype in H2O2-challenged chondrocytes. In addition, the in vivo biodistribution data demonstrated a sustained retention of Ta-NH2 NPs in the joint cavity, particularly in articular cartilage without organ toxicity and abnormality in hemogram or blood biochemistry indexes. Finally, compared with catalase (CAT), Ta-NH2 NPs exhibited long-term therapeutic effect in monosodium iodoacetate (MIA) induced osteoarthritis model. This study preliminarily explored the potential of simply modified metal nanoparticles as effective reactive oxygen species scavenging agent for osteoarthritis intervention, and offered a novel strategy to achieve sustained reactive oxygen species suppression using biocompatible Ta-based nano-medicine in oxidative stress related diseases.

In the present study, a thermo-mechanical simulator (Gleeble-1500D) is applied to conduct compression tests on homogenized Mg–6Zn-1.2Y–1Mn (wt.%) alloy and investigate features of this alloy in terms of flow behavior, dynamic recrystallization (DRX) evolution and hot workability. Different strain rates varying from 0.005 to 5 s−1 and different temperatures within the range of 200–400 °C are used in the experiments. An apparent mean deformation activation energy of 216.027 kJ/mol with a stress exponent of 10.88964 are achieved by regression analysis of Arrhenius type flow behavior equation. Using true stress-true strain data analysis, a kinetic model of dynamic recrystallization is presented as: XDRX=1−exp[−1.41((ε−εc)/ε∗)1.51]. Furthermore, the processing maps are developed and analyzed according to the dynamic material model (DMM). Based on the processing maps, the flow stability and instability domains are determined. It is found that the optimal hot working region of the alloy is temperature of 325–400 °C and strain rate of 0.005–0.05 s−1. Finally, a finite element analysis is carried out, and the reasonability of the optimal deformation parameters are verified.

Background: Bone marrow stimulation (BMS) is the most used operative treatment in repairing cartilage defect clinically, but always results in fibrocartilage formation, which is easily worn out and needs second therapy. In this study, we prepared an Etanercept (Ept) embedded silk fibroin/pullulan hydrogel to enhance the therapeutic efficacy of BMS.Methods: Ept was dissolved in silk fibroin (SF)—tyramine substituted carboxymethylated pullulan (PL) solution and enzyme crosslinked to obtain the Ept contained SF/PL hydrogel. The synergistical effect of SF/PL hydrogel and Ept was verified by rabbit osteochondral defect model. The mechanism of Ept in promoting articular cartilage repair was studied on human osteoarthritic chondrocytes (hOACs) and human bone marrow mesenchymal stromal cells (hBMSCs) in vitro, respectively.Results: At 4 and 8 weeks after implanting the hydrogel into the osteochondral defect of rabbit, histological analysis revealed that the regenerated tissue in Ept + group had higher cellular density with better texture, and the newly formed hyaline cartilage tissue was seamlessly integrated with adjacent native tissue in the Ept + group. In cellular experiments, Ept treatment significantly promoted both gene and protein expression of type II collagen in hOACs, while decreased the protein levels of metalloproteinase (MMP)-13 and a disintegrin and metalloprotease with thrombospondin motifs 5 (ADAMTS5); alcian blue staining, type II collagen and aggrecan stainings showed that addition of Ept significantly reversed the chondrogenesis inhibition effect of tumor necrosis factor alpha (TNF-α) on hBMSCs.Conclusion: BMS could be augmented by Ept embedded hydrogel, potentially by regulating the catabolic and anabolic dynamics in adjacent chondrocytes and enhancement of BMSCs chondrogenesis.

This work analyzes the Tungsten Inert Gas (TIG)welded joint of AZ31 magnesium alloy and the pitting corrosion stress field at different depths under tensile load via the ANSYS finite element method. The strengths of the stress and strain fields inside the corrosion pit were substantially higher than the average strength level of the matrix. Therefore, under the influence of the applied load, the corrosion pit will fail first. Based on the study of pitting corrosion, a model was developed to explain how pitting corrosion cracks propagate in magnesium alloy welded joints. Finally, the variation of residual strength was revealed to study the corrosion dynamic mechanism of the joints.

Abstract Acute leukemias of ambiguous lineage, not otherwise specified (ALAL-NOS) is a rare type of acute leukemia. Management of relapse/refractory (R/R) patients is still challenging.traditional chemotherapy treatment is not effective. In this paper, we reported 6 R/R patients diagnosed as ALAL-NOS in our hospital, who were treated with venetoclax based treatment (venetoclax combining with azacitidine or chemotherapy). All 6 patients achieved CR. Five of the six patients received allo-HSCT, four patients were still alive in CR until the follow-up day. Our data provide preliminary evidence and show that venetoclax based regimens are effective and safety in patients with R/R ALAL-NOS.

Abstract Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

Abstract Background Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis. Methods In this study, we showed that asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase-13 (MMP-13), alkaline phosphatase (ALP), and runt-related transcription factor 2 (Runx2); chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA); and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II), and aggrecan (ACAN). Further, we tested the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model. Results We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found that AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis. Conclusion AA treatment could reduce hypertrophic and fibrotic differentiation and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.

Although pediatric-like treatment regimen has remarkably improved the survival rates of adults with acute lymphoblastic leukemia (ALL), the outcome of some adult patients is still poor owing to adverse genetic features. These molecular abnormalities, especially gene deletions, may be considered for the prognosis assessment for adult patients with ALL. In this study, using multiplex ligation-dependent probe amplification (MLPA) method, gene deletions were analyzed in from 211 adult B-ALL patients treated in our center. The data showed that 68.2% (144/211) adult B-ALL patients carried gene deletions, and the frequency is much higher in Ph+B-ALL patients. IKZF1 gene deletion is the most common gene deletion in adult B-ALL, followed by CDKN2A/B deletion. In Ph-B-ALL patients, the overall survival of patients with gene deletions is inferior to that of patients without any gene deletions. More obviously, patients with IKZF1 or CDKN2A/B deletion had a worse prognosis, whereas, allogeneic hematopoietic stem cell transplantation could improve OS in patients with IKZF1 deletion, but not in patients with CDKN2A/B deletion. Moreover, the outcome of Ph-B-ALL patients with double deletion of IKZF1and CDKN2A/B may be much worse than that of patients with IKZF1 or CDKN2A/B alone. Minimal residual disease (MRD) was also analyzed together with gene deletions and demonstrated that gene deletions have a negative impact on survival only in MRD positive Ph-B-ALL patients. In conclusion, gene deletions are closely related with the prognosis of adult Ph-B-ALL patients.

Hyperoside, isolated from Drosera rotundifolia L., seeds of Cuscuta chinensis Lam., or Hypericum perforatum L., originally showed to possess an antifungal and antibacterial activity, while recently showed the protective effects against oxidative stress-induced liver injury. This study investigated such a protective effect of hyperoside and the underlying molecular mechanisms in vitro and in carbon tetrachloride (CCl4)-injured rat livers. The data showed that hyperoside was able to prevent the oxidative stress-induced liver morphological changes and CCl4-induced rat liver injury. Hyperoside reversed the decrease of superoxidase dismutase (SOD) level and the increase of malondialdehyde (MDA) level in vivo. Moreover, hyperoside regulated the pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 2 (PHLPP2)-protein kinase B (AKT)-glycogen synthase kinase 3β (GSK-3β) signaling pathway in tert-butylhydroquinone (t-BHP)-treated liver cells, e.g., Hyperoside reduced PHLPP2 expression to activate AKT phosphorylation, induce GSK-3β phosphorylation, and then increased nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation, reduced nuclear translocation of phosphorylated Fyn, and promoted heme oxygenase-1 (HO-1) expression in vivo and in vitro. In contrast, siRNA-mediated knockdown of PHLPP2 expression enhanced hyperoside-mediated activation of the AKT-GSK-3β kinase pathway in liver cells. In conclusion, the present study demonstrated that hyperoside could protect against oxidative stress-induced liver injury by regulating the PHLPP2-AKT-GSK-3β signaling pathway in vivo and in vitro.

The study of candidemia in Chinese leukemia patients has been limited. This retrospective study aims to investigate the characteristics and prognostic factors of candidemia among leukemia patients in a Chinese chemotherapy center. From 2009 to 2015, 30 isolates of candidemia were detected in 19 patients with acute leukemia after chemotherapy. The overall incidence of candidemia was 2.12 episode per 1000 admissions. Candida tropicalis was the most common Candida species (n = 17; 89.5%), followed by Candida albicans (n = 2; 10.5%). The most common underlying disease was acute myeloid leukemia (94.7%) and induction chemotherapy phase was the most susceptible stage. The vast majority of candidal infections are endogenous rather than central venous catheter-related. The overall 30-day crude mortality rate was 31.6%. Neutrophil recovery (P = 0.000) and initiation of empiric antifungal treatment before first positive blood culture (P = 0.041) were associated with a significant improvement in overall survival. Although the incidence of candidaemia appears to be quite low in patients with leukemia submitted to intensive chemotherapy, its high mortality rate continues to be a crucial problem despite the availability of new effective antifungal drugs. Early diagnosis followed by rapid antifungal treatment remains the cornerstone of successful management. Catheter removal should be considered on an individual basis. The widespread use of newer antifungal agents as prophylaxis among patients with acute leukemia may result in a decreased candidemia incidence.

Abstract Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.

Abstract Background Cell source plays a key role in cell-based cartilage repair and regeneration. Recent efforts in cell coculture have attempted to combine the advantages and negate the drawbacks of the constituent cell types. The aim of this study was to evaluate the chondrogenic outcome of articular chondrocytes (ACs) and infrapatellar fat pad (IPFP)-derived mesenchymal stem cells (MSCs) in direct coculture. Methods ACs and IPFP MSCs from the same patients with knee osteoarthritis (OA) were cocultured in monolayer and in pellets. The monocultures of each cell type were also used as controls. Morphological and histologic analysis, immunofluorescence staining, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to characterize the chondrogenic differentiation of cocultures. Furthermore, the effects of chitosan/hyaluronic acid (CS/HA) nanoparticle exposure on the chondrogenesis of cocultures were examined. Results In both monolayer and pellet coculture, the hypertrophy of MSCs and the inflammatory activities of ACs were inhibited, although the chondrogenic production in coculture was not promoted compared with that in monoculture. In addition, the exposure of CS/HA nanoparticles to pellet coculture improved the production of type II collagen and aggrecan. Conclusions We demonstrate for the first time that pellet coculture of ACs and IPFP MSCs with CS/HA nanoparticles could promote chondrogenic outcome while preventing the inflammatory status of ACs and the hypertrophic differentiation of MSCs. These findings suggest that the combination of ACs, IPFP MSCs, and CS/HA might be useful in cartilage repair in knee OA.

Abstract Background The incidence of acute erythroid leukemia subtype (AEL) is rare, accounting for 5% of cases of acute myeloid leukemia (AML), and the outcome is dismal. However, in 2016 revision to the WHO classification, the subcategory of AEL has been removed. Myeloblasts are redefined as the percentage of total marrow cells, not non-erythroid cells. Therefore, the previously diagnosed AEL cases are currently diagnosed as AML or myelodyspalstic syndrome (MDS) according to new criteria. Methods We respectively reviewed cases of 97 de novo previously diagnosed AEL and all the patients were diagnosed as AML or MDS according to the new classification scheme, and then the clinical characteristics of these two subtypes were compared. Statistical analyses were performed by SPSS software version 18.0. Results The median age was 37 years-old, the two-thirds of previous AEL cases were diagnosed as MDS, and there was no obvious difference between two subtypes except for male/female ratio and age. Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. When the cytogenetic risk of patients belonged to MRC intermediate category and age were below 40 years-old in previous AEL cases, the patients who received induction chemotherapy without transplantation had a similar survival compared with the patients who underwent transplantation (3-year OS: 67.2% vs 68.5%). Conclusions Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. Transplantation was a better choice for those whose cytogenetic category was unfavorable.

Abstract Target-specific next-generation sequencing technology was used to analyze 112 genes in adult patients with acute lymphoblastic leukemia (ALL). This sequencing mainly focused on the specific mutational hotspots. Among the 121 patients, 93 patients were B-ALL (76.9%), and 28 patients (23.1%) were T-ALL. Of the 121 patients, 110 (90.9%) harbored at least one mutation. The five most frequently mutated genes in T-ALL are NOTCH1, JAK3, FBXW7, FAT1, and NRAS. In B-ALL, FAT1, SF1, CRLF2, TET2, and PTPN1 have higher incidence of mutations. Gene mutations are different between Ph+ALL and Ph−ALL patients. B-ALL patients with PTPN11 mutation and T-ALL patients with NOTCH1 and/or FBXW7 mutations showed better survival. But B-ALL with JAK1/JAK2 mutations showed worse survival. The results suggest that gene mutations exist in adult ALL patients universally, they are related with prognosis.

Hematopoietic recovery is considered to be associated with the number of multipotent hematopoietic stem cells in the bone marrow, as observed in functional assays involving stem cell transplantation. However, there is little evidence related to hematopoietic recovery in non-transplantation settings, which is accomplished by endogenous hematopoietic cells. A recent study suggested that progenitors are the main contributors during this steady-state hematopoiesis, which differs from exogenous transplantation. We hypothesized that endogenous progenitor support post-chemotherapy hematopoietic recovery. To investigate the potential impact of these progenitor cell percentage on hematopoietic recovery, we retrospectively analyzed the percentage of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells (P cells) and hematopoietic recovery in 223 newly diagnosed acute myeloid leukemia patients during two courses of consolidation chemotherapy after complete remission. We found that a lower P cell percentage was significantly associated with prolonged neutropenia recovery time after the first and second courses of consolidation chemotherapy (p = 0.001; p = 0.045, respectively). We also observed similar results with regard to platelet recovery time after the first course of consolidation chemotherapy (p = 0.000). Univariate analysis showed that P cell percentage and consolidation chemotherapy regimens, and not gender, age, induction chemotherapy regimens, infection grade, WHO classification and NCCN risk category, were associated with neutrophil recovery after chemotherapy. Multivariate analysis demonstrated that P cell percentage is an independent factor affecting neutrophil recovery capacity for both the first and second courses (p = 0.008; p = 0.032, respectively). Our results indicate that CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells before each course of chemotherapy is independently associated with chemotherapy-related hematopoietic reconstitution capacity. These findings may help modify future chemotherapy regimens based on progenitor cell percentages.

The optimal dose, scheme, and clinical setting for Ara-C in acute myeloid leukemia (AML) treatment remain uncertain. In this study, we performed a meta-analysis to systematically assess the impact of high-dose cytarabine (HDAC) on AML therapy during the induction and consolidation stages. Twenty-two trials with a total of 5,945 de novo AML patients were included in the meta-analysis. Only patients less than 60 year-old were included in the study. Using HDAC in induction therapy was beneficial for RFS (HR = 0.57; 95% CI, 0.35-0.93; P = 0.02) but not so for CR rate (HR = 1.01; 95% CI, 0.93-1.09; P = 0.88) and OS (HR = 0.83; 95% CI, 0.66-1.03; P = 0.1). In consolidation therapy, HDAC showed significant RFS benefits (HR = 0.67; 95% CI, 0.49-0.9; P = 0.008) especially for the favorable-risk group (HR = 0.38; 95% CI, 0.21-0.69; P = 0.001) compared with SDAC (standard dose cytarabine), although no OS advantage was observed (HR = 0.84; 95% CI, 0.55-1.27; P = 0.41). HDAC treatment seemed less effective than auto-BMT/allo-BMT treatment (HR = 1.66, 95% CI, 1.3-2.14; P