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Chronic skin ulcers are a primary global health problem. Velvet antler polypeptide (VAP) regulates endothelial cell migration and angiogenic sprout. Adipose-derived stem cells (ADSCs) are reported to make pivotal impacts upon wound healing. This study aimed to explore the role of VAP combined with ADSCs in wound healing of chronic skin ulcers. The effect of VAP on phenotypes of ADSCs, and VAP (PLGA microspheres) combining with ADSCs on wound healing of chronic skin ulcers in vivo was evaluated. VAP generally promoted the proliferation, migration and invasion of ADSCs, and ADSC-induced angiogenesis in human umbilical vein endothelial cells (HUVECs) through PI3K/Akt/HIF-1α pathway. VAP-PLGA (PLGA microspheres) enhanced the promoting effect of ADSCs on wound healing, pathological changes, and angiogenesis in chronic skin ulcers in vivo. VAP-PLGA intensified the effect of ADSCs on up-regulating the levels of p-PI3K/PI3K, p-Akt/Akt, HIF-1α, vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), C-X-C motif chemokine receptor 4 (CXCR4), angiopoietin-4 (Ang-4), VEGF receptor (VEGFR), and transforming growth factor-β1 (TGF-β1), and down-regulating the levels of interleukin-1 β (IL-1β), IL-18 and IL-6 in wound tissues in chronic skin ulcers in vivo. Collectively, VAP promoted the growth, migration, invasion, and angiogenesis of ADSCs through activating PI3K/Akt/HIF-1α pathway, and VAP-PLGA enhanced the function of ADSCs in promoting wound healing in vivo, which was associated with angiogenesis, inflammation inhibition, and dermal collagen synthesis.

This study aimed to explore the safety and efficacy of using nano-hydroxyapatite/polyamide (N-HA/PA) composite in anterior cervical vertebral body subtotal corpectomy and interbody fusion. Total 50 patients with cervical spondylotic myelopathy were enrolled to undergo anterior cervical spondylectomy. Bone graft pedicles were compounded with N-HA/PA and intervertebral body fusion was performed. Study outcomes included surgical efficacy and the degree of fusion. Patients in whom vertebral body fusion was performed with N-HA/PA composite pedicles had significantly improved symptoms. The postoperative Japanese Orthopaedic Association scores increased to 18.56±4.37 from 11.37±3.52, reflecting an improvement rate of 87.3%. The composite pedicle fusion rate was 96.4%. Therefore, N-HA/PA composite pedicle as a bone graft material in fusion surgery provides significant therapeutic efficacy. Moreover, the composite pedicle fusion rate is high, making it ideal for anterior cervical vertebral body subtotal corpectomy and fusion.

Municipal sludge is a by-product of urban sewage treatment; it has high water content and contains many hydrophilic extracellular polymeric substances (EPS). It is difficult to achieve deep dewatering of sludge. Therefore, it is necessary to find an efficient method to treat sludge. In this study, an acid-microwave treatment method was proposed to improve the dewatering ability of sludge. A vacuum filtration test and particle size analysis test were used to explore the improvement effect of dehydration performance. After centrifugation, the concentrations of soluble proteins and polysaccharides in the supernatant were measured to explore the disintegration of acid-microwave treatment on EPS. Finally, the microstructure of sludge treated by acid-microwave was studied via the SEM test. The results showed that short-term microwave radiation was conducive to sludge dewatering. However, the sludge dewatering performance deteriorated significantly when the treatment time was too long. The optimal microwave treatment condition was 700 W for 180 s, and the SRF of sludge was the lowest, which was 10.11 × 10 12 m / kg . After acid-microwave treatment, sludge particle size increased significantly. The concentration of protein and polysaccharide in supernatant increased with the increase of microwave treatment time. Acid-microwave treatment could significantly improve the release efficiency of the polysaccharide. Through the SEM test, it can be verified that the bulk floc structure of sludge is broken after microwave treatment, and acid-microwave treatment is beneficial to the aggregation of floc fragments to form large particles, which can provide larger pores for drainage.

Ambulatory motion sensors can generate a mobile system for human kinematics measurement as an alternative to the more constrained optical motion capture systems. Flexible inertial sensors are emerging as a potential solution to overcome the drawback of the conventional inertial measurement sensors with a soft, flexible design that allows for direct body-conforming adhesion to the skin. Thus, this study aims to establish the viability of the flexible inertial sensors for the ambulatory measurement of human knee flexion–extension (F/E) during level walking. The accuracy of flexible inertial sensors with our proposed algorithm is investigated by comparing the derived kinematics with those measured using a conventional motion capture system. Three volunteers (two males and one female, aged 24–27) served as subjects. Three flexible inertial sensors were placed on the subjects’ right legs, two on the thigh (lateral thigh and distal anterolateral thigh), and one on the lateral shank, and subjects performed level walking with varied walking cadence (80, 100, and 120 steps/min). The overall root-mean-square-error across all participants is 7.8° for distal anterolateral thigh sensor (using the data of distal anterolateral thigh sensor and shank sensor to estimate knee F/E) and 4.5° for lateral thigh sensor (using the data of lateral thigh sensor and shank sensor to estimate knee F/E). The results illustrate that our proposed method can generate comparable results with motion capture systems and is insensitive to different walking cadence. A significant effect of sensor placement is observed, and a more proximal lateral thigh strategy is suggested. The advantages of the flexible inertial sensors in human motion analysis over the existing inertial measurement units are also highlighted.

Purpose There is no optimal prognostic model for T-cell lymphoblastic lymphoma (T-LBL). Here, we discussed the predictive value of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) in T-LBL.Materials and Methods Thirty-seven treatment naïve T-LBL patients with PET-CT scans were enrolled. TMTV was obtained using the 41% maximum standardized uptake value (SUVmax) threshold method, and TLG was measured as metabolic tumor volume multiplied by the mean SUV. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier curves and compared by the log-rank test.Results The optimal cutoff values for SUVmax, TMTV, and TLG were 12.7, 302 cm3, and 890, respectively. A high SUVmax, TMTV, and TLG indicated a shorten PFS and OS. On multivariable analysis, TMTV ≥ 302 cm3, and central nervous system (CNS) involvement predicted inferior PFS, while high SUVmax, TLG and CNS involvement were associated with worse OS. Subsequently, we generated a risk model comprising high SUVmax, TMTV or TLG and CNS involvement, which stratified the population into three risk groups, which had significantly different median PFS of not reached, 14 months, and 7 months for low-risk group, mediate-risk group, and high-risk group, respectively (p < 0.001). Median OS were not reached, 27 months, and 13 months, respectively (p < 0.001).Conclusion Baseline SUVmax, TMTV, and TLG measured on PET-CT are strong predictors of worse outcome in T-LBL. A risk model integrating these three parameters with CNS involvement identifies patients at high risk of disease progression.

Tamoxifen has been used for years for treating estrogen receptor-positive breast cancer; drug resistance, however, constitutes one of the main challenges for this therapy. We found that the protein expression level of ATF3 is significantly higher in tamoxifen-resistant (TamR) MCF-7 cells than the corresponding parental cancer cells. In addition, ATF3 protein expression is positively correlated with the resistance of TamR MCF-7 cells to 4-hydroxytamoxifen (4-OHT). Mechanistically, elevated ATF3 protein expression in TamR MCF-7 cells results from a lower level of expression of YTHDF2, an m6A reader protein, and the ensuing stabilization and increased translational efficiency of ATF3 mRNA. Additionally, TamR MCF-7 cells exhibited decreased methylation at A131, a consensus motif site for m6A, in the 5'-untranslated region (5'-UTR) of ATF3 mRNA. Moreover, augmented ATF3 stimulates the expression of ABCB1, an efflux pump that confers drug resistance in breast cancer cells, and ATF3 itself is also positively regulated by adenylate kinase 4. Together, our results uncovered a novel molecular target for m6A modification (i.e., ATF3 mRNA) and the epitranscriptomic regulator for this target (i.e., YTHDF2). We also illustrated the role of ATF3 in drug resistance, revealed its downstream target (i.e., ABCB1), and suggested ATF3 as a candidate therapeutic target for overcoming drug resistance in cancer cells.

Objective: To analyze the effects of twirling reinforcing and reducing manipulations on protein expression in parietal cortex of spontaneously hypertensive rats (SHRs), and elucidate the main mechanisms and differences between two manipulations in hypertension treatment. Methods: Rats were randomly divided into the control, model, twirling reinforcing manipulation (TRFM), and twirling reducing manipulation (TRDM) groups. The control and model groups received catch and fixation stimulations once a day for 14 days. The TRFM and TRDM groups were intervened once a day for 20 min for 14 days. On days 0, 2, 6, 10, and 14 after acupuncture, rat systolic blood pressures (SBPs) were measured. Differential protein (DP) expression in the rat parietal cortices was detected. Thereafter, GO functional significance and KEGG pathway enrichment analyses were performed. Results: Compared with the model group, SBP of rats in the TRDM and TRFM groups decreased on days 6 and 10 of acupuncture, respectively (P = .009; P

Cluster of differentiation 36 (CD36), also referred to as scavenger receptor B2, has been shown to serve multiple functions in lipid metabolism, inflammatory signaling, oxidative stress, and energy reprogramming. As a scavenger receptor, CD36 interacts with various ligands, such as oxidized low-density lipoprotein (oxLDL), thrombospondin 1 (TSP-1), and fatty acid (FA), thereby activating specific downstream signaling pathways. Cardiac CD36 is mostly expressed on the surface of cardiomyocytes and endothelial cells. The pathophysiological process of diabetic cardiomyopathy (DCM) encompasses diverse metabolic abnormalities, such as enhanced transfer of cardiac myocyte sarcolemmal FA, increased levels of advanced glycation end-products, elevation in oxidative stress, impaired insulin signaling cascade, disturbance in calcium handling, and microvascular rarefaction which are closely related to CD36 signaling. This review presents a summary of the CD36 signaling pathway that acts mainly as a long-chain FA transporter in cardiac myocytes and functions as a receptor to bind to numerous ligands in endothelial cells. Finally, we summarize the recent basic research and clinical findings regarding CD36 signaling in DCM, suggesting a promising strategy to treat this condition.

Compared with the growing applications of peritectic alloy, none research on the freckle formation during peritectic solidification has been reported before. Observation on the dendritic mushy zone of Sn-36 at.%Ni peritectic alloy during directional solidification at different growth velocities shows that the freckles are formed in two different regions: region I before peritectic reaction and region II after peritectic reaction. In addition, more freckles can be observed at lower growth velocities. Examination on the experimental results demonstrates that both the temperature gradient zone melting (TGZM) and Gibbs-Thomson (G–T) effects have obvious influences on the morphology of dendritic network during directional solidification. The current theories onKI Rayleigh number Ra characterizing the thermosolutal convection of dendritic mushy zone to predict freckle formation through the maximum of Ra can only explain the existence of region I while the appearance of region II after peritectic reaction cannot be predicted. Thus, a new Rayleigh number RaP is proposed in consideration of evolution of dendritic mushy zone by both effects and peritectic reaction. Theoretical prediction of RaP also shows a maximum after peritectic reaction in addition to that before peritectic reaction, thus, agreeing well with the freckle formation in region II. In addition, more severe thermosolutal convection can be predicted by the new Rayleigh number RaP at lower growth velocities, which further demonstrates the reliability of RaP in describing the dependence of freckle formation on growth velocity.

Extranodal natural killer (NK)/T-cell lymphoma (NKTL) is a rare non-Hodgkin lymphoma that rarely arise exclusively in or metastasizes to the central nervous system (CNS). Globally, CNS involvement of NKTL heralds a serious prognosis and there is no standard treatment. 19 of 414 patients (4.59%) with ENKL followed were diagnosed with CNS involvement between 2006 and 2020. Two patients had primary CNS (PCNS) NKTL, and 17 patients had secondary CNS (SCNS) invasion. A total of 9 patients survived and 10 patients died. The median overall survival time was 55 months, and the median survival time after CNS invasion was 17 months. The 5-year cumulative survival probability was 45.7%. In conclusion, CNS risk evaluation and prophylaxis treatment can be carried out for patients with NK/T-cell lymphoma prognostic index risk group III/IV. In terms of treatment, systemic therapy based on methotrexate combined with radiotherapy and intrathecal chemotherapy can be selected.

Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.

RNA N6-methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1–2, YTHDF1–3, IGF2BP1–3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein–induced resistance to cancer therapy.

Purpose: TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.

Long noncoding RNAs (LncRNAs) are emerging as crucial regulators in the pathophysiological process of various tumors, including HCC. Here, we identify a novel lncRNA Linc-KILH (KRT19 interacting long noncoding RNA in hepatocellular carcinoma), which is significantly up-regulated in HCC tissues and positively correlated with larger tumor size, severer microvascular invasion, more intrahepatic metastasis and decreased survival of HCC patients. Silence of Linc-KILH remarkably inhibited the proliferation and metastasis abilities of KRT19-positive HCC cells in vitro and in vivo. Mechanistically, Linc-KILH interacts with KRT19 and then inhibits the phosphorylation of KRT19 on Ser35, thereby, enhancing the translocation of KRT19 from cytoplasm to membrane in KRT19 positive HCC cells. Additionally, we validated that KRT19 interacts with β-catenin but not RAC1 in HCC cells. Linc-KILH enhanced the interaction between β-catenin and KRT19 in cytoplasm and promoted the nuclear translocation of β-catenin in HCC cells. Furthermore, Linc-KILH could enhance the promoting function of KRT19 on Notch1 signaling with the existence of KRT19 in HCC cells. Collectively, we revealed that Linc-KILH exerts a vital function in KRT19 positive HCC progression and may likely be developed into an effective therapeutic target for HCC.

Objective The present study aimed to establish a normative database of neck strength and endurance while exploring personal and work-related factors that can significantly influence neck strength and endurance. Background A normative database combining both neck strength and endurance and delineating how they are affected by personal and work-related factors is currently lacking. It is needed for the development of tools and guidelines for designing work requiring head-neck exertions to contain the risk of occupational neck pain. Methods Forty healthy participants (20 males and 20 females) performed sustained-till-exhaustion head-neck exertions, while seated, at 50% and 100% of their maximal efforts in anterior, anterior-superior, and posterior-superior directions in neutral, 40° extended, and 40° flexed neck postures. Exertion force and endurance time data from 38 participants were recorded and analyzed using regression models. Results Overall, multiple regression analyses of the neck strength and endurance database revealed that head-neck posture is the most significant determinant of both neck strength and endurance. The time of day significantly influenced neck endurance. Among the personal factors, a significant sex effect on neck strength and significant age and body mass index (BMI) effects on neck endurance were identified. Conclusion The work-related factors play a more significant role in shaping both neck strength and endurance than personal factors and therefore are more important modifiable factors in meeting the physical demands of work. Application The study findings can aid in work design as well as in pre-employment screening to reduce the incidence of neck pain in the workplace.

Chloride (Cl−) is required for photosynthesis and regulates osmotic balance. However, excess Cl− application negatively interacts with nitrate ($${\mathrm{NO}}_{3}^{-}$$ NO 3 - ) uptake, although its effect on $${\mathrm{NO}}_{3}^{-}$$ NO 3 - metabolism remains unclear. The aim was to test whether Cl− stress disturbs nitrate reductase activity (NRA). A maize variety (Zea mays L. cv. LG 30215) was hydroponically cultured in a greenhouse under the following conditions: control (2 mM CaCl2), moderate Cl− (10 mM CaCl2), high Cl− (60 mM CaCl2). To substantiate the effect of Cl− stress further, an osmotic stress with lower intensity was induced by 60 g polyethylene glycol (PEG) 6000 L−1 + 2 mM CaCl2), which was 57% of the osmotic pressure being produced by 60 mM CaCl2. Results show that high Cl− and PEG-induced osmotic stress significantly reduced shoot biomass, stomatal conductance and transpiration rate, but NRA was only decreased by high Cl− stress. The interference of NRA in chloride-stressed maize is supposed to be primarily caused by the antagonistic uptake of Cl− and $${\mathrm{NO}}_{3}^{-}$$ NO 3 - .

The purpose of this study was to analyze the acute effect of ambient temperature on hospitalization due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), stroke, and myocardial infarction (MI) in Shenyang, China. We used the distributed delayed nonlinear model to evaluate the impact of ambient temperature on respiratory and cardiovascular diseases. The study population was divided into four groups: < 65 group and ≥ 65 age groups, female and male groups. The < 65 age group of AECOPD patients was more likely to be affected by high ambient temperature, while the ≥ 65 age group of AECOPD patients was more sensitive to low ambient temperature. The hospitalization risk of MI admission increased in the ≥ 65 age group at 1–8 days delay under low ambient temperature conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-020-11934-2.

Notably, a growing number of long noncoding RNAs (lncRNAs) have been recognized to play critical roles in hepatocellular carcinoma (HCC) progression. In this study, we identified a new lncRNA, Linc1749808 (ID: XR_001749808.1) based on microarray data from HCC tissues. Linc1749808 levels in 72 HCC tissues and paracancerous samples were detected by qRT-PCR. The interaction between Linc1749808 and microRNA-206 (miR-206) was assessed by bioinformatic analysis and luciferase assays. Linc1749808 depletion assays, Transwell assays, and miR-206-inhibitor rescue experiments were performed to examine the role of the Linc1749808/miR-206 axis in HCC cells. Our results showed that Linc1749808 was highly expressed in both HCC tissues and cell lines. Linc1749808 expression was significantly correlated with microvascular invasion, metastasis, and prognosis. After the knockdown of Linc1749808, the metastatic potential of 97H and HepG2 cells was attenuated in vitro and in vivo, but the proliferative capacity did not significantly change. Furthermore, Linc1749808 was found to act as a sponge of miR-206. Inhibition of miR-206 counteracted the effect of Linc1749808 knockdown in 97H cells by regulating YAP1 and epithelial-mesenchymal transition (EMT). In summary, these findings show that Linc1749808 can exacerbate the metastasis of HCC by sponging miR-206.

Rationale: Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Methods: Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Results: Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Conclusion: Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.

Extranodal natural killer/T‐cell lymphoma, nasal type (ENKL) is a rare peripheral T‐cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L‐asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty‐one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5‐year progression‐free survival (PFS): 24.6–66.2%; 95% CI of 5‐year overall survival (OS): 8.5–91.7%) was also significantly associated with longer 5‐year PFS and 5‐year OS (P = 0.008 for 5‐year PFS, P = 0.023 for 5‐year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post‐treatment Epstein–Barr virus (EBV)‐DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post‐treatment EBV‐DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.

Immune checkpoint blockade therapies, especially those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have achieved impressive clinical responses in multiple types of cancers. To optimize the therapeutic effect of the checkpoint antibodies, many strategies including targeting delivery, controlled release, and cellular synthesis have been developed. However, within these strategies, antibodies were attached to drug carriers by chemical bonding, which may affect the steric configuration and function of the antibodies. Herein, we prepared cluster of differentiation 64 (CD64), a natural catcher of the fragment crystalline (Fc) of monomeric immunoglobulin G (IgG), and over-expressed it on the cell membrane nanovesicles (NVs) as PD-L1 antibody delivery vehicle (CD64-NVs-aPD-L1), which was employed to disrupt the PD-1/PD-L1 immunosuppressive signal axis for boosting T cell dependent tumor elimination. Meanwhile, chemical immunomodulatory drug cyclophosphamide (CP) was also encapsulated in the vesicle (CD64-NVs-aPD-L1-CP), to simultaneously restrain the regulatory T cells (Tregs) and invigorate Ki67+CD8+ T cells, then further enhance their anti-tumor ability. Methods: The cell membrane NVs overexpressing CD64 were incubated with PD-L1 antibody and chemotherapeutic agent CP to prepare CD64-NVs-aPD-L1-CP. Results: The CD64-NVs-aPD-L1-CP could simultaneously interrupt the immunosuppressive effect of PD-L1 and decrease the inhibition of Tregs, leading to tumor growth suppression and survival time extension. Conclusion: CD64-NVs are charismatic carriers to achieve both checkpoint blockade and immunomodulatory drugs for combined cancer immunotherapy.

Rationale: Recurrent and metastatic cancers often undergo a period of dormancy, which is closely associated with cellular quiescence, a state whereby cells exit the cell cycle and are reversibly arrested in G0 phase. Curative cancer treatment thus requires therapies that either sustain the dormant state of quiescent cancer cells, or preferentially, eliminate them. However, the mechanisms responsible for the survival of quiescent cancer cells remain obscure. Methods: Dual genome-editing was carried out using a CRISPR/Cas9-based system to label endogenous p27 and Ki67 with the green and red fluorescent proteins EGFP and mCherry, respectively, in melanoma cells. Analysis of transcriptomes of isolated EGFP-p27highmCherry-Ki67low quiescent cells was conducted at bulk and single cell levels using RNA-sequencing. The extracellular acidification rate and oxygen consumption rate were measured to define metabolic phenotypes. SiRNA and inducible shRNA knockdown, chromatin immunoprecipitation and luciferase reporter assays were employed to elucidate mechanisms of the metabolic switch in quiescent cells. Results: Dual labelling of endogenous p27 and Ki67 with differentiable fluorescent probes allowed for visualization, isolation, and analysis of viable p27highKi67low quiescent cells. Paradoxically, the proto-oncoprotein c-Myc, which commonly drives malignant cell cycle progression, was expressed at relatively high levels in p27highKi67low quiescent cells and supported their survival through promoting mitochondrial oxidative phosphorylation (OXPHOS). In this context, c-Myc selectively transactivated genes encoding OXPHOS enzymes, including subunits of isocitric dehydrogenase 3 (IDH3), whereas its binding to cell cycle progression gene promoters was decreased in quiescent cells. Silencing of c-Myc or the catalytic subunit of IDH3, IDH3α, preferentially killed quiescent cells, recapitulating the effect of treatment with OXPHOS inhibitors. Conclusion: These results establish a rigorous experimental system for investigating cellular quiescence, uncover the high selectivity of c-Myc in activating OXPHOS genes in quiescent cells, and propose OXPHOS targeting as a potential therapeutic avenue to counter cancer cells in quiescence.

We previously reported that transplantation of menstrual blood-derived stromal cells (MenSCs) significantly improved fertility restoration in intrauterine adhesion (IUA). However, it is difficult to obtain menstrual blood samples in some severe IUA patients who have amenorrhea or oligomenorrhea. Thus, a safe and effective stem cell replacement therapy is necessary to promote endometrial regeneration. Recent studies demonstrated that the effects of MenSCs are partly mediated in a paracrine manner via small extracellular vesicles (sEVs). To explore this possibility, we performed a pre-clinical study to investigate whether concentrated MenSC-derived sEVs (MenSCs-sEVs) are sufficient to repair IUA and the mechanisms underlying their action. Rat IUA models were established by mechanical injury, followed by the administration of MenSCs or MenSCs-sEVs through intrauterine transplantation. Consistent with the efficacy of MenSCs, MenSCs-sEVs effectively recovered the morphology, promoted regeneration of the glands and angiogenesis, and reversed endometrial fibrosis in the IUA uterus. The endometrial receptivity and pregnancy outcome significantly improved after repeated MenSCs-sEVs transplantations. In addition, all rats in the MenSCs-sEVs group had no hematological or biochemical abnormalities. Three-dimensional fluorescence imaging suggested that MenSCs tended to migrate through the bloodstream, whereas MenSCs-sEVs had a better localized therapeutic effect. Moreover, MenSCs and MenSCs-sEVs inhibited the TGFβ1/SMAD3 pathway in the IUA endometrium, while promoting the phosphorylation of SMAD1/5/8 and ERK 1/2 and upregulating the expression of BMP7. Thus, MenSCs-sEVs safely and effectively enhanced endometrial restoration, suggesting a promising non-cellular therapy for endometrial regeneration and a key role in MenSC-mediated IUA treatment.

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, with a dismal 5-year survival of 5%. Recently, ARRB1, as a molecular scaffold, has been proposed to participate in the progression of multiple malignancies. However, the effect and regulatory mechanisms of ARRB1 in GBC have not been investigated. Our study aimed to explore the biological functional status and the possible molecular mechanisms of ARRB1 with respect to GBC progression. The survey showed that human GBC tissues exhibited increased levels of ARRB1 compared with normal tissues, and the high expression of ARRB1 was associated with poor prognosis of GBC patients. A series of in vitro and in vivo functional experiments based on knockdown of ARRB1 uncovered that ARRB1 enhanced GBC cell proliferation, migration, and invasion. Furthermore, we reported that TAK1, a component of the TNF /MAPK pathway, is a vital downstream effector of ARRB1. In addition, siTAK1 could abolish the functional changes between ARRB1 overexpression GBC cells and control ones. Our data revealed that ARRB1 facilitated the carcinogenesis and development of GBC through TNF/TAK1/MAPK axis, suggesting that ARRB1 may be a promising biomarker and treatment target for GBC patients.

An accelerator, 3-(2-benzthiazolylthio)-1-propanesulfonsaure (ZPS), was used and formulated with a suppressor (polyethylene glycol, PEG) and chloride ions (Cl−) in electroplated Cu plating solution containing electrolytes (Cu sulfate and sulfuric acid) to prepare the Cu films. The preferred orientation of Cu film transformed from (200) to (220) with the addition of ZPS in plating solution containing (PEG and Cl−). The addition of ZPS in basic plating solution promoted the growth of Cu grains and increased the surface roughness of Cu film. The root mean square roughness of Cu film increased from 206.9 to 230.8 nm with increasing ZPS concentration. The impurity elements of electroplated Cu film were O, C, Cl, and S elements. With the further increase in ZPS, the number of void within Cu3Sn layer obviously reduced, improving the stability of the electroplated Cu solder joints subjected to thermal aging.

Pancreatic cancer (PC) is a leading cause of cancer‐related mortality globally. Though increasing evidence has demonstrated that circular RNAs (circRNAs) are linked to the development and progression of cancers, the biological functions of circRNAs in PC remain largely unexplored so far. Based on previous studies, Hsc_circ_0075829 (circ_0075829) was screened out and then further identified in PC clinical specimens and cell lines by real‐time PCR. After the stability tests, a series of in vitro and in vivo functional experiments were performed to investigate the role of circ_0075829 in PC development. Furthermore, fluorescent in situ hybridization (FISH), bioinformatics tools, dual‐luciferase assays and rescue experiments were conducted to clarify the regulatory mechanisms of circ_0075829 in SW1990 and BxPC‐3 cells. Compared with paracancerous tissues, the expression of circ_0075829 was increased in PC tissues, which was positively correlated with the clinical features of PC. Knockdown of circ_0075829 significantly suppressed the proliferative, migratory and invasive rates of SW1990 and BxPC‐3 cells both in vitro and in vivo. Bioinformatics analysis and dual‐luciferase reporter gene assay indicated that circ_0075829 could bind to miR‐1287‐5p. Mechanism research and rescue experiments demonstrated that circ_0075829 could regulate the LAMTOR3/p‐ERK signalling pathway via sponging miR‐1287‐5p in PC cell lines. Our data reveal that the circ_0075829 could facilitate the proliferation and metastasis of PC through circ_0075829/miR‐1287‐5p/LAMTOR3 axis.

Metabolic reprogramming in cancer describes the multifaceted alterations in metabolism that contribute to tumorigenesis. Major determinants of metabolic phenotypes are the changes in signalling pathways associated with oncogenic activation together with cues from the tumor microenvironment. Therein, depleted oxygen and nutrient levels elicit metabolic stress, requiring cancer cells to engage adaptive mechanisms. Non-coding RNAs (ncRNAs) act as regulatory elements within metabolic pathways and their widespread dysregulation in cancer contributes to altered metabolic phenotypes. Indeed, ncRNAs are the regulatory accomplices of many prominent effectors of metabolic reprogramming including c-MYC and HIFs that are activated by metabolic stress. By example, this review illustrates the range of ncRNAs mechanisms impacting these effectors throughout their DNA-RNA-protein lifecycle along with presenting the mechanistic roles of ncRNAs in adaptive responses to glucose, glutamine and lipid deprivation. We also discuss the facultative activation of metabolic enzymes by ncRNAs, a phenomenon which may reflect a broad but currently invisible level of metabolic regulation. Finally, the translational challenges associated with ncRNA discoveries are discussed, emphasizing the gaps in knowledge together with importance of understanding the molecular basis of ncRNA regulatory mechanisms.

Maize has to avoid excess tissue accumulation of Cl- to withstand conditions of Cl--salinity. Restriction of loading of Cl- into the root xylem is one mechanism to keep shoot Cl--concentrations low. The proportion of Cl- that reaches the shoot has to be stored away from the primary site of photosynthesis and growth. We tested whether or not maize is able to re-translocate significant amounts of Cl- from shoot back to root and out into the rooting media. Ion analysis revealed that maize cannot re-translocate Cl-; however, it is stored in sheaths of the old leaves and, surprisingly, in roots. Sequestration of Cl- in the roots might be a strategy to keep concentrations low in young growing shoot tissues and in leaf blades where photosynthesis is running.

Introduction To investigate the effects of crocin on proliferation and migration of endogenous neural stem cells and the Notch1 signalling pathway in rats after cerebral ischemia reperfusion. Material and methods SD rats were randomly divided into the sham operation group, model group and administration group (crocin). Middle cerebral artery occlusion (MCAO/R) was used to establish the focal cerebral ischemia reperfusion model in rat. After surgical treatment, the treatment group was treated with crocin. Quantitative polymerase chain reaction (qPCR) was used to detect the changes in the expression of Notch1, Bax and bcl-2 proteins in rat endogenous neural stem cells after cerebral ischemia reperfusion. ELISA was used to detect changes in inflammatory factors. Neural stem cells were cultured in vitro, which were divided into: the normal control group, the hypoglycaemic deprivation/reoxygenation group, hypoglycaemic deprivation/reoxygenation group with a low concentration of crocin, and hypoglycaemic deprivation/reoxygenation group with a high concentration of crocin. The cell proliferation assay detects cell activity. The cell migration assay tests the cell migration ability. And flow cytometry was used to determine cell apoptosis. Results Compared with the sham group, the Notch1 signalling pathway was activated in the model group. The expression of Notch1 in the crocin group was increased compared to the model group. Crocin can inhibit the release of inflammatory factors. The results of our experiments showed that crocin could induce the proliferation and migration of neural stem cells and inhibit the apoptosis of neural stem cells in the hypoglycaemic/reoxygenation model group. Conclusions Crocin sufficiently promotes the proliferation and migration of neural stem cells and inhibits the apoptosis of these cells in rats after ischemia-reperfusion by manipulating the Notch signalling pathway.