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Background/purpose: The aim of this study was to investigate the role and mechanisms of the formyl peptide receptor (FPR) and the toll-like receptor 9 (TLR9) in hypoxia-induced chemoresistance of human ovarian cancer cells. Materials and methods: SKOV3 cells were exposed to hypoxia for 24 hours, the supernatant was collected to stimulate normoxia-cultured SKOV3, and the inhibition rate of cell growth was detected with CCK8 test. The agonist of TLR9 CpG ODN and the agonist of FPR fMLF were applied to investigate the chemosensitivity of SKOV3 cells to cisplatin. The cells were also treated with FPR antagonist t-Boc or TLR9 antagonist CQ. Western blot was applied to detect protein levels of FPR, TLR9, MRP, P-gp, p53 and Beclin-1. Immunofluorescence staining was applied to observe the distribution of TLR9 in SKOV3 cells. Results: Hypoxia exposure reduced the inhibition rate of cisplatin on SKOV3 cells. WB showed that FPR and TLR9 were expressed in human ovarian cancer tissues and SKOV3 cells, and the levels were increased with longer hypoxia time. After SKOV3 was stimulated with fMLF or ODN2006, cisplatin-induced inhibition rate was significantly decreased. tBoc and CQ significantly attenuated hypoxia supernatant-induced chemoresistance of SKOV3 cells. Hypoxia supernatants significantly increased MRP, P-gp, p53 and Beclin-1 proteins in SKOV3 cells, which were significantly reduced by tBoc. Conclusion: Hypoxia upregulates the expression of FPR and TLR9, and promotes the release of ligands for both receptors in human ovarian cancer cell line. FPR and TLR9 may be noval targets for chemosensitizing to ovarian cancer cells. [ABSTRACT FROM AUTHOR]

Background: As the important suppressor of P53, iASPP is found to be overexpressed in leukemia, and functions as oncogene that inhibited apoptosis of leukemia cells. Sertad1 is identified as one of the proteins that can bind with iASPP in our previous study by two-hybrid screen.Methods: Co-immunoprecipitation and immunofluorescence were perfomed to identified the interaction between iASPP and Sertad1 protein. Westernblot and Real-time quantitative PCR were used to determine the expression and activation of proteins. Cell proliferation assays, cell cycle and cell apoptosis were examined by flow cytometric analysis.Results: iASPP combined with Sertad1 in leukemic cell lines and the interaction occurred in the cytoplasm near nuclear membrane. iASPP could interact with Sertad1 through its Cyclin-A, PHD-bromo, C terminal domain, except for S domain. Overexpression of iASPP in leukemic cells resulted in the increased cell proliferation and resistance to apoptosis induced by chemotherapy drugs. While overexpression of iASPP and Sertad1 at the same time could slow down the cell proliferation, lead the cells more vulnerable to the chemotherapy drugs, the resistance to chemotherapeutic drug in iASPPhi leukemic cells was accompanied by Puma protein expression. Excess Sertad1 protein could tether iASPP protein in the cytoplasm, further reduced the binding between iASPP and P53 in the nucleus.Conclusions: Sertad1 could antagonize iASPP function by hindering its entrance into nuclei to interact with P53 in leukemic cells when iASPP was in the stage of overproduction. [ABSTRACT FROM AUTHOR]

Objective: To explore the sociocultural factors influencing depression in Chinese infertile women in Hunan Province.Methods: A cross-sectional study was carried out. A total of 211 Chinese infertile women completed demographic details, a disease-related information questionnaire, a self-rating depression scale (SDS) and a social support rating scale (SSRS).Results: One hundred and seven (50.71%) of the participants were classified as depressed according to the self-rating depression scale. The average SDS index score was 50.06 ± 10.59. Using analysis of variance (ANOVA), Pearson correlation and a multivariable regression analysis, the results showed family type, feelings of discrimination, social support, feelings of shame and reproductive pressures were influential factors in depression among Chinese infertile women.Conclusion: Sociocultural factors influence depression levels in Chinese female infertile patients. The unique aspects of Chinese culture may have a negative mental impact on the patients, and cultural factors should be taken into consideration in the development of coping strategies for Chinese infertile women. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to examine psychological health of left-behind children (LBC), social support and rearing behavior towards LBC as well as their correlations in the city of Shaoxing, China.Methods: By stratified sampling, 401 LBC and 527 non-left-behind children (NLBC) had completed the questionnaires in 2014. Spearman's correlation was performed to clarify the relationship between psychological health, social support and rearing behavior in LBC. Multiple linear regression analytical methods were used to identify the variables that were associated with psychological health.Results: Compared to NLBC, LBC got lower scores in psychological health, general social support, subjective support and emotional warmth, but higher in rejection. Psychological health was positively correlated with social support, and negatively with rearing behavior (rejection, overprotection) in LBC. It was also closely connected with the subjective support, rejection and general health status.Conclusion: These data show that LBC suffer significant impairment on psychological health, and receive less social support and worse rearing behavior than NLBC. Psychological health may be affected by subjective support, rejection, and general health status. Urgent government assessment and support from the community, school, mental health systems are warranted. [ABSTRACT FROM AUTHOR]

Acute Lymphoblastic Leukemia (ALL) is a common hematological malignancy in children, with a prognosis much worse in adults. The molecular characterization of ALL and its correlated prognostic significance are largely unknown. In this study, we analyzed the frequency of IKZF1 deletions, IK6 isoform, and CRLF2 overexpression in 118 Chinese adult B-cell precursor ALL (B-ALL) patients to explore their associations with clinical prognosis. Our data showed that IKZF1 deletions and IK6 isoform were highly detected in adult patients, and both of them were related with worse prognosis in Ph− B-ALL, HR group of Ph− B-ALL, and/or B-ALL patients. Though the frequency of CRLF2 overexpression was similar to children, it had an independent prognostic significance for standard-risk and Ph− adult patients. Our study provided insights into the prognostic significance of certain genetic features in B-ALL patients. Further therapeutic strategies targeting these abnormalities potentially improving the prognosis of B-ALL are warranted. [ABSTRACT FROM AUTHOR]

Metal magnetic memory(MMM) testing has been widely used to detect welded joints. However, load levels, environmental magnetic field, and measurement noises make the MMM data dispersive and bring difficulty to quantitative evaluation. In order to promote the development of quantitative MMM reliability assessment, a new MMM model is presented for welded joints. Steel Q235 welded specimens are tested along the longitudinal and horizontal lines by TSC-2M-8 instrument in the tensile fatigue experiments. The X-ray testing is carried out synchronously to verify the MMM results. It is found that MMM testing can detect the hidden crack earlier than X-ray testing. Moreover, the MMM gradient vector sum K is sensitive to the damage degree, especially at early and hidden damage stages. Considering the dispersion of MMM data, the K statistical law is investigated, which shows that K obeys Gaussian distribution. So K is the suitable MMM parameter to establish reliability model of welded joints. At last, the original quantitative MMM reliability model is first presented based on the improved stress strength interference theory. It is shown that the reliability degree R gradually decreases with the decreasing of the residual life ratio T, and the maximal error between prediction reliability degree R and verification reliability degree R is 9.15%. This presented method provides a novel tool of reliability testing and evaluating in practical engineering for welded joints. [ABSTRACT FROM AUTHOR]

A20, also known as tumor necrosis factor-α (TNFα)-induced protein 3 (TNFAIP3), has been identified as a key regulator of cell survival in many solid tumors. However, little is known about the protein expression level and function of A20 in acute lymphoblastic leukemia (ALL). In this study, we found that A20 is up-regulated in ALL patients and several cell lines. Knockdown of A20 in Jurkat, Nalm-6, and Reh cells resulted in reduced cell proliferation, which was associated with cell cycle arrest. Phospho-ERK (p-ERK) was also down-regulated, while p53 and p21 were up-regulated in A20 knockdown cells. In addition, A20 knockdown induced apoptosis in Jurkat and Reh cells and enhanced the sensitivity of these cell lines to chemotherapeutic drugs. These results indicate that A20 may stimulate cell proliferation by regulating cell cycle progression. A20 inhibited apoptosis in some types of ALL cells, thereby enhancing their resistance to chemotherapy. This effect was abolished through A20 silencing. These findings suggest that A20 may contribute to the pathogenesis of ALL and that it may be used as a new therapeutic target for ALL treatment. [ABSTRACT FROM AUTHOR]

In order to propel the development of metal magnetic memory (MMM) technique in fatigue damage detection, a modified Jiles–Atherton (J–A) model is constructed to describe MMM mechanism in elastic stress stage. The MMM phenomenon is discussed from the view of energy minimum theory and equivalent magnetic field theory, the modified J–A model is constructed based on the energy balance in the process of magnetisation and the idea of J–A model, and the new model is used to simulate magnetomechanical effect by Matlab and compare with experimental results. It is shown that the forming process of MMM field is cyclic magnetisation in the range of equivalent magnetic field and the MMM field moves irreversibly towards a local equilibrium state . is the intermediate state with some pinning before M reaches the anhysteretic magnetisation state . The curve is a loop around the curve, and it changes with , H and the type of stress cycle. The modified J–A model that is suited for MMM detection is constructed by replacing in J–A model with and changing some parameters, and it can describe magnetisation features in tension, release processes better and explain the changes in the sign of that have been observed in experiments more reasonably. The modified J–A model can simulate the process of MMM field to become steady and the MMM field variation at fatigue process theoretically by changing model parameters, which is confirmed by experimental results. The results of theoretical research, simulation analysis and experiment verification all indicate that the modified J–A model can be used to describe MMM mechanism in elastic stress stage and analyse MMM field changes at fatigue process. [ABSTRACT FROM AUTHOR]

Parents influence the physical activity (PA) of the childhood cancer survivors (CCS). This mixed-methods study, aiming to obtain an understanding of Chinese parents' perceptions of PA in CCS and how the cancer experience changes their views, which may affect these children's PA engagement. A mixed methods study was conducted at two hospitals in Hangzhou. A qualitative investigation using the thematic descriptive phenomenological approach analyzed data concerning the parents of 9-18-year-old childhood cancer survivors who had completed hospitalized treatment for at least three months. A cross-sectional investigation examined the association between parents' attitudes and children's PA levels using unconditioned binary logistic regression analysis. The qualitative investigation included 35 parents (74.3% female). More than half of the parents understood the benefits of regular PA. Most parents supported children's participation in low-intensity PA, but opposed high-intensity activities. Many parents changed their parenting style after cancer diagnosis, which might affect the development and persistence of children's PA. In the cross-sectional investigation, CCS were more likely to engage in low-level moderate-to-vigorous physical activity (MVPA) or less MVPA when receiving less paternal support (adjusted OR = 0.92, 95%CI:0.88–0.96) and maternal support (adjusted OR = 0.91, 95%CI:0.87–0.95). Insufficient paternal MVPA engagement (adjusted OR = 3.83, 95%CI: 2.57–5.70) and maternal MVPA engagement (adjusted OR = 5.65, 95%CI: 3.74–8.54) were associated with lower MVPA engagement in CCS. This study identified the understanding of parents of childhood cancer survivors concerning PA engagement and related life changes brought about by cancer experiences from the parental perspectives. These changes affect parental attitude towards children's participation in PA, and parental attitude and behavior affect children's participation in PA. Based on the above findings, some tentative practical implications for physical activity participation among childhood cancer survivors are drawn: (1) childhood cancer survivors should be encouraged to participate in more MVPA and consult a rehabilitation physician if necessary; (2) parents and children engage in exercise together is an important way to promote the levels of physical activity among childhood cancer survivors; (3) Chinese parents have insufficient awareness of the benefits of childhood cancer survivors participation in physical activity. We should strengthen health education for parents, promote parents to support childhood cancer survivors participate in physical activity. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes. Methods: Based on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo. Results: In vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed. Conclusions: Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape. [ABSTRACT FROM AUTHOR]

Background: Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy. Methods: Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts. Results: We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs. Conclusions: Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes. [ABSTRACT FROM AUTHOR]

Skin toxicities induced by epidermal growth factor receptor inhibitors such as Erlotinib plagues clinical challenges. Chinese formulas have a unique advantage in reducing side effects. Here, we aim to investigate the skin protecting function of XiaoZhenFang (XZF), a clinical adjuvant prescription made up of Lonicerae Japonicae Flos, Lithospermum Erythrorhizon, Smilacis Glabrae Rhizoma, Forsythiae Fructus, Spirodelae Herba, Cortex Moutan and Prunellae Spica. Our data showed that XZF aqueous extract effectively reduced skin toxicities induced by Erlotinib in vivo using established mice model. Next, we used a systems pharmacology approach to investigate the pharmacological mechanism of XZF with the goal of understanding its effects at the system, organ, and molecular levels. 44 candidate compounds and 103 potential targets were identified by network pharmacology. Inflammation, cell stress and the EGFR-related signal pathways, which may participate in the skin protection afforded by XZF, were analyzed by gene enrichment. Importantly, our in vivo experimental results largely validated XZF's mechanism of action, as predicted by the system pharmacology analysis. Our study uncovered the effect and mechanism of XZF in attenuating skin toxicities induced by EGFRI, providing a basis for the development of in-hospital preparations and new drugs for the prevention of skin toxicities. [ABSTRACT FROM AUTHOR]