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Gefitinib is a tyrosine kinase inhibitor of EGFR (epidermal growth factor receptor) and represents the first-line treatment for EGFR mutation patients with NSCLC (non-small-cell lung cancer) therapeutics. However, NSCLC patients are inclined to develop acquired gefitinib drug resistance through nowadays, unarticulated mechanisms of chemoresistance. Here, we investigated the role of TF (Trifolium flavonoids) on sensitizing gefitinib resistance in NSCLC cells and revealed its potential mechanism of action. We demonstrated that TF exerted significantly potential chemosensitivity in gefitinib resistant NSCLC cells. MTT assay and cytological methods were used to analyze cell viability and apoptosis in NSCLC cell line PC-9R. Both TF and gefitinib suppressed PC-9R cell growth in a dose-dependent manner. Subtoxic concentrations of TF did significantly augment gefitinib-induced apoptosis in PC-9R cell line. The TF promoted chemosensitivity was major mediated by the PARP and caspases activation. Meanwhile, the TF promoted chemosensitivity also decreased the expression of Bcl-2 and Mcl-1. Finally, TF significantly reduced the phosphorylation levels of STAT3 and ERK. Altogether, the results of the present study indicated the potential mechanisms of chemosensitivity of TF in gefitinib-induced apoptosis of NSCLC by downregulating ERK and STAT3 signaling pathways and Bcl2 and Mcl-1 expression and a promising application of TF in therapy of NSCLC with gefitinib resistant. [ABSTRACT FROM AUTHOR]

Background. Upper partial fibulectomy has been preliminarily proved to have the efficacy for pain alleviation and improvement of function in patients with mild to moderate medial compartment knee osteoarthritis (KOA). However, the previous studies lack the control group with other treatments. The aim of this prospective, randomized controlled study is to compare the clinical and biomechanical effects between upper partial fibulectomy and drug conservative treatment on improvement of clinical pain, function, and gait for patients with mild to moderate medial knee osteoarthritis (KOA) and further discuss its biomechanical mechanism. Methods. From August 2016 to February 2017, 49 and 48 patients with mild to moderate medial KOA were allocated to fibulectomy and drug groups. We assessed the patients' visual analog scale (VAS) pain score, Hospital for Special Surgery (HSS) knee score, limb alignment, passive flexion/extension range of motion (ROM) of the knee, and 3D gait kinematics and kinetics parameters before and after intervention. Repeated-measures ANOVA with Dunnett's post hoc assessment and multivariate analysis of variance were applied for intragroup and intergroup comparisons, respectively. Results. The improvement in the fibulectomy group on the VAS pain score, HSS knee score, walking speed, and walking knee range of motion (ROM) was statistically better than that in the drug group. The decreased overall peak knee adduction moment (KAM) (decreased by 16.1%) and hip-knee-ankle (HKA) angle (decreased by 0.99° from a more varus alignment to a more neutral alignment) of the affected and operated side 1 year after surgery were observed in the fibulectomy group. Conclusion. This research demonstrated that as a biomechanical intervention, upper partial fibulectomy can be a better choice in pain relief and function and gait improvement than drug conservative treatment for patients with early-stage knee OA. The long-term clinical outcomes, indication, and rationale for the improvement in clinical symptoms should be investigated further. [ABSTRACT FROM AUTHOR]

Objectives. To investigate the relationship between external knee adduction moment (KAM) and knee osteoarthritis (OA) symptoms according to static alignment and pelvic drop. Methods. Ninety-five participants with symptomatic knee OA were included. Radiographic severity was graded by Kellgren and Lawrence (KL) scale. The hip-knee-ankle (HKA) angle was used to assess limb alignment from a full-length lower-limb radiograph. KAM-related variables (peak KAM and KAM impulse) and pelvic drop angle were determined from 3D gait analysis. Symptoms were assessed via visual analog scale (VAS) for pain and hospital for special surgery (HSS) score for physical function. The relationship between KAM and symptoms was evaluated according to radiographic severity and pelvic drop using linear models. Results. According to the more affected knee in the varus group, both the two KAM-related measures (peak KAM and KAM impulse) were positively associated with greater VAS pain and were negatively associated with HSS score. Only peak KAM was correlated with VAS and HSS in the valgus group. VAS pain score of the more affected knee was positively correlated with pelvic drop angle. Stratified by pelvic drop angle, KAM-related variables were more positively associated with VAS pain and negatively associated with HSS score for patients with pelvic drop angle ≤3 degrees. The relationships between KAM and symptoms according to radiographic disease severity remained confusing. Conclusions. Static alignment and pelvic drop angle significantly affected relationships between KAM-related variables and knee OA symptoms, which may explain the confusing results as shown by previous studies. [ABSTRACT FROM AUTHOR]

A thin endometrium affects the success of assisted reproduction due to low endometrial receptivity. Acupuncture improves endometrial receptivity and promotes the formation of pinopodes, the ultrastructure marker implantation window. However, the specific underlying mechanisms remain unclear. In this study, the efficacy of acupuncture treatment and its underlying mechanism were investigated by analyzing pregnancy rate, pinopode formation, and related molecular markers in thin endometrium model rats. Absolute ethanol (95%) was injected into the uteruses of female Sprague-Dawley rats to construct a thin endometrium model. In this model, acupuncture stimulation at EX-CA1, SP6, and CV4 ameliorated the pregnancy rate. Significantly increased embryo implantation, endometrial thickness, numbers of glands, and blood vessels were observed in the electroacupuncture (EA) group compared to the model group. The number of pinopodes in the EA group was abundant, with a shape similar to that of the control group. Additionally, significantly higher expression levels of pinopode-related markers, including integrin αvβ3, homeobox A10 (HOXA10), heparin-binding EGF-like growth factor (HBEGF), estrogen receptor alpha (ERα), and progesterone receptor (PR), were observed in the EA group than those in the model group. In conclusion, EA had a positive effect on the endometrial receptivity of thin endometrium model rats by improving pinopode formation through multiple molecular targets. [ABSTRACT FROM AUTHOR]

Background. Osteonecrosis of the femoral head (ONFH) is a challenge for surgeons and is still without effective treatment method. This study is aimed at evaluating the combined pharmacotherapy with alendronate and desferoxamine for preventing glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) and evaluating the efficacy of the combined medicine in regulating the bone resorption and bone regeneration. Materials and Methods. Thirty-six rats were randomly assigned to three groups: group A received alendronate and desferoxamine (n = 12), group B received alendronate only (n = 12), and group C acted as the control group received placebo (n = 12). All rats induced the GIOFH using methylprednisolone combined with lipopolysaccharide. Eight weeks later, all rats were killed and their tissues were subjected to radiographic and histological analyses. Results. According to the results, alendronate administration improved the trabecular thickness and separation in micro-CT analysis but had no significant evidence in increasing the bone area and decreasing the ratio of osteocyte lacunae in histological analysis when compared with the control group. Meanwhile, the alendronate group had more OCs, but less OCN and VEGF levels along with decreased p-AKT, HIF-1α, RANKL, and NFATc1 expressions than the control group. For comparison, alendronate combined with DFO further improved the bone volume, trabecular number, trabecular separation, and trabecular thickness with lower ratio of osteocyte lacunae and OC number, higher expression of OCN and VEGF and upregulated signal factors of HIF-1α and β-catenin, and decreased RANKL and NFATc1. Conclusion. Combined pharmacotherapy with alendronate and desferoxamine provide significant effects in regulating the bone resorption and bone regeneration for preventing GIOFN. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effects of human bone marrow mesenchymal stem cells (hBMSCs) and osteoblasts (hFOB1.19) on PC3 prostate cancer cells. Methods. To simulate the in vivo interaction between the bone/bone marrow microenvironments and prostate cancer cells, we established cocultures of PC3 cells with hBMSC or hFOB1.19 cells and evaluated their effects on the proliferation, cell cycle distribution, cell migration, and invasion of PC3 cells. Quantitative reverse transcription polymerase chain reaction was used to detect CD59 mRNA expression in PC3 cells. The expression of receptor activator of nuclear factor- (NF-) κB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), CD59, NF-κB (p50 subunit), and cyclin D1 in PC3 cells was analyzed by immunofluorescence and western blotting. Results. hBMSCs and hFOB1.19 cells enhanced the proliferation, migration, and invasion of PC3 cells; increased the proportion of PC3 cells in the S and G2/M phases of the cell cycle; and upregulated RANK, RANKL, OPG, CD59, cyclin D1, and NF-κB (p50 subunit) expression by PC3 cells. The RANKL inhibitor, scutellarin, inhibited these effects in PC3-hFOB1.19 cocultures. Conclusion. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway. [ABSTRACT FROM AUTHOR]

ELK3, an ETS domain-containing transcription factor, participates in various physiological and pathological processes including cell proliferation, migration, angiogenesis, and malignant progression. However, the role of ELK3 in prostate cancer cells and its mechanism are not fully understood. The contribution of ELK3 to prostate cancer progression was investigated in the present study. We showed that silencing of ELK3 by siRNA in prostate cancer cell DU145 induced S-M phase arrest, promoted apoptosis, inhibited cell proliferation and migration in vitro, and suppressed xenograft growth in mice in vivo. In accordance with its ability to arrest cells in S-M phase, the expression of cyclin A and cyclin B was downregulated. In addition, the expression of p53 was upregulated following ELK3 knockdown, while that of antiapoptotic Bcl-2 was decreased. The migration inhibition may partly due to upregulation of SERPINE1 (a serine protease inhibitor) followed ELK3 knockdown. Consistently, downregulation of SERPINE1 resulted in a modest elimination of migration inhibition resulted from ELK3 knockdown. Furthermore, we found that the AKT signaling was activated in ELK3 knockdown cells, and treatment these cells with AKT inhibitor attenuated SERPINE1 expression induced by ELK3 silencing, suggesting that activation of AKT pathway may be one of the reasons for upregulation of SERPINE1 after ELK3 knockdown. In conclusion, modulation of ELK3 expression may control the progression of prostate cancer partly by regulating cell growth, apoptosis, and migration. [ABSTRACT FROM AUTHOR]

Background: Maternal thyroid dysfunction in early pregnancy may increase the risk of adverse pregnancy complications and neurocognitive deficiencies in the developing fetus. Currently, some researchers demonstrated that body mass index (BMI) is associated with thyroid function in nonpregnant population. Hence, the American Thyroid Association recommended screening thyroid function in obese pregnant women; however, the evidence for this is weak. For this purpose, our study investigated the relationship between high BMI and thyroid functions during early pregnancy in Liaoning province, an iodine-sufficient region of China.Methods: Serum thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb) concentration, urinary iodine concentration (UIC), and BMI were determined in 6303 pregnant women.Results: BMI ≥ 25 kg/m(2) may act as an indicator of hypothyroxinemia and TPOAb positivity and BMI ≥ 30 kg/m(2) was associated with increases in the odds of hypothyroidism, hypothyroxinemia, and TPOAb positivity. The prevalence of isolated hypothyroxinemia increased among pregnant women with BMI > 24 kg/m(2).Conclusions: High BMI during early pregnancy may be an indicator of maternal thyroid dysfunction; for Asian women whose BMI > 24 kg/m(2) and who are within 8 weeks of pregnancy, thyroid functions should be assessed especially. [ABSTRACT FROM AUTHOR]