Palliative effect of rotating magnetic field on glucocorticoid-induced osteonecrosis of the femoral head in rats by regulating osteoblast differentiation.

With the substantial increase in the overuse of glucocorticoids (GCs) in clinical medicine, the prevalence of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) continues to rise in recent years. However, the optimal treatment for GC-ONFH remains elusive. Rotating magnetic field (RMF), considered as a non-invasive, safe and effective approach, has been proved to have multiple beneficial biological effects including improving bone diseases. To verify the effects of RMF on GC-ONFH, a lipopolysaccharide (LPS) and methylprednisolone (MPS)-induced invivo rat model, and an MPS-induced invitro cell model have been employed. The results demonstrate that RMF alleviated bone mineral loss and femoral head collapse in GC-ONFH rats. Meanwhile, RMF reduced serum lipid levels, attenuated cystic lesions, raised the expression of anti-apoptotic proteins and osteoprotegerin (OPG), while suppressed the expression of pro-apoptotic proteins and nuclear factor receptor activator-κB (RANK) in GC-ONFH rats. Besides, RMF also facilitated the generation of ALP, attenuated apoptosis and inhibits the expression of pro-apoptotic proteins, facilitated the expression of OPG, and inhibited the expression of RANK in MPS-stimulated MC3T3-E1 cells. Thus, this study indicates that RMF can improve GC-ONFH in rat and cell models, suggesting that RMF have the potential in the treatment of clinical GC-ONFH.

BIX-01294 enhances the effect of chemotherapy on colorectal cancer by inhibiting the expression of stemness genes.

During the development of colorectal cancer, tumor cells will generate some cancer stem cells with self-renewal ability because they adapt to the environment. Therefore, in the treatment of colorectal cancer, it has certain potential clinical application value to effectively inhibit cancer stem cells. A small molecule EHMT-2 inhibitor, BIX-01294, was evaluated for its activity in inhibiting cancer stem cells in human colorectal cancer by in vitro and in vivo experiments. Transcriptome analysis was performed on BIX-01294 treated cells for holistic analysis to elucidate how BIX-01294 inhibits the expression of genes related to cancer stem cells. The results show that BIX-01294 significantly inhibited the proliferative phenotype of human colorectal cancer in vivo and in vitro, reduced the proportion of cancer stem cells, and inhibited some stemness-related gene. Morever, it is synergistic with 5-fluorouracil in inhibiting the proliferation of colorectal cancer. In summary, EHMT-2 is a novel target of anti-tumor drugs. The combination of BIX-01294 and 5-fluorouracil has a synergistic therapeutic effect on human colorectal cancer.

Diagnostic value of an enhanced MRI combined with serum CEA, CA19-9, CA125 and CA72-4 in the liver metastasis of colorectal cancer.

OBJECTIVE: This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. METHODS: A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. RESULTS: The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). CONCLUSION: The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

A large-scale genomic association analysis identifies the candidate causal genes conferring stripe rust resistance under multiple field environments.

The incorporation of resistance genes into wheat commercial varieties is the ideal strategy to combat stripe or yellow rust (YR). In a search for novel resistance genes, we performed a large-scale genomic association analysis with high-density 660K single nucleotide polymorphism (SNP) arrays to determine the genetic components of YR resistance in 411 spring wheat lines. Following quality control, 371 972 SNPs were screened, covering over 50% of the high-confidence annotated gene space. Nineteen stable genomic regions harbouring 292 significant SNPs were associated with adult-plant YR resistance across nine environments. Of these, 14 SNPs were localized in the proximity of known loci widely used in breeding. Obvious candidate SNP variants were identified in certain confidence intervals, such as the cloned gene Yr18 and the major locus on chromosome 2BL, despite a large extent of linkage disequilibrium. The number of causal SNP variants was refined using an independent validation panel and consideration of the estimated functional importance of each nucleotide polymorphism. Interestingly, four natural polymorphisms causing amino acid changes in the gene TraesCS2B01G513100 that encodes a serine/threonine protein kinase (STPK) were significantly involved in YR responses. Gene expression and mutation analysis confirmed that STPK played an important role in YR resistance. PCR markers were developed to identify the favourable TraesCS2B01G513100 haplotype for marker-assisted breeding. These results demonstrate that high-resolution SNP-based GWAS enables the rapid identification of putative resistance genes and can be used to improve the efficiency of marker-assisted selection in wheat disease resistance breeding.

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer.

Selpercatinib, a novel, highly selective and potent, inhibitor of RET, demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities.

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4+ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4+ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4+ T cells from UC patients. Naive CD4+ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4+ T cells. CD4+ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.

An Observational Study: Is N-Acetylcysteine Helpful in Performance Improvement of Mycoplasma IST2 Testing through Sample Homogenization?

BACKGROUND: Culture is still the gold standard for the detection of genital mycoplasma which could cause urogenital infections in humans. Mycoplasma IST2 is a commercial kit widely used for the detection of M. hominis and Ureaplasma species. Its accuracy was partially impaired because clinical specimens are usually mixed with purulent or transparent mucus. We aimed to solve this problem through sample homogenization by N-acetylcysteine (NAC) treatment. METHODS: Twenty-two endocervical swab samples were collected from 22 female patients with suspected mycoplasma infection, while 11 of these specimens were with purulent or transparent mucus. Mycoplasma IST2 testing kit was used for mycoplasma culture and AST for the control group and NAC-treated group. RESULTS: Genital mycoplasma was detected in 15 of 22 samples for both groups. The colony number in 6 out of 11 purulent specimens (54.5%) was more than 104 CFU/ml of genital mycoplasma for the NAC-treated group, while only one of 11 (9.1%) for the control group. For the nonpurulent specimens, no significant difference had been found in colony counting of genital mycoplasma between the control group and NAC-treated group (P > 0.05). The results of antimicrobial susceptibility testing for the NAC-treated group were highly similar to those for the control group. CONCLUSIONS: Our results demonstrate that NAC is helpful in sample homogenization and NAC treatment can improve the detection efficiency of mycoplasma with Mycoplasma IST2 testing.

Magnon-driven interfacial magnetoelectric coupling in Co/PMN-PT multiferroic heterostructures.

Magnon-driven interfacial magnetoelectric coupling in Co/PMN-PT multiferroic heterostructures is investigated at room temperature. The electric field controlled ferromagnetic resonance field possesses a loop-like curve, with a large resonance field shift between positive and negative remanent polarizations, which confirms a non-volatile strong magnetoelectric coupling. However, with a non-magnetic Ta layer inserted at the Co/PMN-PT interface, a piezostrain-induced butterfly-like curve of the resonance field versus applied electric field of the Co/Ta/PMN-PT multiferroic heterostructure is observed. Further, the non-volatile behavior of the resonance field changing with the applied electric field can be obtained, consistent with the result of polarization versus applied electric field curve, which can be attributed to the magnon-driven interfacial magnetoelectric coupling, showing a strong correlation of magnetization of Co thin film and the polarization of PMN-PT. The result is promising for the design of future multiferroic devices.

In-Fiber Mach-Zehnder Interferometer Based on Three-Core Fiber for Measurement of Directional Bending.

A highly sensitive directional bending sensor based on a three-core fiber (TCF) Mach-Zehnder interferometer (MZI) is presented in this study. This MZI-based bending sensor was fabricated by fusion-splicing a section of TCF between two single-mode fibers (SMF) with core-offset. Due to the location of the core in the TCF, a bend applied to the TCF-based MZI led to an elongation or shortening of the core, which makes the sensor suitable for directional bending measurement. To analyze the bending characteristics, two types of TCF-based sensors, with the fusion-spliced core located at different positions between the SMFs, were investigated. A swept source was employed in the measurement technique. The experimental results showed that, for the two types of sensors in this setup, the bending sensitivities of the two sensors were 15.36 nm/m-1 and 3.11 nm/m-1 at the bending direction of 0°, and -20.48 nm/m-1 and -5.29 nm/m-1 at the bending direction of 180°. The temperature sensitivities of the two sensors were 0.043 nm/°C and 0.041 nm/°C, respectively. The proposed sensors are compact, versatile, inexpensive to fabricate, and are expected to have potential applications in biomedical sensing.

SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer.

FAS-associated protein with death domain (FADD) is the pivotal adaptor protein, which transmits apoptotic signals mediated by the death receptors. Here we report that high FADD protein level predicts poor prognosis of non-small cell lung cancer (NSCLC) patients and its protein level is mainly regulated by the 26S proteasome. We also found that ubiquitin ligase SPOP (speckle-type POZ protein) binds to FADD and mediates its degradation, which can be blocked by MG132 treatment. Notably, SPOP inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity and its target genes expression via FADD. These results reveal the function of SPOP-FADDNFκB axis in NSCLC cells, which is associated with prognosis of NSCLC patients.

Bcl2L12 mediates effects of protease-activated receptor-2 on the pathogenesis of Th2-dominated responses of patients with ulcerative colitis.

The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.

Electric-field control of non-volatile 180° switching of the unidirectional anisotropy field in a multiferroic heterostructure.

We investigate the room-temperature, electric-field-mediated, non-volatile 180° switching of the unidirectional anisotropy field in an IrMn/CoFeB/Ta/Pb(Mg1/3Nb2/3)O3-PbTiO3 heterostructure. The variation in exchange bias under different electric fields appears clearly in the magnetic hysteresis loops. The remnant magnetization as a function of electric field, as determined by static magnetic measurements, exhibits a non-volatile behavior, which is consistent with the results of the ferromagnetic resonance field as a function of electric field. Moreover, the measured ferromagnetic resonance shows that the uniaxial magnetic anisotropy field is non-volatile and the unidirectional anisotropy field undergoes 180° switching that can be acquired and separated distinctly. This result is attributed to the piezo-strain effect. The electric-field-mediated non-volatile 180° switching of the unidirectional anisotropy field paves the way for sensors and other spintronic devices.

Alternative splicing of the androgen receptor in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.

Fusarium graminearum ATP-Binding Cassette Transporter Gene FgABCC9 Is Required for Its Transportation of Salicylic Acid, Fungicide Resistance, Mycelial Growth and Pathogenicity towards Wheat.

ATP-binding cassette (ABC) transporters hydrolyze ATP to transport a wide range of substrates. Fusarium graminearum is a major causal agent of Fusarium head blight, which is a severe disease in wheat worldwide. FgABCC9 (FG05_07325) encodes an ABC-C (ABC transporter family C) transporter in F. graminearum, which was highly expressed during the infection in wheat and was up-regulated by the plant defense hormone salicylic acid (SA) and the fungicide tebuconazole. The predicted tertiary structure of the FgABCC9 protein was consistent with the schematic of the ABC exporter. Deletion of FgABCC9 resulted in decreased mycelial growth, increased sensitivity to SA and tebuconazole, reduced accumulation of deoxynivalenol (DON), and less pathogenicity towards wheat. Re-introduction of a functional FgABCC9 gene into ΔFgABCC9 recovered the phenotypes of the wild type strain. Transgenic expression of FgABCC9 in Arabidopsis thaliana increased the accumulation of SA in its leaves without activating SA signaling, which suggests that FgABCC9 functions as an SA exporter. Taken together, FgABCC9 encodes an ABC exporter, which is critical for fungal exportation of SA, response to tebuconazole, mycelial growth, and pathogenicity towards wheat.

Impact of International Collaborative Training Programs on Medical Students' Research Ability.

International collaborative training programs for graduate students are widespread, but studies on their educational impact are limited. As an advanced cancer institute in China, Cancer Hospital Chinese Academy of Medical Science (CHCAMS) attaches great importance to international exchanges and cooperation within graduate education. The Department of Epidemiology of CHCAMS has been involved in several existing international training programs and has also launched a short-term training program in cooperation with foreign universities and institutes from 2008. Fogarty International Clinical Research Scholars and Fellows (FICRS-F) Program and the Fulbright-Fogarty Fellowship Program are the most typical examples of our practice in international cooperation on graduate education over these years. Our department has gained substantial experience in graduate-level international collaborative training, focused on cancer epidemiology. This paper is a brief introduction to the practice of different programs in our department and students' achievements during and after training. Moreover, we attempt to serve as a reference and help promote the training of graduate students pursuing careers in cancer research or global health by other universities or research institutes.

Evaluation of toxicity studies of flavonoid fraction of Lithocarpus polystachyus Rehd in rodents.

The aim of the study was to evaluate the safety of flavonoid fraction of Lithocarpus polystachyus Rehd (Sweet Tea-F, ST-F) in mice and rats through acute and sub-chronic toxicity studies respectively. For acute toxicity study, a single dose of 5000 mg/kg of ST-F was given orally to healthy KM mice. The mice were observed mortality and toxic symptoms for 24 h, then once a day up to 14 days. In the sub-chronic toxicity study, ST-F was administered orally at doses of 0, 70, 140, 560 mg/kg/day to rats for 26 weeks. Body weight and food intake were recorded weekly. Hematological, biochemical, coagulation and organ parameters were analyzed at the end of 26 weeks administration. Vital organs were evaluated by histopathology. In the acute toxicity study, ST-F caused neither significant toxic symptoms, nor mortality in mice. In sub-chronic toxicity study, daily oral administration of ST-F at the dose of 70 mg/kg resulted in a significant increase (P < 0.05) in the relative body weight at the 10-week, and the same situation brought at the dose of 140 mg/kg/day at the 22-week. Hematological and biochemical showed significant changes (P < 0.01 or P < 0.05) in WBC, GLU, ALP, AST and serum electrolytes levels at the dose of 560 mg/kg/day. The amount of RBC decreased significantly (P < 0.05) while the content of PLT slightly increased (P < 0.05) at the dose of 140 mg/kg/day. In additional, no obvious histological changes were observed in vital organs of ST-F treated animals compared to control group. The ST-F may be exit slight side effects at the dose of 560 mg/kg/day in rats. Thus, the overall results show that the no-observed adverse effect level (NOAEL) of ST-F was considered to be 140 mg/kg for male SD rats.

Salvianolic Acid B Ameliorates Hyperglycemia and Dyslipidemia in db/db Mice through the AMPK Pathway.

BACKGROUND/AIMS: Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. METHODS: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks. RESULTS: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver. CONCLUSION: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.