DNA Interaction and Cleavage Modes of Anthraquinone-Fused Enediynes: A Study on Tiancimycins, Yangpumicins, and Their Semisynthetic Analogues.

Dynemicin A has been the sole prototypical anthraquinone-fused enediyne (AFE) explored since its discovery in 1989. This study investigates the distinct DNA binding and cleavage mechanisms of emerging AFEs, represented by tiancimycins and yangpumicins, along with semisynthetic analogues. Our findings reveal their potent cytotoxicity against various tumor cell lines, while 18-methoxy tiancimycin A treatment could significantly suppress breast tumor growth with minimal toxicity. One of the most potent AFEs, i.e., tiancimycin A, preferentially targets DNA sequences 5'-ATT, 5'-CTT, 5'-GAA, 5'-GAT, and 5'-TTA. Molecular dynamics simulations suggest that emerging AFEs intercalate deeper into AT-rich DNA base pairs compared to dynemicin A. Importantly, tiancimycin A may equilibrate between insertional and intercalative modes without deintercalation, enabling selective cleavage of T and A bases. This study underscores how subtle structural variations among AFEs significantly influence their DNA recognition and cleavage, facilitating future design of novel AFEs as potent and selective payloads for antibody-drug conjugates.

Generation of DNA Aptamers with Functional Activity in Mammalian Cells by Mimicking Retroviruses.

DNA aptamers are single-stranded DNA oligonucleotide sequences that bind to specific targets with high affinity. Currently, DNA aptamers can be produced only by in vitro synthesis. It is difficult for DNA aptamers to have a sustained impact on intracellular protein activity, which limits their clinical application. In this study, we developed a DNA aptamer expression system to generate DNA aptamers with functional activity in mammalian cells by mimicking retroviruses. Using this system, DNA aptamers targeting intracellular Ras (Ra1) and membrane-bound CD71 (XQ2) were successfully generated in cells. In particular, the expressed Ra1 not only specifically bound to the intracellular Ras protein but also inhibited the phosphorylation of downstream ERK1/2 and AKT. Furthermore, by inserting the DNA aptamer expression system for Ra1 into a lentivirus vector, the system can be delivered into cells and stably produce Ra1 over time, resulting in the inhibition of lung cancer cell proliferation. Therefore, our study provides a novel strategy for the intracellular generation of DNA aptamers with functional activity and opens a new avenue for the clinical application of intracellular DNA aptamers in disease treatment.

A Phytophthora infestans RXLR effector AVR8 suppresses plant immunity by targeting a desumoylating isopeptidase DeSI2.

The potato's most devastating disease is late blight, which is caused by Phytophthora infestans. Whereas various resistance (R) genes are known, most are typically defeated by this fast-evolving oomycete pathogen. However, the broad-spectrum and durable R8 is a vital gene resource for potato resistance breeding. To support an educated deployment of R8, we embarked on a study on the corresponding avirulence gene Avr8. We overexpressed Avr8 by transient and stable transformation, and found that Avr8 promotes colonization of P. infestans in Nicotiana benthamiana and potato, respectively. A yeast-two-hybrid (Y2H) screen showed that AVR8 interacts with a desumoylating isopeptidase (StDeSI2) of potato. We overexpressed DeSI2 and found that DeSI2 positively regulates resistance to P. infestans, while silencing StDeSI2 downregulated the expression of a set of defense-related genes. By using a specific proteasome inhibitor, we found that AVR8 destabilized StDeSI2 through the 26S proteasome and attenuated early PTI responses. Altogether, these results indicate that AVR8 manipulates desumoylation, which is a new strategy that adds to the plethora of mechanisms that Phytophthora exploits to modulate host immunity, and StDeSI2 provides a new target for durable resistance breeding against P. infestans in potato.

The investigation of reduced field-of-view diffusion-weighted imaging (DWI) in patients with nasopharyngeal carcinoma: comparison with conventional DWI.

BACKGROUND: Field-of-view optimized and constrained undistorted single-shot imaging (FOCUS) is a new sequence that shows enhanced anatomical details, improving the diffusion-weighted (DW) images. PURPOSE: To investigate the value of FOCUS diffusion-weighted imaging (DWI) in the evaluation of nasopharyngeal carcinoma (NPC) and compare it with the single-shot echo planner imaging (SS-EPI) DWI approach. MATERIAL AND METHODS: A total of 87 patients with NPC underwent magnetic resonance imaging, including FOCUS and SS-EPI DWI sequences. The signal-to-noise ratio (SNR), signal-intensity ratio (SIR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient (ADC) values of the nasopharyngeal lesions were measured and compared. According to the clinical stages of patients, T and N were divided into early and advanced stage groups, respectively. The mean ADC values of the two techniques were computed, and the area under the curve (AUC) was estimated to calculate the diagnostic efficiency. RESULTS: Subjective and objective image qualitative values of FOCUS were significantly higher than those of SS-EPI. The ADC values for FOCUS of early T and N stages were significantly lower than those of the advanced stages. CONCLUSION: FOCUS provides significantly better image quality in NPC compared to SS-EPI, with lower ADC values for early-stage disease than late-stage disease.

High value valorization of lignin as environmental benign antimicrobial.

Lignin is a natural aromatic polymer of p-hydroxyphenylpropanoids with various biological activities. Noticeably, plants have made use of lignin as biocides to defend themselves from pathogen microbial invasions. Thus, the use of isolated lignin as environmentally benign antimicrobial is believed to be a promising high value approach for lignin valorization. On the other hand, as green and sustainable product of plant photosynthesis, lignin should be beneficial to reduce the carbon footprint of antimicrobial industry. There have been many reports that make use of lignin to prepare antimicrobials for different applications. However, lignin is highly heterogeneous polymers different in their monomers, linkages, molecular weight, and functional groups. The structure and property relationship, and the mechanism of action of lignin as antimicrobial remains ambiguous. To show light on these issues, we reviewed the publications on lignin chemistry, antimicrobial activity of lignin models and isolated lignin and associated mechanism of actions, approaches in synthesis of lignin with improved antimicrobial activity, and the applications of lignin as antimicrobial in different fields. Hopefully, this review will help and inspire researchers in the preparation of lignin antimicrobial for their applications.

Quantitative synthetic MRI for predicting locally advanced rectal cancer response to neoadjuvant chemoradiotherapy.

OBJECTIVES: To investigate the value of pre-treatment quantitative synthetic MRI (SyMRI) for predicting a good response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer. METHODS: This prospective study enrolled 63 patients with locally advanced rectal cancer scheduled to undergo preoperative chemoradiotherapy from January 2019 to June 2021. T1 relaxation time (T1), T2 relaxation time (T2), proton density (PD) from synthetic MRI, and apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) were measured. Independent-sample t-test, the Mann-Whitney U test, the Delong test, and receiver operating characteristic curve (ROC) analyses were used to predict the pathologic complete response (pCR) and T-downstaging. RESULTS: Among the 63 patients, 19 (30%) achieved pCR and 44 (70%) did not, and 24 (38%) achieved T-downstaging, while 44 (62%) did not. The mean T1 and T2 values were significantly lower in the pCR group compared with those in the non-pCR group and in the T-downstage group compared with those in the non-T-downstage group (all p < 0.05). There were no significant differences in the PD and ADC values between the two groups. There were no significant differences between the mean values of T1 and T2 for predicting pCR after CRT (AUC, 0.767 vs. 0.831, p = 0.37). There were no significant differences between the AUC values of T1 and T2 values for the assessment of post-CRT T-downstaging (AUC, 0.746 vs. 0.820, p = 0.506). CONCLUSIONS: In patients with locally advanced rectal cancer, the synthetic MRI-derived T1 relaxation time and T2 relaxation time values are promising imaging markers for predicting a good response to neoadjuvant chemoradiotherapy. KEY POINTS: • Mean T1 and T2 values were significantly lower in the pathologic complete response group and the T-downstage group. • There were no significant differences in the proton density and apparent diffusion coefficient values between the two groups.

Application of synthetic magnetic resonance imaging and DWI for evaluation of prognostic factors in cervical carcinoma: a prospective preliminary study.

OBJECTIVES: To determine the values of quantitative metrics derived from synthetic MRI (SyMRI) and apparent diffusion coefficient (ADC) in evaluating the prognostic factors of cervical carcinoma (CC). METHODS: In this prospective study, 74 patients with pathologically confirmed CC were enrolled. Pretreatment quantitative metrics including T1, T2 and ADC values were obtained from SyMRI and diffusion-weighted imaging (DWI) sequences. The values of all metrics were compared for different prognostic features using Student's t-test or Mann-Whitney U-test. The receiver operating characteristic (ROC) curve and multivariate logistic regression analysis were utilized to evaluate the diagnostic performance of quantitative variables. RESULTS: T1 and T2 values of parametrial involvement (PMI)-negative were significantly higher than those of PMI-positive (p = 0.002 and < 0.001), while ADC values did not show a significant difference. The area under curve (AUC) of T1 and T2 values for identifying PMI were 0.743 and 0.831. Only the T2 values showed a significant difference between the lymphovascular space involvement (LVSI)-negative and LVSI-positive (p < 0.001), and the AUC of T2 values for discriminating LVSI was 0.814. The differences of T1, T2, and ADC values between the well/moderately and the poorly differentiated CC were significant (all p < 0.001). The AUCs of T1, T2 and ADC values for predicting differentiation grades were 0.762, 0.830, and 0.808. The combined model of all metrics proved to achieve good diagnostic performance with the AUC of 0.866. CONCLUSION: SyMRI may be a potential noninvasive tool for assessing the prognostic factors such as PMI, LVSI, and differentiation grades in CC. Moreover, the overall diagnostic performances of synthetic quantitative metrics were superior to the ADC values, especially in identifying PMI and LVSI. ADVANCES IN KNOWLEDGE: This is the first study to assess the utility of SyMRI-derived parameters and ADC value in evaluating the prognostic factors in CC.

Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation.

Previous studies have shown mitochondrial dysfunction in various acute kidney injuries and chronic kidney diseases. Lipoic acid exerts potent effects on oxidant stress and modulation of mitochondrial function in damaged organ. In this study we investigated whether alpha lipoamide (ALM), a derivative of lipoic acid, exerted a renal protective effect in a type 2 diabetes mellitus mouse model. 9-week-old db/db mice were treated with ALM (50 mg·kg-1·d-1, i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels in db/db mice, but restored renal function and significantly improved fibrosis of kidneys. We demonstrated that ALM administration significantly ameliorated mitochondrial dysfunction and tubulointerstitial fibrotic lesions, along with increased expression of CDX2 and CFTR and decreased expression of ß-catenin and Snail in kidneys of db/db mice. Similar protective effects were observed in rat renal tubular epithelial cell line NRK-52E cultured in high-glucose medium following treatment with ALM (200 µM). The protective mechanisms of ALM in diabetic kidney disease (DKD) were further explored: Autodock Vina software predicted that ALM could activate RXRα protein by forming stable hydrogen bonds. PROMO Database predicted that RXRα could bind the promoter sequences of CDX2 gene. Knockdown of RXRα expression in NRK-52E cells under normal glucose condition suppressed CDX2 expression and promoted phenotypic changes in renal tubular epithelial cells. However, RXRα overexpression increased CDX2 expression which in turn inhibited high glucose-mediated renal tubular epithelial cell injury. Therefore, we reveal the protective effect of ALM on DKD and its possible potential targets: ALM ameliorates mitochondrial dysfunction and regulates the CDX2/CFTR/ß-catenin signaling axis through upregulation and activation of RXRα. Schematic figure illustrating that ALM alleviates diabetic kidney disease by improving mitochondrial function and upregulation and activation of RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on ß-catenin activation and nuclear translocation. RTEC renal tubular epithelial cell. ROS Reactive oxygen species. RXRα Retinoid X receptor-α. Mfn1 Mitofusin 1. Drp1 dynamic-related protein 1. MDA malondialdehyde. 4-HNE 4-hydroxynonenal. T-SOD Total-superoxide dismutase. CDX2 Caudal-type homeobox transcription factor 2. CFTR Cystic fibrosis transmembrane conductance regulator. EMT epithelial mesenchymal transition. α-SMA Alpha-smooth muscle actin. ECM extracellular matrix. DKD diabetic kidney disease. Schematic figure was drawn by Figdraw ( www.figdraw.com ).

Perirenal Fat Thickness Significantly Associated with Prognosis of Metastatic Renal Cell Cancer Patients Receiving Anti-VEGF Therapy.

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value.

Immune checkpoint inhibitors further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy.

Background: Increasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria's and renal function's condition since the administration of PD-1 inhibitor. Methods: To assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%). Results: Of the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m2 to 66.75 mL/min/1.73 m2 after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent's survival (P<0.001). Conclusions: Targeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.

Liposome-Encapsulated Tiancimycin A Is Active against Melanoma and Metastatic Breast Tumors: The Effect of cRGD Modification of the Liposomal Carrier and Tiancimycin A Dose on Drug Activity and Toxicity.

Enediyne natural products, including neocarzinostatin and calicheamicin γ1, are used in the form of a copolymer or antibody-drug conjugate to treat hepatomas and leukemia. Tiancimycin (TNM) A is a novel anthraquinone-fused enediyne that can rapidly and completely kill tumor cells. Herein, we encapsulated TNM A in liposomes (Lip-TNM A) and cyclic arginine-glycine-aspartate (cRGD)-functionalized liposomes (cRGD-Lip-TNM A) and demonstrated its antitumor activity using mouse xenografts. Because TNM A causes rapid DNA damage, cell cycle arrest, and apoptosis, these nanoparticles exhibited potent cytotoxicity against multiple tumor cells for 8 h. In B16-F10 and KPL-4 xenografts, both nanoparticles showed superior potency over doxorubicin and trastuzumab. However, cRGD-Lip-TNM A reduced the tumor weight more significantly than Lip-TNM A in B16-F10 xenografts, in which the αvß3-integrin receptors are significantly overexpressed in this melanoma. Lip-TNM A was slightly more active than cRGD-Lip-TNM A against KPL-4 xenografts, which probably reflected the difference of their in vivo fate in this mouse model. In a highly metastatic 4T1 tumor model, cRGD-Lip-TNM A reduced tumor metastasis induced by losartan, a tumor microenvironment-remodeling agent. These findings suggest that targeted delivery of enediynes with unique modes of action may enable more effective translation of anticancer nanomedicines.

BMP-7 ameliorates partial epithelial-mesenchymal transition by restoring SnoN protein level via Smad1/5 pathway in diabetic kidney disease.

Tubulointerstitial fibrosis (TIF) is involved in the development of diabetic kidney disease (DKD). Transforming growth factor ß1 (TGF-ß1) is involved in the extensive fibrosis of renal tissue by facilitating the partial epithelial-mesenchymal transition (EMT), increasing the synthesis of extracellular matrix (ECM), inhibiting degradation, inducing apoptosis of renal parenchyma cells, and activating renal interstitial fibroblasts and inflammatory cells. Recent studies indicated that bone morphogenetic protein-7 (BMP-7) upregulated the expression of endogenous SnoN against renal TIF induced by TGF-ß1 or hyperglycemia. Nevertheless, the mechanisms underlying the BMP-7-mediated restoration of SnoN protein level remains elusive. The present study demonstrated the increased expression of BMP-7 in diabetic mellitus (DM) mice by hydrodynamic tail vein injection of overexpressed BMP-7 plasmid, which attenuated the effects of DM on kidney in mice. Partial tubular EMT and the accumulation of Collagen-III were resisted in DM mice that received overexpressed BMP-7 plasmid. Similar in vivo results showed that BMP-7 was competent to alleviate NRK-52E cells undergoing partial EMT in a high-glucose milieu. Furthermore, exogenous BMP-7 activated the Smad1/5 pathway to promote gene transcription of SnoN and intervened ubiquitination of SnoN; both effects repaired the SnoN protein level in renal tubular cells and kidney tissues of DM mice. Therefore, these findings suggested that BMP-7 could upregulate SnoN mRNA and protein levels by activating the classical Smad1/5 pathway to refrain from the partial EMT of renal tubular epithelial cells and the deposition of ECM in DKD-induced renal fibrosis.

Overexpressed versican promoted cell multiplication, migration and invasion in gastric cancer.

Versican (VCAN) is verified to promote development among many cancers, whose function on gastric cancer (GC) is less studied. This work explored the effect of VCNA on GC. The differentially expressed VCAN between tumor and normal samples, among different cancer stages and the overall survival of GC patients with high and low VCAN levels were predicted through Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The association between VCAN and clinicopathological parameters was analyzed by clinical investigation. AGS and NCI-N87 cells were transfected with VCAN short hairpin RNA (shVCAN) and VCAN overexpression plasmid. The VCNA, Cyclin D1, Cyclin E, E-Cadherin, N-Cadherin and Vimentin expression was detected through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Cell viability was assessed through MTT assay. Cell migration was measured by wound healing assay and cell invasion was evaluated through Transwell assay. Cell cycle was determined by flow cytometry assay. VCAN was upregulated in GC and its high expression related to advanced TNM stage, Lymph node metastasis, Depth of invasion and Grade. VCAN knockdown inhibited multiplication, migration, invasion, Cyclin D1, Cyclin E, N-Cadherin and Vimentin expression while induced cycle arrest and E-Cadherin level of GC cells, whereas overexpressed VCAN showed opposite results. VCAN had a potential to be a biomarker for GC and overexpressed VCAN promoted GC cell multiplication, migration and invasion.

Neoadjuvant combination of pazopanib or axitinib and programmed cell death protein-1-activated dendritic cell-cytokine-induced killer cells immunotherapy may facilitate surgery in patients with renal cell carcinoma.

BACKGROUND: Radical/cytoreductive nephrectomy or nephron-sparing surgery may be thought to be not safe or unfeasible in some renal cell carcinoma (RCC) patients in which tumor is locally advanced or highly complicated. Neoadjuvant therapy may reduce the volume of the tumor, thus facilitates surgery. The aim the study is to evaluate the efficacy and safety of neoadjuvant combination of pazopanib or axitinib and PD-1-activated dendritic cell-cytokine-induced killer (PD-1/DC-CIK) cell immunotherapy in those patients. METHODS: Data from 16 RCC patients who received neoadjuvant pazopanib (Group P, n=9) or axitinib (Group A, n=7) plus PD-1/DC-CIK cells immunotherapy were reviewed retrospectively. A total of 9 participants that were potential candidates for radical/cytoreductive nephrectomy (RN/CN) had locally advanced tumor and 5 participants with partial nephrectomy (PN) absolute indications had highly complicated tumors. The efficacy outcomes were based on volume changes of the primary tumor, lymph nodes, and tumor thrombus in 13 participants with complete computed tomography (CT) imaging. The treatment-related toxicities and surgical complications were also reported. RESULTS: With a median of 2.1 months treatment, the overall volume of the tumors decreased by a median of 42.30% [interquartile range (IQR): 19.37-66.78%]. Specifically, the median reduction of tumor volume was 88.77 and 15.50 cm3 in group P and group A, respectively (P=0.014). However, participants in Group P were more likely to experience grade 3 or 4 treatment-related adverse events (AEs) than those in Group A (44.4% vs. 0). Finally, all participants were candidates for appropriate surgery after neoadjuvant therapy (as assessed by the surgeon), and 10 participants accepted surgery, including 5 PN, 4 RN/CN, and 1 lymph node dissection. A solitary participant had Clavien grade IV acute renal failure required dialysis and another had grade II lymphatic leakage. CONCLUSIONS: Neoadjuvant combination of pazopanib or axitinib and PD-1/DC-CIK cells immunotherapy was well-tolerated and could effectively reduce the volume of tumors in locally advanced or highly complicated RCC patients.

The role of CDX2 in renal tubular lesions during diabetic kidney disease.

Renal tubules are vulnerable targets of various factors causing kidney injury in diabetic kidney disease (DKD), and the degree of tubular lesions is closely related to renal function. Abnormal renal tubular epithelial cells (RTECs) differentiation and depletion of cell junction proteins are important in DKD pathogenesis. Caudal-type homeobox transcription factor 2 (CDX2), represents a key nuclear transcription factor that maintains normal proliferation and differentiation of the intestinal epithelium. The present study aimed to evaluate the effects of CDX2 on RTECs differentiation and cell junction proteins in DKD. The results demonstrated that CDX2 was mainly localized in renal tubules, and downregulated in various DKD models. CDX2 upregulated E-cadherin and suppressed partial epithelial-mesenchymal transition (EMT), which can alleviate hyperglycemia-associated RTECs injury. Cystic fibrosis transmembrane conductance regulator (CFTR) was regulated by CDX2 in NRK-52E cells, and CFTR interfered with ß-catenin activation by binding to Dvl2, which is an essential component of Wnt/ß-catenin signaling. CFTR knockdown abolished the suppressive effects of CDX2 on Wnt/ß-catenin signaling, thereby upregulating cell junction proteins and inhibiting partial EMT in RTECs. In summary, CDX2 can improve renal tubular lesions during DKD by increasing CFTR amounts to suppress the Wnt/ß-catenin signaling pathway.

EI24 alleviates renal interstitial fibrosis through inhibition of epithelial-mesenchymal transition and fibroblast activation.

Etoposide-induced 2.4 (EI24) exerts tumor suppressor activity through participating in cell apoptosis, autophagy, and inflammation. However, its role in renal diseases has not been elucidated. This study showed that the EI24 level decreased gradually in the kidneys of mice with unilateral ureteral obstruction (UUO) and in another fibrosis model induced by diabetic kidney disease. The overexpression of EI24 was used to investigate the possible role both in vivo and in vitro. The overexpression 1 day after UUO through tail vein injection alleviated the progression of renal interstitial fibrosis (RIF). EI24 inhibited epithelial-mesenchymal transition, excessive deposition of the extracellular matrix, and activation of fibroblasts. Furthermore, administration of EI24-overexpressing plasmids restrained the phosphorylation of nuclear factor-κB (NF-κB) and c-Jun kinase (JNK) through regulating the proteasome-dependent degradation of TRAF2, and then, inhibited the expression of downstream inflammation-associated cytokines (interleukin-6, tumor necrosis factor-α, and monocyte chemotactic protein-1) and infiltration of macrophages and neutrophils in mouse kidney after UUO. In conclusion, the data indicated that EI24, a novel anti-fibrosis regulator, was important in the progression of RIF.

Autophagy-related protein EI24 delays the development of pulmonary fibrosis by promoting autophagy.

Etoposide-induced protein 2.4 (EI24) is an autophagy-associated protein and acts as a tumor suppressor. However, its role in tissue fibrosis remains unknown. Herein, a downregulation of EI24 levels in the lungs from mouse pulmonary fibrosis (PF) model and lung epithelial cells was observed in response to bleomycin (BLM) or transforming growth factor-ß1 (TGF-ß1). Then, the role of EI24 in PF was investigated through the upregulation of EI24 in vitro and in vivo. EI24 inhibited epithelial-mesenchymal transition (EMT) process and extracellular matrix (ECM) production in EI24-overexpressing cells after stimulation with BLM or TGF-ß1. The overexpression of EI24 at 14 days after the establishment of the PF model through tail vein injection delayed the progression of PF. Moreover, the administration of EI24-overexpressing plasmid promoted the autophagy level in the lungs of the PF mouse model. In addition, the inhibition of autophagy by 3-methyladenine limited the role of EI24 in these processes. Thus, the current data indicated that EI24 attenuates PF through inhibition of EMT process and ECM production by promoting autophagy.

Downregulation of lncRNA ZFAS1 inhibits the hallmarks of thyroid carcinoma via the regulation of miR­302­3p on cyclin D1.

At present, treatment options for thyroid carcinoma remain limited. The present study aimed to investigate the role of ZFAS1 in various major hallmarks of cancer and the underlying mechanisms in thyroid carcinoma cells. The interactions between long non­coding RNAs (lncRNAs), microRNAs (miRs) and target genes were predicted by bioinformatics and confirmed by performing dual­luciferase assays. The mRNA and protein expressions were determined by reverse transcription­quantitative PCR and western blotting. Cell invasion, migration, and viability were evaluated via Transwell, wound­healing and Cell Counting Kit­8 assays, respectively. The results demonstrated that lncRNA ZFAS1 expression was upregulated in thyroid carcinoma tissues, TT and SW579 cells, and was associated with the proliferation of these two cell lines. Notably, downregulation ZFAS1 reduced migration and invasion, and reversed the promotive effects of miR­302a­3p inhibitor on the proliferation, migration and invasion of TT and SW579 cells. Moreover, cyclin D1 (CCND1) is targeted by miR­302a­3p, and was regulated by ZFAS1. In addition, the downregulation of ZFAS1 not only reversed the promotive effects of miR­302a­3p inhibitor on CCND1 expression and the epithelial­mesenchymal transition (EMT) of TT and SW579 cells, but also targeted and increased the expression of miR­302a­3p, and further reduced the expression of CCND1, resulting in suppression of the proliferation, migration, invasion and EMT of thyroid carcinoma cells.

The diagnostic performance of quantitative mapping in breast cancer patients: a preliminary study using synthetic MRI.

BACKGROUND: Previous studies have indicated that quantitative MRI (qMR) is beneficial for diagnosis of breast cancer. As a novel qMR technology, synthetic MRI (syMRI) may be advantageous by offering simultaneous generation of T1 and T2 mapping in one scan within a few minutes and without concern to the deposition of the gadolinium contrast agent in cell nucleus. In this study, the potential of quantitative mapping derived from Synthetic MRI (SyMRI) to diagnose breast cancer was investigated. METHODS: From April 2018 to May 2019, a total of 87 patients with suspicious breast lesions underwent both conventional and SyMRI before treatment. The quantitative metrics derived from SyMRI, including T1 and T2 values, were measured in breast lesions. The diagnostic performance of SyMRI was evaluated with unpaired Student's t-tests, receiver operating characteristic curve analysis and multivariate logistic regression analysis. The AUCs of quantitative values were compared using Delong test. RESULTS: Among 77 patients who met the inclusion criteria, 48 were diagnosed with histopathological confirmed breast cancers, and the rest had benign lesions. The breast cancers showed significantly higher T1 (1611.61 ± 215.88 ms) values and lower T2 (80.93 ± 7.51 ms) values than benign lesions. The area under the ROC curve (AUC) values were 0.931 (95% CI: 0.874-0.989) and 0.883 (95% CI: 0.810-0.956) for T1 and T2 maps, respectively, in diagnostic discrimination between breast cancers and benign lesions. A slightly increased AUC of 0.978 (95% CI: 0.915-0.993) was achieved by combining those two relaxation-based quantitative metrics. CONCLUSION: In conclusion, our preliminary study showed that the quantitative T1 and T2 values obtained by SyMRI could distinguish effectively between benign and malignant breast lesions, and T1 relaxation time showed the highest diagnostic efficiency. Furthermore, combining the two quantitative relaxation metrics further improved their diagnostic performance.

Gender disparities in depressive and anxiety symptoms among internal migrant workers in Shenzhen: a cross-sectional study.

OBJECTIVES: To investigate the gender disparities in the prevalence and severity of depressive and anxiety symptoms and associated factors among internal migrant workers in Shenzhen. DESIGN: Cross-sectional study. SETTING: Labour intensive factories in Shenzhen, Guangdong, China. PARTICIPANTS: We recruited 3200 internal migrant workers who aged over 18 years old and above and did not register in Shenzhen's household registration system. There were 3095 participants eligible for this study. METHODS: Participants completed sociodemographic questionnaire, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, the UCLA Loneliness Scale, the Barratt Impulsiveness Scale, the Social Support Rating Scale, the Simplified Coping Style Questionnaire and Meaning in Life Questionnaire. We applied χ2 test, analysis of variance, Wilcoxon rank test, Fisher's exact test and univariate and multivariate multilevel linear regression analysis. RESULTS: The overall prevalence of depressive and anxiety symptoms was 27.85% and 19.26% among internal migrant workers. We reported gender disparities of depressive and anxiety symptoms among participants that the prevalence of depressive and anxiety symptoms was higher in women (30.57% vs 26.43% and 22.67% vs 17.47%), and the symptoms were more severe among women. Female migrant workers were more likely to be singled, have lower prevalence of smoking and drinking, receive less education and monthly income, have higher level of impulsiveness and social support and lower level of meaning in life. We found age, marriage, income, adaption to living in Shenzhen, being discriminated, drinking, loneliness, impulsiveness, social support, coping strategies and meaning of life were associated with the severity of depressive and anxiety symptoms among internal migrant workers in Shenzhen. CONCLUSION: Gender inequality may be the institutional factor leading to disparities in depressive and anxiety symptoms among internal migrant workers. Interventions should be embedded with strategies improving gender equality.