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"Ning, Fang"
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China's democracy path
\"This book argues that democracy is the inevitable product of China's industrialization and modernization, and is necessary for the development of China's current society. It provides a political guarantee for China's industrialization and modernization. There are both similarities and differences between China's version of democracy and those versions of other countries. In this book, the author discusses the country's important experiences in constructing democracy with Chinese characteristics, which it has gathered during the long struggle for national independence, prosperity and social development. The democracy system embodies basic values and universal principles of democracy with uniquely Chinese characteristics.\" -- Back cover.
Book
The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis
Background and aimsLiver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.MethodsThe fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.ResultsExpression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.ConclusionsIn aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
Journal Article
ملامح الديمقراطية الصينية
يتناول كتاب (ملامح الديمقراطية الصينية) والذي قامه بتأليفه (فانغ نينغ) في حوالي (288) صفحة من القطع المتوسط موضوع (الديمقراطية الصين) مستعرضا المحتويات التالية : يتحدث الكتاب عن الديمقراطية اتجاها عاما للتطور السياسي الذي شهده المجتمع الإنساني بعد دخوله الحقبة الصناعية، ولما كانت الصين حاليا في المرحلة التاريخية التي تحقق فيها تطور التصنيع والتحديث، كان وجود الديمقراطية نتاجا حتميا لهذا التطور.
BOOK
Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that
MYC
or
MYCN
amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of
CDK18
, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
PARP inhibitors are mainly used to treat BRCA1/2 mutated cancers. Here, the authors show that MYC amplified glioblastomas are sensitive to PARP inhibition due to CDK18 repression, which impairs ATR regulated homologous recombination repair, and that ATR inhibition sensitises glioblastomas to PARP inhibition.
Journal Article
CircLONP2 enhances colorectal carcinoma invasion and metastasis through modulating the maturation and exosomal dissemination of microRNA-17
Background
Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet.
Methods
A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis.
Results
A circRNA consisting of exon 8–11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo
.
Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness.
Conclusions
Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
Journal Article
PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.
Journal Article
CHD1L contributes to cisplatin resistance by upregulating the ABCB1–NF-κB axis in human non-small-cell lung cancer
Chromodomain helicase/ATPase DNA binding protein 1-like gene (
CHD1L
) is a recently identified gene associated with malignant tumor progression and patient chemotherapy resistance in human hepatocellular carcinoma (HCC). Previously, we found an association between CHD1L overexpression and poor patient survival in non-small-cell lung cancer (NSCLC). However, little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC. By employing immunohistochemistry, we analyzed the expression of CHD1L in NSCLC samples and elucidated the roles and mechanism of CHD1L in NSCLC chemoresistance. We found that the increased expression of CHD1L is positively correlated with a shorter survival time of patients who had received chemotherapy after surgery. We also found that the expression of CHD1L was increased after cisplatin treatment in A549 cells. Conversely, the depletion of CHD1L in cisplatin-resistance cells increased the cell sensitivity to cisplatin, indicating that CHD1L plays a critical role in cisplatin resistance of NSCLC cells. Importantly, we identified the ATP-Binding Cassette Sub-Family B Member (
ABCB1
) gene as a potential downstream target of CHD1L in NSCLC cells. Knocking down ABCB1 coupled with ectopic expression of CHD1L enhanced the effect of cisplatin on NSCLC cells apoptosis. In addition, overexpressed CHD1L increase the transcription of c-Jun which targeted directly to the promoter of ABCB1. Our data demonstrate that CHD1L could induce cisplatin resistance in NSCLC via c-Jun-ABCB1–NF-κB axis, and may serve as a novel predictive marker and the potential therapeutic target for cisplatin resistance in NSCLC.
Journal Article
Diagnostic significance of HRCT imaging features in adult mycoplasma pneumonia: a retrospective study
Mycoplasma pneumoniae pneumonia (MPP) often overlaps with the clinical manifestations and chest imaging manifestations of other types of community-acquired pneumonia (CAP). We retrospectively analyzed the clinical and imaging data of a group of patients with CAP, summarized their clinical and imaging characteristics, and discussed the diagnostic significance of their certain HRCT findings. The HRCT findings of CAP researched in our study included tree-in-bud sign (TIB), ground-glass opacity (GGO), tree fog sign (TIB + GGO), bronchial wall thickening, air-bronchogram, pleural effusion and cavity. The HRCT findings of all cases were analyzed. Among the 200 cases of MPP, 174 cases showed the TIB, 193 showed the GGO, 175 showed the tree fog sign, 181 lacked air-bronchogram. In case taking the tree fog sign and lack of air-bronchogram simultaneously as an index to distinguish MPP from OCAP, the sensitivity was 87.5%, the specificity was 97.5%, the accuracy was 92.5%. This study showed that that specific HRCT findings could be used to distinguish MPP from OCAP. The combined HRCT findings including the tree fog sign and lacked air-bronchogram simultaneously would contribute to a more accurate diagnosis of MPP.
Journal Article
Deep learning network enhances imaging quality of low-b-value diffusion–weighted imaging and improves lesion detection in prostate cancer
Background
Diffusion-weighted imaging with higher
b
-value improves detection rate for prostate cancer lesions. However, obtaining high
b
-value DWI requires more advanced hardware and software configuration. Here we use a novel deep learning network, NAFNet, to generate a deep learning reconstructed (DLR
1500
) images from 800
b
-value to mimic 1500
b
-value images, and to evaluate its performance and lesion detection improvements based on whole-slide images (WSI).
Methods
We enrolled 303 prostate cancer patients with both 800 and 1500
b
-values from Fudan University Shanghai Cancer Centre between 2017 and 2020. We assigned these patients to the training and validation set in a 2:1 ratio. The testing set included 36 prostate cancer patients from an independent institute who had only preoperative DWI at 800
b
-value. Two senior radiology doctors and two junior radiology doctors read and delineated cancer lesions on DLR
1500
, original 800 and 1500
b
-values DWI images. WSI were used as the ground truth to assess the lesion detection improvement of DLR
1500
images in the testing set.
Results
After training and generating, within junior radiology doctors, the diagnostic AUC based on DLR
1500
images is not inferior to that based on 1500
b
-value images (0.832 (0.788–0.876) vs. 0.821 (0.747–0.899),
P
= 0.824). The same phenomenon is also observed in senior radiology doctors. Furthermore, in the testing set, DLR
1500
images could significantly enhance junior radiology doctors’ diagnostic performance than 800
b
-value images (0.848 (0.758–0.938) vs. 0.752 (0.661–0.843),
P
= 0.043).
Conclusions
DLR
1500
DWIs were comparable in quality to original 1500
b
-value images within both junior and senior radiology doctors. NAFNet based DWI enhancement can significantly improve the image quality of 800
b
-value DWI, and therefore promote the accuracy of prostate cancer lesion detection for junior radiology doctors.
Journal Article
Sodium-Glucose Co-transporter-2 Inhibitor of Dapagliflozin Attenuates Myocardial Ischemia/Reperfusion Injury by Limiting NLRP3 Inflammasome Activation and Modulating Autophagy
Background: The sodium-glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin improves cardiovascular outcomes in patients with type 2 diabetes in a manner that is partially independent of its hypoglycemic effect. These observations suggest that it may exert a cardioprotective effect by another mechanism. This study explored the effects of dapagliflozin on myocardial ischemia/reperfusion injury in a mouse model. Materials and Methods: For the in vivo I/R studies, mice received 40 mg/kg/d dapagliflozin, starting 7 days before I/R. Evans Blue/TTC double-staining was used to determine the infarct size. Serum levels of cTnI, CK-MB, and LDH were measured. Inflammation, autophagy protein expression, and caspase-1 activity changes were measured at the protein level. Primary cardiomyocytes were used to investigate the direct effect of dapagliflozin on cardiomyocytes and to verify whether they have the same effect as observed in in vivo experiments. Result: A high dose of dapagliflozin significantly reduced infarct size and decreased the serum levels of cTnI, CK-MB, and LDH. Dapagliflozin also reduced serum levels of IL-1β, reduced expression of myocardial inflammation-related proteins, and inhibited cardiac caspase-1 activity. The treatment restored autophagy flux and promoted the degradation of autophagosomes. Relief of inflammation relied on autophagosome phagocytosis of NLRP3 and autophagosome clearance after lysosome improvement. 10 μM dapagliflozin reduced intracellular Ca 2+ and Na + in primary cardiomyocytes, and increasing NHE1 and NCX expression mitigated dapagliflozin effects on autophagy. Conclusion: Dapagliflozin protects against myocardial ischemia/reperfusion injury independently of its hypoglycemic effect. High-dose dapagliflozin pretreatment might limit NLRP3 inflammasome activation and mediate its selective autophagy. Dapagliflozin directly acts on cardiomyocytes through NHE1/NCX.
Journal Article