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"Shen, Yan"
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أفكار حول تعميق الإصلاح
يناقش الكتاب سلسلة من الإيضاحات الهامة قدمها الرئيس الصيني والأمين العام للجنة المركزية للحزب الشيوعي الصيني، شي جين بينغ، وتدور حول أفكار الإصلاح وتوسيع الانفتاح على نحو شامل في الصين. يضم الكتاب أكثر من 70 وثيقة هامة على صورة كلمات شي جين بينغ وخطاباته وتعليقاته وتوجيهاته وينقسم الكتاب إلى 12 موضوعا خاصا تتضمن 274 قطعة من مقتطفات الأقوال، نشر بعضها لأول مرة.
Book
Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance
Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both
in vitro
and
in vivo
. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified
PARP1
and
MCRS1
as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.
Synopsis
PARP inhibitors (PARPi) resistance is ubiquitous in the clinic. A newly discovered pan‐PARP inhibitor, thioparib, is highly effective against olaparib‐resistant cancer models, which suggests that therapeutic vulnerabilities still exist in PARPi‐resistant tumors.
Thioparib is a novel, potent, and orally bioavailable pan‐PARP inhibitor.
Thioparib overcomes primary and acquired olaparib resistance
in vitro
and
in vivo
.
Thioparib suppresses HR‐mediated DNA repair.
Thioparib induces a robust type I interferon response.
Graphical Abstract
PARP inhibitors (PARPi) resistance is ubiquitous in the clinic. A newly discovered pan‐PARP inhibitor, thioparib, is highly effective against olaparib‐resistant cancer models, which suggests that therapeutic vulnerabilities still exist in PARPi‐resistant tumors.
Journal Article
G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin
G9a, a H3K9 methyltransferase, shows elevated expression in many types of human cancers, particularly breast cancer. However, the tumorigenic mechanism of G9a is still far from clear. Here we report that G9a exerts its oncogenic function in breast cancer by repressing hephaestin and destruction cellular iron homeostasis. In the case of pharmacological inhibition or short hairpin RNA interference-mediated suppression of G9a, the expression and activity of hephaestin increases, leading to the observed decrease of intracellular labile iron content and the disturbance of breast cancer cell growth in vitro and in vivo. We also provide evidence that G9a interacts with HDAC1 and YY1 to form a multi-molecular complex that contributes to hephaestin silencing. Furthermore, high G9a expression and low hephaestin expression correlate with poor survival of breast cancer are investigated. All these suggest a G9a-dependent epigenetic program in the control of iron homeostasis and tumor growth in breast cancer.
G9a is a histone methyltransferase highly expressed in several cancers including breast cancer. Here the authors propose a mechanism through which G9a promotes breast cancer by regulating iron metabolism through the repression of ferroxidase hephaestin.
Journal Article
Management of gastric cancer in Asia: resource-stratified guidelines
Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries.
Journal Article
A systematic review of advances in intestinal microflora of fish
Intestinal flora is closely related to the health of organisms and the occurrence and development of diseases. The study of intestinal flora will provide a reference for the research and treatment of disease pathogenesis. Upon hatching, fish begin to acquire a microbial community in the intestine. In response to the environment and the host itself, the fish gut eventually develops a unique set of microflora, with some microorganisms being common to different fish. The existence of intestinal microorganisms creates an excellent microecological environment for the host, while the fish symbiotically provides conditions for the growth and reproduction of intestinal microflora. The intestinal flora and the host are interdependent and mutually restrictive. This review mainly describes the formation of fish intestinal flora, the function of normal intestinal flora, factors affecting intestinal flora, and a series of fish models.
Journal Article
Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer
Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on
CCL2
gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.
Journal Article
Room-temperature photosynthesis of propane from CO2 with Cu single atoms on vacancy-rich TiO2
Photochemical conversion of CO
2
into high-value C
2+
products is difficult to achieve due to the energetic and mechanistic challenges in forming multiple C-C bonds. Herein, an efficient photocatalyst for the conversion of CO
2
into C
3
H
8
is prepared by implanting Cu single atoms on Ti
0.91
O
2
atomically-thin single layers. Cu single atoms promote the formation of neighbouring oxygen vacancies (V
O
s) in Ti
0.91
O
2
matrix. These oxygen vacancies modulate the electronic coupling interaction between Cu atoms and adjacent Ti atoms to form a unique Cu-Ti-V
O
unit in Ti
0.91
O
2
matrix. A high electron-based selectivity of 64.8% for C
3
H
8
(product-based selectivity of 32.4%), and 86.2% for total C
2+
hydrocarbons (product-based selectivity of 50.2%) are achieved. Theoretical calculations suggest that Cu-Ti-V
O
unit may stabilize the key *CHOCO and *CH
2
OCOCO intermediates and reduce their energy levels, tuning both C
1
-C
1
and C
1
-C
2
couplings into thermodynamically-favourable exothermal processes. Tandem catalysis mechanism and potential reaction pathway are tentatively proposed for C
3
H
8
formation, involving an overall (
20
e
−
–
20
H
+
) reduction and coupling of three CO
2
molecules at room temperature.
A photocatalyst for CO2 reduction to C3H8 is prepared by implanting Cu single atoms on vacancy rich TiO2 single layers. Key reaction intermediates, *CHOCO and *CH2OCOCO, are stabilized on the catalyst which promotes C-C bond formation.
Journal Article
Improving immersive experiences in virtual natural setting for public health and environmental design: A systematic review and meta-analysis of randomized controlled trials
In recent years, virtual reality (VR) technology has emerged as a powerful tool in the field of therapeutic landscapes. For hospitalized patients or individuals with limited mobility, VR provides highly personalized therapy by simulating authentic natural environments within a safe, convenient, and engaging setting. This study investigated the effectiveness of immersing patients in virtual natural environments for health recovery and compared the varying impacts of different types of landscapes on patients’ recovery levels. The aim was to complement traditional medical approaches and enhance environmental design in the field of public health. Researchers systematically reviewed databases (January 2018 to August 2, 2023) to identify randomized controlled trials comparing the efficacy of virtual nature immersion with other treatments. The inclusion/exclusion criteria were established based on the population, intervention, comparison, outcomes, study design, and other aspects (expanded PICO) framework. The Cochrane tool was employed to assess the risk of bias. Meta-analysis was conducted by pooling the mean differences with a 95% confidence interval. Among 30 trials, a total of 2123 patients met the inclusion criteria, with 15 studies included in the meta-analysis. 30 trials met the criteria. Results show significant improvements in pain, anxiety, fear, and some physiological indicators with virtual nature-based treatments. On the other hand, natural scenes incorporating blue and green elements have been applied more extensively and have shown more significant effects. In comparison to conventional methods, this study strongly advocates that virtual reality environments are a crucial tool in bridging the gap between patients and nature, demonstrating their potential to reshape medical interventions and improve environmental design in the field of public health.
Journal Article
Yttrium-doped NiMo-MoO2 heterostructure electrocatalysts for hydrogen production from alkaline seawater
Active and stable electrocatalysts are essential for hydrogen production from alkaline water electrolysis. However, precisely controlling the interaction between electrocatalysts and reaction intermediates (H
2
O*, H*, and *OH) remains challenging. Here, we demonstrate an yttrium-doped NiMo-MoO
2
heterogenous electrocatalyst that efficiently promotes water dissociation and accelerates the intermediate adsorption/desorption dynamics in alkaline electrolytes. Introducing yttrium into the NiMo/MoO
2
heterostructure induces lattice expansion and optimizes the
d
-band center of NiMo alloy component, enhancing water dissociation and H* desorption. Yttrium doping also increases the concentration of oxygen vacancies in MoO
2−x
, which in turn accelerates the charge kinetics and the swift evacuation of *OH intermediates from the active sites. Consequently, the Y-NiMo/MoO
2−x
heterostructure exhibits notable performance by requiring only 189 and 220 mV overpotentials to achieve current density of 2.0 A cm
−2
in alkaline water and seawater, respectively. This work provides a strategy to modulate heterostructure catalysts for scalable, economically viable hydrogen production from low-quality waters.
Hydrogen production from alkaline seawater requires efficient catalysts, but controlling interaction with intermediates is challenging. Here, the authors report an yttrium-doped NiMo-MoO2 catalyst that optimizes water dissociation and enables efficient seawater splitting at high current densities.
Journal Article
Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine
Background
Cancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer.
Methods
The correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells
in vitro
and
in vivo
.
Results
LC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing
ATG5
,
ATG7
, and
BECN1
or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine
in vitro
and
in vivo
. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170–82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival.
Conclusions
Induction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.
Journal Article