Rice cultivar Norin 8 and its mutant Norin 8m harbour bentazon resistance trait and bentazon susceptibility trait respectively. A total of 360 arbitrary 10-mer oligonucleotide primers were screened on the genomic DNA ...Rice cultivar Norin 8 and its mutant Norin 8m harbour bentazon resistance trait and bentazon susceptibility trait respectively. A total of 360 arbitrary 10-mer oligonucleotide primers were screened on the genomic DNA of Norin 8 and Norin 8m with RAPD technique. Among which, five primers produced seven polymorphic RAPD bands between Norin 8 and Norin 8m. Amplified RAPD polymorphic products were cloned and sequenced. The sequences were used to design primers for PCR. Five SCAR markers, SCAR/G18/883, SCAR/G18/890, SCAR/G18/919/948, SCAR/D10/1237 and SCAR/F03/1186, were developed from OPG18/943, OPG18/972, OPD10/1248 and OPF03/1198. F-2 progeny of 320 individuals was analyzed to map SCAR markers in relationship to ben or Ben genes. SCAR markers of SCAR/G18/883, SCAR/G18/890, SCAR/G18/919/948 were shown to cosegregate with ben or Ben genes, and SCAR/D10/1237 to be linked of Ben gene with a distance of (14.8 +/- 2.1) cM. The genetic linkage to ben gene and SCAR markers was identified by a pair of near isogenic lines H121 and Hben121. Southern blotting analysis and segregation ratio of F-2 progeny revealed that OPG18/943 and OPG18/972 were single-copy in genome, and locus of OPG18/943 and OPG18/972 were allelic and sequence tagged sites. It is the first report on molecular markers linked to ben or Ben genes. The markers are useful to marker-assisted selection for the breeding and tag ben gene with map-based cloning.展开更多
Laboratory experiments were conducted to determine the effects of total dissolved gas （TDG） supersaturation on acute lethality and avoidance responses in juvenile rock carp （Procypris rabaudi Tchang）. The juvenile...Laboratory experiments were conducted to determine the effects of total dissolved gas （TDG） supersaturation on acute lethality and avoidance responses in juvenile rock carp （Procypris rabaudi Tchang）. The juvenile rock carp were exposed to water with different levels of supersaturation （105%, 115%, 120%, 125%, 130%, 135%, 140%, and 145%） and depth of 0.20 m at 25℃ for 60 h. Median lethal time （LT50） was used to assess the lethal responses corresponding to different levels of gas supersaturation. The results show that half of the juvenile rock carp died at the 120%, 125%, 130%, 135%, 140%, and 145% levels of supersaturation, and the LT50 corresponding to different levels of supersaturation was 18.7, 15.4, 8.2, 6.6, 3.5, and 1.7 h. When the level of supersaturated water is below 115%, the mortality is negligible. Avoidance responses were observed 5 min after the fish were put into equilibrated water （99%, 0.08 m deep） and water with different supersaturated levels （105%, 115%, 125%, 135%, and 145%, 0.08 m deep） at 25 ℃. The fish exhibited strong avoidance responses in supersaturated water when the gas supersaturation was above 135%. However, they exhibited an obvious preference to supersaturated water when the gas supersaturation was below 115%. Thus, the juvenile rock carp can likely survive in water with a supersaturated level of 115%.展开更多
Objective:To investigate the antibacterial and cytotoxic activity of fourteen different edible vegetables methanolic extract from Bangladesh.Methods:The antibacterial activity was evaluated using disc diffusion assay ...Objective:To investigate the antibacterial and cytotoxic activity of fourteen different edible vegetables methanolic extract from Bangladesh.Methods:The antibacterial activity was evaluated using disc diffusion assay method against 12 bacteria(both gram positive and gram negative).The plant extracts were also screened for cytotoxic activity using the brine shrimp lethality bioassay method and the lethal concentrations(LC_(50))were determined at confidence intervals by analyzing the data on a computer loaded with"Finney Programme??Results:All the vegetable extracts showed low to elevated levels of antibacterial activity against most of the tested strains(zone of inhibition=5-28 mm).The most active extract against all bacterial strains was from Xanthium indicum which showed remarkable antibacterial activity having the diameter of growth inhibition zone ranging from 12 to 28 mm followed by Alternanthera sessilis(zone of inhibition=6-21 mm).All extracts exhibited considerable general toxicity towards brine shrimps.The LC_(50)value of the tested extracts was within the range of 8.447 to 60.323μg/mL with respect to the positive control(vincristine sulphate)which was 0.91μg/mL.Among all studied extracts,Xanthium indicum displayed the highest cytotoxic effect with LC_(50)value of 8.447μg/mL.Conclusions:The results of the present investigation suggest that most of the studied plants are potentially good source of antibacterial and anticancer agents.展开更多
1,2,3,7,8-PeCDD was administrated to juvenile goldfish （Carassius auratus） by peritoneal injections to explore the acute lethality and endocrine effects of 1,2,3,7,8-PeCDD in vivo. The value of acute median lethal d...1,2,3,7,8-PeCDD was administrated to juvenile goldfish （Carassius auratus） by peritoneal injections to explore the acute lethality and endocrine effects of 1,2,3,7,8-PeCDD in vivo. The value of acute median lethal dosage （LD50） of 1,2,3,7,8-PeCDD was determined in acute lethality tests. The endocrine effect of 1,2,3,7,8-PeCDD, whose exposed concentrations were determined based on the LD50 （1.84 mg/kg）, was studied by measuring the plasma vitellogenin （Vtg） content in juvenile male goldfish with enzyme-linked immunosorbent assays （ELISA）. Due to its significant induction of the plasma Vtg after one week＇s exposure in vivo in the 1/2 LD50 and LD30 groups, 1,2,3,7,8-PeCDD might be one of the important contributors to the estrogenic effect of PCDDs in the environment. The values of 1/2 LD50 and LD30 were within the range of the effective dosages of 1,2,3,7,8-PeCDD, indicating that there was a certain relationship between the estrogenic effective dosages and the LD50.展开更多
Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particu...Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination （HR）, are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly （adenosine diphosphate （ADP）-ribose） polymerase （PARP） inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells.展开更多
In progenies resulting from crosses involving rice cultivar Norin 8m susceptible to bentazon as the donor of ben gene, SCARs tightly linked to ben were utilized for selection of ben. The homozygous and heterozygous ge...In progenies resulting from crosses involving rice cultivar Norin 8m susceptible to bentazon as the donor of ben gene, SCARs tightly linked to ben were utilized for selection of ben. The homozygous and heterozygous genotypes with ben could be identified with the SCARs. The molecular markers offer a powerful tool for indirect selection of ben and can accelerate the introgression of ben into current rice cultivars.展开更多
RNA interference （RNAi） is considered as a potential modality for clinical treatment and anti-virus animal breeding. Here, we investigate the feasibility of inhibiting classical swine fever virus （CSFV） replicatio...RNA interference （RNAi） is considered as a potential modality for clinical treatment and anti-virus animal breeding. Here, we investigate the feasibility of inhibiting classical swine fever virus （CSFV） replication by short hairpin RNA （shRNA） in vitro and in vivo. We generate four different shRNA-positive clonal cells and two types of shRNA-transgenic pigs. CSFV could be effectively inhibited in shRNA-positive clonal cells and tail tip fibroblasts of shRNA-transgenic pigs. Unexpectedly, an early lethality due to shRNA is observed in these shRNA-transgenic pigs. With further research on shRNA-positive clonal cells and transgenic pigs, we report a great induction of interferon （IFN）-responsive genes in shRNA-positive clonal cells, altered levels of endogenous microRNAs （miRNA）, and their processing enzymes in shRNA-positive cells. What is more, abnormal expressions of miRNAs and their processing enzymes are also observed in the livers of shRNA-transgenic pigs, indicating saturation of miRNNshRNA pathways induced by shRNA. In addition, we investigate the effects of shRNAs on the development of somatic cell nuclear transfer （SCNT） embryos. These results show that shRNA causes adverse effects in vitro and in vivo and shRNA- induced disruption of the endogenous miRNA pathway may lead to the early lethality of shRNA-transgenic pigs. We firstly report abnormalities of the miRNA pathway in shRNA-transgenic animals, which may explain the early lethality of shRNA-transgenic pigs and has important implications for shRNA-transgenic animal preparation.展开更多
<strong>Background:</strong><span style="font-family:""><span style="font-family:Verdana;"> The latest WHO report shows a decline in the performances achieved concernin...<strong>Background:</strong><span style="font-family:""><span style="font-family:Verdana;"> The latest WHO report shows a decline in the performances achieved concernin</span><span style="font-family:Verdana;">g the fight against malaria since 2017. This research work aimed to investigate the progression of frequency and lethality due to severe malaria from 2017 to 2020 in the pediatric unit of the Borgou University Teaching Hospital in Parakou (CHU</span></span><span style="font-family:Verdana;">D</span><span style="font-family:""><span style="font-family:Verdana;">-Parakou). </span><b><span style="font-family:Verdana;">Patients and Methods:</span></b><span style="font-family:Verdana;"> This research work is a descriptive and analytical case-control study focused on all the children aged 1 month and more, hospitalized in the pediatric unit of CHU</span></span><span style="font-family:Verdana;">D-</span><span style="font-family:""><span style="font-family:Verdana;">Parakou from January 1, 2017, to December 31, 2020. Recruitment criteria were the following: be admitted to hospital during the period specified above;have a usable medical record containing the diagnosis and type of discharge, and the findings of thick smear examination and/or of a rapid diagnostic test. Sampling was complete and takes into account all the medical records of children meeting the inclusion criteria. Epi Info 7.2.2 was the software used to perform data processing. </span><b><span style="font-family:Verdana;">Results: </span></b><span style="font-family:Verdana;">The frequencies of severe malaria in the unit were estimated at 19.89%, 22.65%, 29.65% and 27.51% respectively in 2017, </span></span><span style="font-family:Verdana;">2018, 2019 and 2020. Lethality rates varied from 7.76% to 8.68 from 2017 through 2020. The death risk associated with severe malaria was 3.08 times</span><span style="font-family:""><span style="font-family:Verdana;"> higher in children suffering from severe acute undernutrition. </span><b><span style="font-family:Verdana;">Conclusion: </span></b><span style="font-family:Verdana;">Despite all the efforts made by the health authorities and the technical and financial part</span><span style="font-family:Verdana;">ners, the frequency and lethality of severe malaria are increasing in the pediatric</span><span style="font-family:Verdana;"> unit of the B/A Regional University Teaching Hospital (CHUD-B/A).</span><span style="font-family:Verdana;"> It is therefore worth investigating the determinants of this situation.</span></span>展开更多
Total dissolved gas(TDG) supersaturation caused by dam sluicing can result in gas bubble trauma(GBT) in fish and threaten their survival.In the present study,Chinese suckers(Myxocyprinus asiaticus Bleeker) were expose...Total dissolved gas(TDG) supersaturation caused by dam sluicing can result in gas bubble trauma(GBT) in fish and threaten their survival.In the present study,Chinese suckers(Myxocyprinus asiaticus Bleeker) were exposed to TDG supersaturated water at levels ranging from 120% to 145% for 48 h.The median lethal concentration(LC 50) and the median lethal time(LT 50) were determined to evaluate acute lethal effects on Chinese suckers.The results showed that the LC 50 values of 4,6,8,and 10 h were 142%,137%,135%,and 130%,respectively.The LT 50 values were 3.2,4.7,7.8,9.2,and 43.4 h,respectively,when TDG supersaturated levels were 145%,140%,135%,130%,and 125%.Furthermore,the biological responses in Chinese suckers were studied by assaying the catalase(CAT) activities in gills and muscles at the supersaturation level of 140% within LT 50.The CAT activities in the gills and muscle tissues exhibited a regularity of a decrease after an increase.CAT activities in the muscles were increased significantly at 3/5LT 50(P<0.05) and then came back to the normal level.However,there were no significant differences between the treatment group(TDG level of 140%) and the control group(TDG level of 100%) on CAT activities in the gills before 3/5LT 50(P>0.05),but the activities were significantly lower than the normal level at 4/5LT 50 and LT 50(P<0.05).展开更多
Mutant proteins containing an expanded polyglutamine tract induce cell death and cause neurodegenerative diseases. These toxic proteins interfere with a variety of physiological pathways, but the key interactions betw...Mutant proteins containing an expanded polyglutamine tract induce cell death and cause neurodegenerative diseases. These toxic proteins interfere with a variety of physiological pathways, but the key interactions between the toxins and cellular factors remain unclear. To model the diseases in Drosophila, the GMR-Gal4/UAS gene expression system has been used extensively, which operates in the eyes. By using the system, genome-wide studies have resulted in the isolation of functionally diverse groups of Drosophila genes that interact with the disease proteins. We previously reported that coexpressing the Drosophila Dikar gene and an expanded polyglutamine tract by GMR-Gal4/UAS induced a synthetic lethality. We carried out follow-up experiments to isolate additional synthetic lethal alleles. Our data provide evidence that synthetic lethality associated with expressing an expanded polyglutamine tract is more common than thought to be and could have escaped the conventional genetic screens. Our results also suggest that 1) the gene expression system is leaky, allowing expression outside of the primary target eye cell types;2) expressing an expanded polyglutamine tract is extremely toxic to cells;and 3) combining the leaky expression and the toxicity results in a lethal-prone condition. Thus, genetic modifications to the disease proteins’ acute toxicity could frequently lead to synthetic lethality. However, synthetic lethal alleles are excluded from most conventional screens, necessitating alternative approaches such as a two-step method used in this study to isolate the modifiers. Since synthetic lethality reflects essential genetic buffering networks, studying these alleles may hold the keys to identify the critical interactions in the disease development between the toxic proteins and the physiological pathways.展开更多
Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used...Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used in an eye-based model to study human neurodegenerative diseases. This system has facilitated the isolation and characterization of abundant Drosophilagenes that interact with the expanded polyglutamine proteins. We used the GMR-Gal4/UAS system to express three proteins containing an expanded polyglutamine tract, or an expanded polyglutamine tract alone. Doubling the dose of these proteins resulted in pupal lethality, indicating that these toxic proteins induced a sensitized condition that is prone to synthetic lethality. By using the GMR-Gal4/UAS system, we showed that a Drosophilagene interacts with three expanded polyglutamine proteins to induce a synthetic lethal phenotype. We further demonstrated that the synthetic lethality was mediated through the toxic expanded polyglutamine tract. Our study raises a possibility that conventional genetic screens may not recover synthetic lethal alleles, which are presumably stronger interacting alleles than the currently known modifiers of an expanded polyglutamine tract, due to synthetic lethality.展开更多
Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan...Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide(CX-5461),the first Pol Ⅰ selective inhibitor with the multitargeting property and synthetical lethality in homologous recombination(HR)deficient cancers,to modify cisplatin,affording two monofunctional platinum Pol Ⅰ selective inhibitors[PtCl(NH_(3))_(2)(LH1)]NO_(3)(P1-Q1)and[PtCl(NH_(3))_(2)(LH_(2))]NO_(3)(P1-Q2)[LH1=N-(3-(N-methylacetimidamido)propyl)-2-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide;LH2=2-(4-methyl-1,4-diazepan-1-yl)-N-(3-(N-methylacetimidamido)propyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide].Our data showed that P1-Q1 and P1-Q2 could preferentially target the Pol Ⅰ transcription machinery,overcome platinum drug resistance,and display more potent antiproliferative activity in BRCA1-deficient A549 cells.Mechanism studies demonstrated that P1-Q1 and P1-Q2 could effectively accumulate in cancer cells and nucleoli,selectively inhibit Pol Ⅰ transcription,stimulate nucleolar stress and p53 stabilization,increase intracellular ROS levels,disrupt the mitochondrial membrane potential,and inhibit migration and metastasis,which further lead to cell cycle arrest and apoptosis.Particularly,P1-Q1 could facilitate the formation and stabilization of R-loops,induce severe DNA damage,and trigger ATR/CHK1 and ATM/CHK2 kinase signaling cascades in BRCA1-deficient A549 cells,suggesting that defects in the HR pathway may exacerbate P1-Q1 induced DNA damage and cause synthetic lethality and apoptosis.Our data demonstrated that P1-Q1 and P1-Q2 are distinct from the clinical platinum anticancer drugs in their mechanism of action,and taking advantage of the selective Pol Ⅰ inhibition,multitargeting property,and synthetic lethality of CX-5461 in HR-deficient cancers to modify platinum-based agents might be a brand-new approach for cancer therapy.展开更多
To the Editor:Synthetic lethality(SL)occurs when the simultaneous perturbation of two genes results in cellular death,whereas the perturbation of an individual gene alone is compatible.Colorectal cancer(CRC)is one of ...To the Editor:Synthetic lethality(SL)occurs when the simultaneous perturbation of two genes results in cellular death,whereas the perturbation of an individual gene alone is compatible.Colorectal cancer(CRC)is one of the leading malignancy,ranking third in global incidence and second in mortality.It is widely believed that most CRCs arise from the accumulations of genetic and epigenetic changes.This tumorigenic process,from normal to dysplastic epithelium to carcinoma,along with multiple genetic alterations,is referred to as the adenoma–carcinoma sequence.展开更多
The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph...The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph neural network-based deep learning methods have been proposed for SL prediction,which reduce the SL search space of wet-lab based methods.However,these methods ignore that most SL interactions depend strongly on genetic context,which limits the application of the predicted results.In this study,we proposed a graph recurrent network-based model for specific context-dependent SL prediction(SLGRN).In particular,we introduced a Graph Recurrent Network-based encoder to acquire a context-specific,low-dimensional feature representation for each node,facilitating the prediction of novel SL.SLGRN leveraged gate recurrent unit(GRU)and it incorporated a context-dependent-level state to effectively integrate information from all nodes.As a result,SLGRN outperforms the state-of-the-arts models for SL prediction.We subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival analysis.Through in vitro experiments and retrospective clinical analysis,we emphasize the potential clinical significance of this context-specific SL prediction model.展开更多
The genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notab...The genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notably the Sterile Insect Technique （SIT）, for both plant and animal insect pests. Tetracycline-suppressible （Tet-off） conditional lethal systems may function together so that transgenic strains will be viable and fertile on a tetracycline-containing diet, but female-lethal and male sterile in tetracycline-free condi- tions. This would allow their most efficacious use in a unified system for sterile male-only production for SIT. A critical consideration for the field release of such transgenic insect strains, however, is a determination of the frequency and genetic basis of lethality revertant survival. This will provide knowledge essential to evaluating the genetic stability of the lethality system, its environmental safety, and provide the basis for modifications ensur- ing optimal efficacy. For Tet-off lethal survival determinations, development of large-scale screening protocols should also allow the testing of these modifications, and test the ability of other conditional lethal systems to fully suppress propagation of rare Tet-off survivors. If a dominant temperature sensitive （DTS） pupal lethality system proves efficient for sec- ondary lethality in Drosophila, it may provide the safeguard needed to support the release of sexing/sterility strains, and potentially, the release of unisex lethality strains as a form of genetic male sterility. Should the DTS Prosβ21 mutation prove effective for redundant lethality, its high level of structural and functional conservation should allow host-specific cognates to be created for a wide range of insect species.展开更多
OsMAPK6 plays a critical role in regulating rice growth,development,and stress responses.However,the embryonic lethality associated with loss-of-function mutations prevents the generation of homozygous mutant seeds,si...OsMAPK6 plays a critical role in regulating rice growth,development,and stress responses.However,the embryonic lethality associated with loss-of-function mutations prevents the generation of homozygous mutant seeds,significantly hindering functional studies of this gene.Although the weak mutant dsg1 has offered valuable insights into OsMAPK6 function,its extremely low seed-setting rate limits its use for detailed genetic analysis.Here,we employed prime editing to perform precise multi-site modifications at the C-terminus of OsMAPK6,generating a series of osmapk6 mutants with truncated proteins of varying lengths.Among these,the osmapk6(379)and osmapk6(383)mutants exhibited phenotypic defects similar to dsg1,while osmapk6(386)showed a significantly improved seed-setting rate despite persistent developmental defects.Through phenotypic characterization and protein functional analysis,we further clarified how different C-terminal deletion lengths affect plant growth,development,stress responses,and OsMAPK6 protein function.In summary,this study elucidates the importance of the OsMAPK6 C-terminus in rice biology and provides a fertile weak mutant with enhanced seed production,offering a valuable genetic resource for future research on OsMAPK6.展开更多
ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphther...ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphtheria toxin-like ADP-ribosyltransferase(ARTD)family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation(MARylation)or poly(ADP-ribosyl)ation(PARylation).These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management.This review explores the roles of these enzymes and current knowledge on specific inhibitors.A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer.Among ARTC family,ART1 and ART3 modulate the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway,influencing angiogenesis,tumor growth,and immune evasion via cluster of differentiation 8+(CD8+)T-cell apoptosis.Within the ARTD family,poly(ADP-ribose)polymerase(PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency,such as breast cancer susceptibility genes 1/2(BRCA1/2)-mutated breast cancer.Their inhibition exemplifies synthetic lethality and has shown clinical efficacy.Four PARP inhibitors,olaparib,niraparib,rucaparib,are approved by the Food and Drug Administration(FDA)approved.Despite these advances,selective inhibitors for ARTs remain underexplored.Ongoing research focuses on overcoming PARP inhibitor resistance,improving biomarker-driven patient selection,and expanding therapeutic strategies that target ART-related pathways.展开更多
Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also be...Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.展开更多
Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits furt...Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.展开更多
文摘Rice cultivar Norin 8 and its mutant Norin 8m harbour bentazon resistance trait and bentazon susceptibility trait respectively. A total of 360 arbitrary 10-mer oligonucleotide primers were screened on the genomic DNA of Norin 8 and Norin 8m with RAPD technique. Among which, five primers produced seven polymorphic RAPD bands between Norin 8 and Norin 8m. Amplified RAPD polymorphic products were cloned and sequenced. The sequences were used to design primers for PCR. Five SCAR markers, SCAR/G18/883, SCAR/G18/890, SCAR/G18/919/948, SCAR/D10/1237 and SCAR/F03/1186, were developed from OPG18/943, OPG18/972, OPD10/1248 and OPF03/1198. F-2 progeny of 320 individuals was analyzed to map SCAR markers in relationship to ben or Ben genes. SCAR markers of SCAR/G18/883, SCAR/G18/890, SCAR/G18/919/948 were shown to cosegregate with ben or Ben genes, and SCAR/D10/1237 to be linked of Ben gene with a distance of (14.8 +/- 2.1) cM. The genetic linkage to ben gene and SCAR markers was identified by a pair of near isogenic lines H121 and Hben121. Southern blotting analysis and segregation ratio of F-2 progeny revealed that OPG18/943 and OPG18/972 were single-copy in genome, and locus of OPG18/943 and OPG18/972 were allelic and sequence tagged sites. It is the first report on molecular markers linked to ben or Ben genes. The markers are useful to marker-assisted selection for the breeding and tag ben gene with map-based cloning.
基金Project (No. 50979063) supported by the National Natural Science Foundation of China
文摘Laboratory experiments were conducted to determine the effects of total dissolved gas （TDG） supersaturation on acute lethality and avoidance responses in juvenile rock carp （Procypris rabaudi Tchang）. The juvenile rock carp were exposed to water with different levels of supersaturation （105%, 115%, 120%, 125%, 130%, 135%, 140%, and 145%） and depth of 0.20 m at 25℃ for 60 h. Median lethal time （LT50） was used to assess the lethal responses corresponding to different levels of gas supersaturation. The results show that half of the juvenile rock carp died at the 120%, 125%, 130%, 135%, 140%, and 145% levels of supersaturation, and the LT50 corresponding to different levels of supersaturation was 18.7, 15.4, 8.2, 6.6, 3.5, and 1.7 h. When the level of supersaturated water is below 115%, the mortality is negligible. Avoidance responses were observed 5 min after the fish were put into equilibrated water （99%, 0.08 m deep） and water with different supersaturated levels （105%, 115%, 125%, 135%, and 145%, 0.08 m deep） at 25 ℃. The fish exhibited strong avoidance responses in supersaturated water when the gas supersaturation was above 135%. However, they exhibited an obvious preference to supersaturated water when the gas supersaturation was below 115%. Thus, the juvenile rock carp can likely survive in water with a supersaturated level of 115%.
文摘Objective:To investigate the antibacterial and cytotoxic activity of fourteen different edible vegetables methanolic extract from Bangladesh.Methods:The antibacterial activity was evaluated using disc diffusion assay method against 12 bacteria(both gram positive and gram negative).The plant extracts were also screened for cytotoxic activity using the brine shrimp lethality bioassay method and the lethal concentrations(LC_(50))were determined at confidence intervals by analyzing the data on a computer loaded with"Finney Programme??Results:All the vegetable extracts showed low to elevated levels of antibacterial activity against most of the tested strains(zone of inhibition=5-28 mm).The most active extract against all bacterial strains was from Xanthium indicum which showed remarkable antibacterial activity having the diameter of growth inhibition zone ranging from 12 to 28 mm followed by Alternanthera sessilis(zone of inhibition=6-21 mm).All extracts exhibited considerable general toxicity towards brine shrimps.The LC_(50)value of the tested extracts was within the range of 8.447 to 60.323μg/mL with respect to the positive control(vincristine sulphate)which was 0.91μg/mL.Among all studied extracts,Xanthium indicum displayed the highest cytotoxic effect with LC_(50)value of 8.447μg/mL.Conclusions:The results of the present investigation suggest that most of the studied plants are potentially good source of antibacterial and anticancer agents.
基金This work was supported by the National Natural Science Foundation of China （No. 40332023, 20621703）.
文摘1,2,3,7,8-PeCDD was administrated to juvenile goldfish （Carassius auratus） by peritoneal injections to explore the acute lethality and endocrine effects of 1,2,3,7,8-PeCDD in vivo. The value of acute median lethal dosage （LD50） of 1,2,3,7,8-PeCDD was determined in acute lethality tests. The endocrine effect of 1,2,3,7,8-PeCDD, whose exposed concentrations were determined based on the LD50 （1.84 mg/kg）, was studied by measuring the plasma vitellogenin （Vtg） content in juvenile male goldfish with enzyme-linked immunosorbent assays （ELISA）. Due to its significant induction of the plasma Vtg after one week＇s exposure in vivo in the 1/2 LD50 and LD30 groups, 1,2,3,7,8-PeCDD might be one of the important contributors to the estrogenic effect of PCDDs in the environment. The values of 1/2 LD50 and LD30 were within the range of the effective dosages of 1,2,3,7,8-PeCDD, indicating that there was a certain relationship between the estrogenic effective dosages and the LD50.
基金US Public Health Service Grants (Grant No. CA107640, to SNP)"Independent Innovation Foundation of Shandong University IIFSDU" (Grant No. 2010 TB017, to ZF)the National Natural Science Foundation of China (Grant No.81172527, to ZF and SNP) for financial support
文摘Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination （HR）, are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly （adenosine diphosphate （ADP）-ribose） polymerase （PARP） inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells.
基金This work was supported by grants from Anhui Province Natura1 Science Foundation(0004111O).
文摘In progenies resulting from crosses involving rice cultivar Norin 8m susceptible to bentazon as the donor of ben gene, SCARs tightly linked to ben were utilized for selection of ben. The homozygous and heterozygous genotypes with ben could be identified with the SCARs. The molecular markers offer a powerful tool for indirect selection of ben and can accelerate the introgression of ben into current rice cultivars.
基金Project supported by the Major Projects of New Varieties of Genetically Modified Organisms (No.2011ZX08006-001)the Program for Changjiang Scholars and Innovative Research Team in the University (No.IRT1248),China
文摘RNA interference （RNAi） is considered as a potential modality for clinical treatment and anti-virus animal breeding. Here, we investigate the feasibility of inhibiting classical swine fever virus （CSFV） replication by short hairpin RNA （shRNA） in vitro and in vivo. We generate four different shRNA-positive clonal cells and two types of shRNA-transgenic pigs. CSFV could be effectively inhibited in shRNA-positive clonal cells and tail tip fibroblasts of shRNA-transgenic pigs. Unexpectedly, an early lethality due to shRNA is observed in these shRNA-transgenic pigs. With further research on shRNA-positive clonal cells and transgenic pigs, we report a great induction of interferon （IFN）-responsive genes in shRNA-positive clonal cells, altered levels of endogenous microRNAs （miRNA）, and their processing enzymes in shRNA-positive cells. What is more, abnormal expressions of miRNAs and their processing enzymes are also observed in the livers of shRNA-transgenic pigs, indicating saturation of miRNNshRNA pathways induced by shRNA. In addition, we investigate the effects of shRNAs on the development of somatic cell nuclear transfer （SCNT） embryos. These results show that shRNA causes adverse effects in vitro and in vivo and shRNA- induced disruption of the endogenous miRNA pathway may lead to the early lethality of shRNA-transgenic pigs. We firstly report abnormalities of the miRNA pathway in shRNA-transgenic animals, which may explain the early lethality of shRNA-transgenic pigs and has important implications for shRNA-transgenic animal preparation.
文摘<strong>Background:</strong><span style="font-family:""><span style="font-family:Verdana;"> The latest WHO report shows a decline in the performances achieved concernin</span><span style="font-family:Verdana;">g the fight against malaria since 2017. This research work aimed to investigate the progression of frequency and lethality due to severe malaria from 2017 to 2020 in the pediatric unit of the Borgou University Teaching Hospital in Parakou (CHU</span></span><span style="font-family:Verdana;">D</span><span style="font-family:""><span style="font-family:Verdana;">-Parakou). </span><b><span style="font-family:Verdana;">Patients and Methods:</span></b><span style="font-family:Verdana;"> This research work is a descriptive and analytical case-control study focused on all the children aged 1 month and more, hospitalized in the pediatric unit of CHU</span></span><span style="font-family:Verdana;">D-</span><span style="font-family:""><span style="font-family:Verdana;">Parakou from January 1, 2017, to December 31, 2020. Recruitment criteria were the following: be admitted to hospital during the period specified above;have a usable medical record containing the diagnosis and type of discharge, and the findings of thick smear examination and/or of a rapid diagnostic test. Sampling was complete and takes into account all the medical records of children meeting the inclusion criteria. Epi Info 7.2.2 was the software used to perform data processing. </span><b><span style="font-family:Verdana;">Results: </span></b><span style="font-family:Verdana;">The frequencies of severe malaria in the unit were estimated at 19.89%, 22.65%, 29.65% and 27.51% respectively in 2017, </span></span><span style="font-family:Verdana;">2018, 2019 and 2020. Lethality rates varied from 7.76% to 8.68 from 2017 through 2020. The death risk associated with severe malaria was 3.08 times</span><span style="font-family:""><span style="font-family:Verdana;"> higher in children suffering from severe acute undernutrition. </span><b><span style="font-family:Verdana;">Conclusion: </span></b><span style="font-family:Verdana;">Despite all the efforts made by the health authorities and the technical and financial part</span><span style="font-family:Verdana;">ners, the frequency and lethality of severe malaria are increasing in the pediatric</span><span style="font-family:Verdana;"> unit of the B/A Regional University Teaching Hospital (CHUD-B/A).</span><span style="font-family:Verdana;"> It is therefore worth investigating the determinants of this situation.</span></span>
基金Project supported by the National Natural Science Foundation ofChina (No. 50979063)the Scientific Research Foundation for Young Teachers of Xihua University (No. Z1120412),China
文摘Total dissolved gas(TDG) supersaturation caused by dam sluicing can result in gas bubble trauma(GBT) in fish and threaten their survival.In the present study,Chinese suckers(Myxocyprinus asiaticus Bleeker) were exposed to TDG supersaturated water at levels ranging from 120% to 145% for 48 h.The median lethal concentration(LC 50) and the median lethal time(LT 50) were determined to evaluate acute lethal effects on Chinese suckers.The results showed that the LC 50 values of 4,6,8,and 10 h were 142%,137%,135%,and 130%,respectively.The LT 50 values were 3.2,4.7,7.8,9.2,and 43.4 h,respectively,when TDG supersaturated levels were 145%,140%,135%,130%,and 125%.Furthermore,the biological responses in Chinese suckers were studied by assaying the catalase(CAT) activities in gills and muscles at the supersaturation level of 140% within LT 50.The CAT activities in the gills and muscle tissues exhibited a regularity of a decrease after an increase.CAT activities in the muscles were increased significantly at 3/5LT 50(P<0.05) and then came back to the normal level.However,there were no significant differences between the treatment group(TDG level of 140%) and the control group(TDG level of 100%) on CAT activities in the gills before 3/5LT 50(P>0.05),but the activities were significantly lower than the normal level at 4/5LT 50 and LT 50(P<0.05).
文摘Mutant proteins containing an expanded polyglutamine tract induce cell death and cause neurodegenerative diseases. These toxic proteins interfere with a variety of physiological pathways, but the key interactions between the toxins and cellular factors remain unclear. To model the diseases in Drosophila, the GMR-Gal4/UAS gene expression system has been used extensively, which operates in the eyes. By using the system, genome-wide studies have resulted in the isolation of functionally diverse groups of Drosophila genes that interact with the disease proteins. We previously reported that coexpressing the Drosophila Dikar gene and an expanded polyglutamine tract by GMR-Gal4/UAS induced a synthetic lethality. We carried out follow-up experiments to isolate additional synthetic lethal alleles. Our data provide evidence that synthetic lethality associated with expressing an expanded polyglutamine tract is more common than thought to be and could have escaped the conventional genetic screens. Our results also suggest that 1) the gene expression system is leaky, allowing expression outside of the primary target eye cell types;2) expressing an expanded polyglutamine tract is extremely toxic to cells;and 3) combining the leaky expression and the toxicity results in a lethal-prone condition. Thus, genetic modifications to the disease proteins’ acute toxicity could frequently lead to synthetic lethality. However, synthetic lethal alleles are excluded from most conventional screens, necessitating alternative approaches such as a two-step method used in this study to isolate the modifiers. Since synthetic lethality reflects essential genetic buffering networks, studying these alleles may hold the keys to identify the critical interactions in the disease development between the toxic proteins and the physiological pathways.
文摘Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used in an eye-based model to study human neurodegenerative diseases. This system has facilitated the isolation and characterization of abundant Drosophilagenes that interact with the expanded polyglutamine proteins. We used the GMR-Gal4/UAS system to express three proteins containing an expanded polyglutamine tract, or an expanded polyglutamine tract alone. Doubling the dose of these proteins resulted in pupal lethality, indicating that these toxic proteins induced a sensitized condition that is prone to synthetic lethality. By using the GMR-Gal4/UAS system, we showed that a Drosophilagene interacts with three expanded polyglutamine proteins to induce a synthetic lethal phenotype. We further demonstrated that the synthetic lethality was mediated through the toxic expanded polyglutamine tract. Our study raises a possibility that conventional genetic screens may not recover synthetic lethal alleles, which are presumably stronger interacting alleles than the currently known modifiers of an expanded polyglutamine tract, due to synthetic lethality.
基金supported by the National Natural Science Foundation of China(No.21977080 and 21401141)the Tianjin Municipal Education Commission Science Foundation(No.2021ZD039).
文摘Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase Ⅰ transcription and upregulation of ribosome biogenesis.Herein,we employed 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide(CX-5461),the first Pol Ⅰ selective inhibitor with the multitargeting property and synthetical lethality in homologous recombination(HR)deficient cancers,to modify cisplatin,affording two monofunctional platinum Pol Ⅰ selective inhibitors[PtCl(NH_(3))_(2)(LH1)]NO_(3)(P1-Q1)and[PtCl(NH_(3))_(2)(LH_(2))]NO_(3)(P1-Q2)[LH1=N-(3-(N-methylacetimidamido)propyl)-2-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide;LH2=2-(4-methyl-1,4-diazepan-1-yl)-N-(3-(N-methylacetimidamido)propyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide].Our data showed that P1-Q1 and P1-Q2 could preferentially target the Pol Ⅰ transcription machinery,overcome platinum drug resistance,and display more potent antiproliferative activity in BRCA1-deficient A549 cells.Mechanism studies demonstrated that P1-Q1 and P1-Q2 could effectively accumulate in cancer cells and nucleoli,selectively inhibit Pol Ⅰ transcription,stimulate nucleolar stress and p53 stabilization,increase intracellular ROS levels,disrupt the mitochondrial membrane potential,and inhibit migration and metastasis,which further lead to cell cycle arrest and apoptosis.Particularly,P1-Q1 could facilitate the formation and stabilization of R-loops,induce severe DNA damage,and trigger ATR/CHK1 and ATM/CHK2 kinase signaling cascades in BRCA1-deficient A549 cells,suggesting that defects in the HR pathway may exacerbate P1-Q1 induced DNA damage and cause synthetic lethality and apoptosis.Our data demonstrated that P1-Q1 and P1-Q2 are distinct from the clinical platinum anticancer drugs in their mechanism of action,and taking advantage of the selective Pol Ⅰ inhibition,multitargeting property,and synthetic lethality of CX-5461 in HR-deficient cancers to modify platinum-based agents might be a brand-new approach for cancer therapy.
基金The study was supported by grants from the Project of Science and Technology Department of Sichuan Province(No.2023NSFSC1928)the Project of State Administration of Traditional Chinese Medicine of China(No.ZYYCXTD-D-202209)the Fundamental Research Funds for the Central Universities,and the Project of Sichuan Provincial Administration of Traditional Chinese Medicine(No.2022C001).
文摘To the Editor:Synthetic lethality(SL)occurs when the simultaneous perturbation of two genes results in cellular death,whereas the perturbation of an individual gene alone is compatible.Colorectal cancer(CRC)is one of the leading malignancy,ranking third in global incidence and second in mortality.It is widely believed that most CRCs arise from the accumulations of genetic and epigenetic changes.This tumorigenic process,from normal to dysplastic epithelium to carcinoma,along with multiple genetic alterations,is referred to as the adenoma–carcinoma sequence.
基金supported by the National Key Research and Development Program of China(2023YFC2604400)the National Natural Science Foundation of China(62103436)。
文摘The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph neural network-based deep learning methods have been proposed for SL prediction,which reduce the SL search space of wet-lab based methods.However,these methods ignore that most SL interactions depend strongly on genetic context,which limits the application of the predicted results.In this study,we proposed a graph recurrent network-based model for specific context-dependent SL prediction(SLGRN).In particular,we introduced a Graph Recurrent Network-based encoder to acquire a context-specific,low-dimensional feature representation for each node,facilitating the prediction of novel SL.SLGRN leveraged gate recurrent unit(GRU)and it incorporated a context-dependent-level state to effectively integrate information from all nodes.As a result,SLGRN outperforms the state-of-the-arts models for SL prediction.We subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival analysis.Through in vitro experiments and retrospective clinical analysis,we emphasize the potential clinical significance of this context-specific SL prediction model.
文摘The genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notably the Sterile Insect Technique （SIT）, for both plant and animal insect pests. Tetracycline-suppressible （Tet-off） conditional lethal systems may function together so that transgenic strains will be viable and fertile on a tetracycline-containing diet, but female-lethal and male sterile in tetracycline-free condi- tions. This would allow their most efficacious use in a unified system for sterile male-only production for SIT. A critical consideration for the field release of such transgenic insect strains, however, is a determination of the frequency and genetic basis of lethality revertant survival. This will provide knowledge essential to evaluating the genetic stability of the lethality system, its environmental safety, and provide the basis for modifications ensur- ing optimal efficacy. For Tet-off lethal survival determinations, development of large-scale screening protocols should also allow the testing of these modifications, and test the ability of other conditional lethal systems to fully suppress propagation of rare Tet-off survivors. If a dominant temperature sensitive （DTS） pupal lethality system proves efficient for sec- ondary lethality in Drosophila, it may provide the safeguard needed to support the release of sexing/sterility strains, and potentially, the release of unisex lethality strains as a form of genetic male sterility. Should the DTS Prosβ21 mutation prove effective for redundant lethality, its high level of structural and functional conservation should allow host-specific cognates to be created for a wide range of insect species.
基金supported by the National Natural Science Foundation of China(Grant Nos.32441024,32572315,and U25A20674)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.2021229)+1 种基金the Heilongjiang Key Research and Development Program,China(Grant No.2025ZX04B02)the Young Scientist Group Project of Northeast Institute of Geography and Agroecology,Chinese Academy of Sciences(Grant No.2023QNXZ02).
文摘OsMAPK6 plays a critical role in regulating rice growth,development,and stress responses.However,the embryonic lethality associated with loss-of-function mutations prevents the generation of homozygous mutant seeds,significantly hindering functional studies of this gene.Although the weak mutant dsg1 has offered valuable insights into OsMAPK6 function,its extremely low seed-setting rate limits its use for detailed genetic analysis.Here,we employed prime editing to perform precise multi-site modifications at the C-terminus of OsMAPK6,generating a series of osmapk6 mutants with truncated proteins of varying lengths.Among these,the osmapk6(379)and osmapk6(383)mutants exhibited phenotypic defects similar to dsg1,while osmapk6(386)showed a significantly improved seed-setting rate despite persistent developmental defects.Through phenotypic characterization and protein functional analysis,we further clarified how different C-terminal deletion lengths affect plant growth,development,stress responses,and OsMAPK6 protein function.In summary,this study elucidates the importance of the OsMAPK6 C-terminus in rice biology and provides a fertile weak mutant with enhanced seed production,offering a valuable genetic resource for future research on OsMAPK6.
文摘ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphtheria toxin-like ADP-ribosyltransferase(ARTD)family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation(MARylation)or poly(ADP-ribosyl)ation(PARylation).These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management.This review explores the roles of these enzymes and current knowledge on specific inhibitors.A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer.Among ARTC family,ART1 and ART3 modulate the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway,influencing angiogenesis,tumor growth,and immune evasion via cluster of differentiation 8+(CD8+)T-cell apoptosis.Within the ARTD family,poly(ADP-ribose)polymerase(PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency,such as breast cancer susceptibility genes 1/2(BRCA1/2)-mutated breast cancer.Their inhibition exemplifies synthetic lethality and has shown clinical efficacy.Four PARP inhibitors,olaparib,niraparib,rucaparib,are approved by the Food and Drug Administration(FDA)approved.Despite these advances,selective inhibitors for ARTs remain underexplored.Ongoing research focuses on overcoming PARP inhibitor resistance,improving biomarker-driven patient selection,and expanding therapeutic strategies that target ART-related pathways.
基金supported by grants from the National Natural Science Foundation of China(No.81872885 to Ji Cao)the Zhejiang Provincial Natural Science Foundation of China(No.LY15H160009 to Wen Meng)
文摘Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.
基金supported by the National Natural Science Foundation of China(82202873,32200566)the Natural Science Foundation of Zhejiang Province(LQ22H160003)the Fundamental Research Funds for the Central Universities(2262022-00141)。
文摘Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.
