Colon cancer stemness as a reversible epigenetic state:Implications for anticancer therapies

The recent discovery of cancer cell plasticity,i.e.their ability to reprogram into cancer stem cells(CSCs)either naturally or under chemotherapy and/or radiotherapy,has changed,once again,the way we consider cancer treatment.If cancer stemness is a reversible epigenetic state rather than a genetic identity,opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs.However,the systematic use of DNA methyltransferase and histone deacetylase inhibitors,alone or in combination,in advanced solid tumors including colorectal cancers,regardless of their molecular subtypes,does not seem to be the best strategy.In this review,we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells.We raise questions about the relevant use of currently available epigenetic inhibitors(epidrugs)while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms.These markers include the three cluster of differentiation CD133,CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and.Finally,we describe current treatment strategies using epidrugs,and we hypothesize that,using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression,we could identify better candidates for epienzyme targeting.

The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy

Histone modifications are key factors in chromatin packaging,and are responsible for gene regulation during cell fate determination and development.Abnormal alterations in histone modifications potentially affect the stability of the genome and disrupt gene expression patterns,leading to many diseases,including cancer.In recent years,mounting evidence has shown that various histone modifications altered by aberrantly expressed modifier enzymes contribute to tumor development and metastasis through the induction of epigenetic,transcriptional,and phenotypic changes.In this review,we will discuss the existing histone modifications,both well-studied and rare ones,and their roles in solid tumors and hematopoietic cancers,to identify the molecular pathways involved and investigate targeted therapeutic drugs to reorganize the chromatin and enhance cancer treatment efficiency.Finally,clinical inhibitors of histone modifications are summarized to better understand the developmental stage of cancer therapy in using these drugs to inhibit the histone modification enzymes.

The prevalence and distribution of aminoglycoside resistance genes

Choosing the appropriate antibiotics to treat bacterial infections has grown more challenging as a result of the emergence of antibiotic-resistant bacteria.Aminoglycosides,as broad-spectrum antibiotics,are increasingly being used clinically;however,for most effective employment of aminoglycosides,a comprehensive understanding of aminoglycoside resistance genes’prevalence and dissemination is required.Therefore,to better understand the global resistance status of aminoglycoside antibiotics and the prevalence of antibiotic-resistance genes(ARGs)in various bacterial species,this systematic review gathered relevant data from multiple studies.Two primary resistance mechanisms-aminoglycoside enzymatic modification and 16S rRNA methylation-were assessed,and the prevalence of the corresponding ARGs was described.The coexistence of aminoglycoside ARGs with other ARGs was also demonstrated,as was the relationship between aminoglycoside ARGs and resistant phenotypes.The lack of effective therapeutic agents to combat resistant pathogens presents a real threat to public health.The combination of aminoglycosides with other antibiotics may provide a novel treatment strategy.

Genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii from Beijing,China

The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 A.baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance(HLAR,MIC to gentamicin and amikacin>512 mg/mL)phenotype selection by broth microdilution method.The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes(aac(3)-Ⅰ,aac(3)-Ⅱc,aac(60)-Ⅰb,aac(60)-Ⅱ,aph(4)-Ⅰa,aph(30)-Ⅰ,aph(30)-Ⅱb,aph(30)-Ⅲa,aph(30)-Ⅵa,aph(2″)-Ⅰb,aph(2″)-Ⅰc,aph(2″)-Ⅰd,ant(2″)-Ⅰa,ant(3″)-Ⅰand ant(40)-Ⅰa)and the 16S rRNA methylase genes(armA,rmtB and rmtC).Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS.Totally 102(58.96%)HLAR isolates were selected.The HLAR rates for year 2006,2007,2008 and 2009 were 52.63%,65.22%,51.11%and 70.83%,respectively.Five modifying enzyme genes(aac(3)-Ⅰ,detection rate of 65.69%;aac(60)-Ⅰb,detection rate of 45.10%;aph(30)-Ⅰ,detection rate of 47.06%;aph(30)-Ⅱb,detection rate of 0.98%;ant(3″)-Ⅰ,detection rate of 95.10%)and one methylase gene(armA,detection rate of 98.04%)were detected in the 102 A.baumannii with aac(3)-Ⅰ+aac(60)-Ⅰ+þant(3″)-Ⅰ+armA(detection rate of 25.49%),aac(3)-Ⅰ+aph(30)-Ⅰ+ant(3″)-Ⅰ+armA(detection rate of 21.57%)and ant(3″)-Ⅰ+armA(detection rate of 12.75%)being the most prevalent gene profiles.The values of chi-square tests showed correlation of armA,ant(3″)-Ⅰ,aac(3)-Ⅰ,aph(30)-Ⅰand aac(60)-Ⅰb with HLAR.armA had significant correlation(contingency coefficient 0.685)and good contingency with HLAR(kappa 0.940).The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A.baumannii infections.As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides(gentamicin,amikacin,tobramycin,etc),the function of aminoglycoside modifying enzyme gene(s)in A.baumannii carrying armA deserves further investigation.