Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men an...Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women.Almost all cervical cancers are HPV-associated,however,an increasing number of head and neck cancers(HNCs),especially oropharyngeal cancer,can be linked to HPV infection.Moreover,anogenital cancers,including vaginal,vulvar,penial,and anal cancers,represent a subset of HPVrelated cancers.Whereas testing and prevention of cervical cancer have significantly improved over past decades,anogenital cancers remain more difficult to confirm.Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments.The HPV viral oncoproteins,E6 and E7,lead to degradation of,respectively,p53 and pRb resulting in entering the S phase without G1 arrest.These high-risk HPV viral oncogenes alter numerous cellular processes,including DNA repair,angiogenesis,and/or apoptosis,which eventually result in carcinogenesis.Additionally,a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks(DSB)repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers.In this review,we discuss the current knowledge regarding HPV-related cancers,current screening,and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.展开更多
The local recurrence rate of phyllodes tumors of the breast varies widely among different subtypes, and distant metastasis is associated with poor survival. This study aimed to identify factors that are predictive of ...The local recurrence rate of phyllodes tumors of the breast varies widely among different subtypes, and distant metastasis is associated with poor survival. This study aimed to identify factors that are predictive of local recurrence-free survival(LRFS), distant metastasis-free survival(DMFS), and overall survival(OS) in patients with phyllodes tumors of the breast. Clinical data of all patients with a phyllodes tumor of the breast(n = 192) treated at Sun Yat-sen University Cancer Center between March 1997 and December 2012 were reviewed. The Pearson χ2 test was used to investigate the relationship between clinical features of patients and histotypes of tumors. Univariate and multivariate Cox regression analyses were performed to identify factors that are predictive of LRFS, DMFS, and OS. In total, 31(16.1%) patients developed local recurrence, and 12(6.3%) developed distant metastasis. For the patients who developed local recurrence, the median age at the diagnosis of primary tumor was 33 years(range, 17-56 years), and the median size of primary tumor was 6.0 cm(range, 0.8-18 cm). For patients who developed distant metastasis, the median age at the diagnosis of primary tumor was 46 years(range, 24-68 years), and the median size of primary tumor was 5.0 cm(range, 0.8-18 cm). In univariate analysis, age, size, hemorrhage, and margin status were found to be predictive factors for LRFS(P = 0.009, 0.024, 0.004, and 0.001, respectively), whereas histotype, epithelial hyperplasia, margin status, and local recurrence were predictors of DMFS(P = 0.001, 0.007, 0.007, and < 0.001, respectively). In multivariate analysis, independent prognostic factors for LRFS included age [hazard ratio(HR) = 3.045, P = 0.005], tumor size(HR = 2.668, P = 0.013), histotype(HR = 1.715, P = 0.017), and margin status(HR = 4.530, P< 0.001). Histotype(DMFS: HR = 4.409, P = 0.002; OS: HR = 4.194, P = 0.003) and margin status(DMFS: HR = 2.581, P = 0.013; OS: HR = 2.507, P = 0.020) were independent predictors of both DMFS and OS. In this cohort, younger age, a larger tumor size, a higher tumor grade, and positive margins were associated with lower rates of LRFS. Histotype and margin status were found to be independent predictors of DMFS and OS.展开更多
AIM:To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal ad- enocarcinoma. METHODS:Methylation-specific polymerase chain reac- tion (MSPCR) was used to examine the promo...AIM:To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal ad- enocarcinoma. METHODS:Methylation-specific polymerase chain reac- tion (MSPCR) was used to examine the promoter meth- ylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal dis- ease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. Apaired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postopera- tive serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent sur- gical therapy. RESULTS:The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION:Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomark- er for gastric and colorectal cancer.展开更多
Molecule hydrogen(H_(2)) has been used to suppress tumor growth. To employ the H_(2) therapy, it is necessary to use a proper agent for continuous generation of H_(2). As a biodegradable metal, magnesium(Mg) generates...Molecule hydrogen(H_(2)) has been used to suppress tumor growth. To employ the H_(2) therapy, it is necessary to use a proper agent for continuous generation of H_(2). As a biodegradable metal, magnesium(Mg) generates H_(2) in an aqueous environment, but the H_(2) release rate is still too low. Here, we design a Mg-Al-Ca(AX) alloy that degrades very rapidly due to the presence of a secondary phase Al_(2)Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al_(2)Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al_(2)Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors.This work suggests that the H_(2) therapy using highly degradable Mg alloys may provide an effective cancer treatment.展开更多
Coronavirus disease 2019(COVID-19)is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)with typical respiratory symptoms.SARS-CoV-2 invades not only the respiratory syst...Coronavirus disease 2019(COVID-19)is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)with typical respiratory symptoms.SARS-CoV-2 invades not only the respiratory system,but also other organs expressing the cell surface receptor angiotensin converting enzyme 2.In particular,the digestive system is a susceptible target of SARS-CoV-2.Gastrointestinal symptoms of COVID-19 include anorexia,nausea,vomiting,diarrhea,abdominal pain,and liver damage.Patients with digestive damage have a greater chance of progressing to severe or critical illness,a poorer prognosis,and a higher risk of death.This paper aims to summarize the digestive system symptoms of COVID-19 and discuss fecal-oral contagion of SARS-CoV-2.It also describes the characteristics of inflammatory bowel disease patients with SARSCoV-2 infection and discusses precautions for preventing SARS-CoV-2 infection during gastrointestinal endoscopy procedures.Improved attention to digestive system abnormalities and gastrointestinal symptoms of COVID-19 patients may aid health care providers in the process of clinical diagnosis,treatment,and epidemic prevention and control.展开更多
癌细胞经常会上调营养转运蛋白的表达,以满足它们日益增加的生物合成和生物能量需求,并维持氧化还原的动态平衡。在人类癌症中有一种经常过表达的营养转运蛋白,是胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11(solute carrier family 7...癌细胞经常会上调营养转运蛋白的表达,以满足它们日益增加的生物合成和生物能量需求,并维持氧化还原的动态平衡。在人类癌症中有一种经常过表达的营养转运蛋白,是胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11,也称为xCT)。SLC7A11促进胱氨酸摄取和谷胱甘肽生物合成,从而防止氧化应激和细胞铁死亡。最近的研究意外地揭示了SLC7A11在谷氨酰胺代谢中也起着关键作用,并调节癌细胞的葡萄糖和谷氨酰胺依赖性。本文综述了SLC7A11在调节癌细胞抗氧化反应和营养依赖中的作用,探讨了SLC7A11在肿瘤代谢中的调控作用,并提出了这一新兴研究领域中有待进一步研究的关键问题。对癌症代谢中SLC7A11的更深入了解可能会为这种重要的氨基酸转运蛋白靶向癌症治疗提供新的治疗机会。展开更多
Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers i...Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.展开更多
DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleter...DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation.Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.展开更多
Understanding and treating since tumors dawn have been a long journey when for mankind the of and the 1st century the Greek terms the'carcinoma''onco-'emerged not to the attempted document end recognit...Understanding and treating since tumors dawn have been a long journey when for mankind the of and the 1st century the Greek terms the'carcinoma''onco-'emerged not to the attempted document end recognition War of tumors.the It was until of World using II when first and chemotherapy succeeded was nitrogen mustard in curtailing the tumor burden and of a lymphoma 1946).patient(Gilman,types 1963;展开更多
Proteins are major functional units that are tightly connected to form complex and dynamic networks.These networks enable cells and organisms to operate properly and respond efficiently to environmental cues.Over the ...Proteins are major functional units that are tightly connected to form complex and dynamic networks.These networks enable cells and organisms to operate properly and respond efficiently to environmental cues.Over the past decades,many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected.At the same time,rapid development in proteomics and mass spectrometry(MS)techniques makes it possible to identify interacting proteins and build comprehensive protein-protein interaction networks.The resulting interactomes and networks have proven informative in the investigation of biological functions,such as in the field of DNA damage repair.In recent years,a number of proteins involved in DNA damage response and DNA repair pathways have been uncovered with MS-based protein-protein interaction studies.As the technologies for enriching associated proteins and MS become more sophisticated,the studies of protein-protein interactions are entering a new era.In this review,we summarize the strategies and recent developments for exploring protein-protein interaction.In addition,we discuss the application of these tools in the investigation of protein-protein interaction networks involved in DNA damage response and DNA repair.展开更多
Systemic lupus erythematosus(SLE),the most common form of lupus,is a chronic autoimmune disorder characterized by a global loss of self-tolerance and hyper-activation of both innate and adaptive immune systems(Kaul et...Systemic lupus erythematosus(SLE),the most common form of lupus,is a chronic autoimmune disorder characterized by a global loss of self-tolerance and hyper-activation of both innate and adaptive immune systems(Kaul et al.,2016).Neutrophils,the most abundant leukocytes in human blood,have a critical role in maintaining immune surveillance and tissue homeostasis,and its dysregulation is of high relevance to SLE(Ricklin et al.,2010).In patients with SLE,accelerated neutrophil death and the deficiency in clearing dying neutrophils cause nuclear and cytoplasmic antigen exposure,excessive production of type I interferon(IFN),and neutrophil extracellular trap(NET)release,subsequently inducing autoimmune responses(Garcia-Romo et al.,2011).Dysregulated neutrophil death is believed to be a major cause of SLE;however,the underlying mechanism of neutrophil death in SLE is not well-defined.展开更多
Ferroptosis represents an oxidative form of iron-dependent cell death resulting from unrestrained peroxidized phospholipids on cellular membranes(Jiang et al.,2021).In recent years,research interest in ferroptosis has...Ferroptosis represents an oxidative form of iron-dependent cell death resulting from unrestrained peroxidized phospholipids on cellular membranes(Jiang et al.,2021).In recent years,research interest in ferroptosis has increased steeply partly due to its high relevance to diverse diseases(such as cancer and neurodegener-ative diseases)and the enormous potential of ferroptosis induc-ers and inhibitors to treat these diseases(Jiang et al.,2021;Tang et al.,2021.展开更多
Chronic inflammation is recognized as a crucial hallmark of cancer.Interleukin-1β(IL-1β),one of the proinflammatory cytokines,plays an ambiguous or even contradictory role in cancer development[1].While increased ex...Chronic inflammation is recognized as a crucial hallmark of cancer.Interleukin-1β(IL-1β),one of the proinflammatory cytokines,plays an ambiguous or even contradictory role in cancer development[1].While increased expression of IL-1βin the tumor microenvironment is associated with tumor development,and invasiveness[1],it has also shown anti-tumorigenic effects in other contexts[2].Therefore,it is difficult to define IL-1β’s role as either tumor-promoting or anti-tumorigenic in cancers.Further investigation of IL-1βin specific contexts is essential to comprehensively understand its role in cancers.展开更多
Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysoso...Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysosomal proteins were proposed as potential therapeutic targets in cancer[1].As one of the lysosome-related signaling pathways,mTOR signaling regulates cell proliferation,survival,motility,and metabolism[2].SincemTOR signaling activation promotes tumorigenesis,mTOR inhibitors(mTORi),AZD8055[3],MLN0128[4],and Rapalink-1(the latest third-generation mTORi)[4],have been applied to several cancers.However,the limitations of mTORi include drug resistance and the lack of biomarkers.展开更多
The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has ide...The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has identified hyperoxidized perox-iredoxin 3(PRDX3)as a promising marker for ferroptosis,open-ing up new avenues for monitoring and targeting ferroptosis in disease treatment.展开更多
Poly(ADP-ribose)polymerase inhibitors(PARPi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair pathways.However,de novo and acquired PARPi resistance...Poly(ADP-ribose)polymerase inhibitors(PARPi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair pathways.However,de novo and acquired PARPi resistance limits clinical benefits.1 The MRE11-RAD50-NBS1(MRN)complex mediates the sensing,processing,and signaling of DNA double-strand breaks(DSBs)and plays important roles in the efficacy of PARPi and radiation treatment,2 and yet the mechanisms for the regulation and degradation of the MRN complex are not well understood.ZRANB1,also known as Trabid,is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-,K33-,and K63-linked ubiquitin chains,3 but its role in therapy resistance remains unknown.展开更多
The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies reveal...The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis,a form of regulated cell death induced by excessive lipid peroxidation.However,cancer cells with high expression of SLC7A11(SLC7A11^(high))also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming,leading to glucose-and glutamine-dependency in SLC7A11^(high) cancer cells,which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^(high) cancer.In this review,we summarize diverse regulatory mechanisms of SLC7A11 in cancer,discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development,explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells,and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment.This review will provide the foundation for further understanding SLC7A11 in ferroptosis,nutrient dependency,and tumor biology and for developing novel effective cancer therapies.展开更多
Ferroptosis,an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsatu-rated-fatty-acid-containing phospholipids in cellular membranes,has recently been revealed to play an important r...Ferroptosis,an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsatu-rated-fatty-acid-containing phospholipids in cellular membranes,has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression,and to mediate the synergy between radiotherapy and immunotherapy.In this review,we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and fer-roptosis,discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy,and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy.This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.展开更多
基金supported by the Pamela and Wayne Garrison Distinguished Chair in Cancer Research to J.C.J.C.also received support from the CPRIT awards(Grant Nos RP160667 and RP180813)NIH grants(Grant Nos P01CA193124,R01CA210929,R01CA216911,and R01CA216437)。
文摘Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women.Almost all cervical cancers are HPV-associated,however,an increasing number of head and neck cancers(HNCs),especially oropharyngeal cancer,can be linked to HPV infection.Moreover,anogenital cancers,including vaginal,vulvar,penial,and anal cancers,represent a subset of HPVrelated cancers.Whereas testing and prevention of cervical cancer have significantly improved over past decades,anogenital cancers remain more difficult to confirm.Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments.The HPV viral oncoproteins,E6 and E7,lead to degradation of,respectively,p53 and pRb resulting in entering the S phase without G1 arrest.These high-risk HPV viral oncogenes alter numerous cellular processes,including DNA repair,angiogenesis,and/or apoptosis,which eventually result in carcinogenesis.Additionally,a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks(DSB)repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers.In this review,we discuss the current knowledge regarding HPV-related cancers,current screening,and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.
文摘The local recurrence rate of phyllodes tumors of the breast varies widely among different subtypes, and distant metastasis is associated with poor survival. This study aimed to identify factors that are predictive of local recurrence-free survival(LRFS), distant metastasis-free survival(DMFS), and overall survival(OS) in patients with phyllodes tumors of the breast. Clinical data of all patients with a phyllodes tumor of the breast(n = 192) treated at Sun Yat-sen University Cancer Center between March 1997 and December 2012 were reviewed. The Pearson χ2 test was used to investigate the relationship between clinical features of patients and histotypes of tumors. Univariate and multivariate Cox regression analyses were performed to identify factors that are predictive of LRFS, DMFS, and OS. In total, 31(16.1%) patients developed local recurrence, and 12(6.3%) developed distant metastasis. For the patients who developed local recurrence, the median age at the diagnosis of primary tumor was 33 years(range, 17-56 years), and the median size of primary tumor was 6.0 cm(range, 0.8-18 cm). For patients who developed distant metastasis, the median age at the diagnosis of primary tumor was 46 years(range, 24-68 years), and the median size of primary tumor was 5.0 cm(range, 0.8-18 cm). In univariate analysis, age, size, hemorrhage, and margin status were found to be predictive factors for LRFS(P = 0.009, 0.024, 0.004, and 0.001, respectively), whereas histotype, epithelial hyperplasia, margin status, and local recurrence were predictors of DMFS(P = 0.001, 0.007, 0.007, and < 0.001, respectively). In multivariate analysis, independent prognostic factors for LRFS included age [hazard ratio(HR) = 3.045, P = 0.005], tumor size(HR = 2.668, P = 0.013), histotype(HR = 1.715, P = 0.017), and margin status(HR = 4.530, P< 0.001). Histotype(DMFS: HR = 4.409, P = 0.002; OS: HR = 4.194, P = 0.003) and margin status(DMFS: HR = 2.581, P = 0.013; OS: HR = 2.507, P = 0.020) were independent predictors of both DMFS and OS. In this cohort, younger age, a larger tumor size, a higher tumor grade, and positive margins were associated with lower rates of LRFS. Histotype and margin status were found to be independent predictors of DMFS and OS.
文摘AIM:To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal ad- enocarcinoma. METHODS:Methylation-specific polymerase chain reac- tion (MSPCR) was used to examine the promoter meth- ylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal dis- ease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. Apaired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postopera- tive serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent sur- gical therapy. RESULTS:The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION:Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomark- er for gastric and colorectal cancer.
基金financially supported by Shanghai Rising-Star Program (20QA1405000)the National Natural Science Foundation of China (nos.U2032124 and 82204850)。
文摘Molecule hydrogen(H_(2)) has been used to suppress tumor growth. To employ the H_(2) therapy, it is necessary to use a proper agent for continuous generation of H_(2). As a biodegradable metal, magnesium(Mg) generates H_(2) in an aqueous environment, but the H_(2) release rate is still too low. Here, we design a Mg-Al-Ca(AX) alloy that degrades very rapidly due to the presence of a secondary phase Al_(2)Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al_(2)Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al_(2)Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors.This work suggests that the H_(2) therapy using highly degradable Mg alloys may provide an effective cancer treatment.
文摘Coronavirus disease 2019(COVID-19)is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)with typical respiratory symptoms.SARS-CoV-2 invades not only the respiratory system,but also other organs expressing the cell surface receptor angiotensin converting enzyme 2.In particular,the digestive system is a susceptible target of SARS-CoV-2.Gastrointestinal symptoms of COVID-19 include anorexia,nausea,vomiting,diarrhea,abdominal pain,and liver damage.Patients with digestive damage have a greater chance of progressing to severe or critical illness,a poorer prognosis,and a higher risk of death.This paper aims to summarize the digestive system symptoms of COVID-19 and discuss fecal-oral contagion of SARS-CoV-2.It also describes the characteristics of inflammatory bowel disease patients with SARSCoV-2 infection and discusses precautions for preventing SARS-CoV-2 infection during gastrointestinal endoscopy procedures.Improved attention to digestive system abnormalities and gastrointestinal symptoms of COVID-19 patients may aid health care providers in the process of clinical diagnosis,treatment,and epidemic prevention and control.
基金Andrew Sabin Family Fellow Award和Institutional Research Grant from the University of Tex as MD Anderson Cancer Center,Grants from National Institutes of Health(CA181196和CA190370)Anna Fuller Fund和Ellison Medical Foundation(AGNS-0973-13)的资助
文摘癌细胞经常会上调营养转运蛋白的表达,以满足它们日益增加的生物合成和生物能量需求,并维持氧化还原的动态平衡。在人类癌症中有一种经常过表达的营养转运蛋白,是胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11,也称为xCT)。SLC7A11促进胱氨酸摄取和谷胱甘肽生物合成,从而防止氧化应激和细胞铁死亡。最近的研究意外地揭示了SLC7A11在谷氨酰胺代谢中也起着关键作用,并调节癌细胞的葡萄糖和谷氨酰胺依赖性。本文综述了SLC7A11在调节癌细胞抗氧化反应和营养依赖中的作用,探讨了SLC7A11在肿瘤代谢中的调控作用,并提出了这一新兴研究领域中有待进一步研究的关键问题。对癌症代谢中SLC7A11的更深入了解可能会为这种重要的氨基酸转运蛋白靶向癌症治疗提供新的治疗机会。
基金supported by the Andrew Sabin Family Fellow Award and Institutional Research Grant from the University of Texas MD Anderson Cancer Center,Grants from National Institutes of Health(CA181196 and CA190370)Anna Fuller Fund,and Ellison Medical Foundation(AG-NS-0973-13).
文摘Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.
基金supported by the National Institutes of Health (CA179441, CA193124-Project 3 to Lei Li)
文摘DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks(DPCs)—the covalent linkage of proteins with a DNA strand—are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation.Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.
文摘Understanding and treating since tumors dawn have been a long journey when for mankind the of and the 1st century the Greek terms the'carcinoma''onco-'emerged not to the attempted document end recognition War of tumors.the It was until of World using II when first and chemotherapy succeeded was nitrogen mustard in curtailing the tumor burden and of a lymphoma 1946).patient(Gilman,types 1963;
基金support from the Pamela and Wayne Garrison Distinguished Chair in Cancer Research,the Cancer Prevention&Research Institute of Texas(Nos.RP160667 and RP180813)the National Institutes of Health(NIH)(Nos.CA210929,CA216911,and CA216437)。
文摘Proteins are major functional units that are tightly connected to form complex and dynamic networks.These networks enable cells and organisms to operate properly and respond efficiently to environmental cues.Over the past decades,many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected.At the same time,rapid development in proteomics and mass spectrometry(MS)techniques makes it possible to identify interacting proteins and build comprehensive protein-protein interaction networks.The resulting interactomes and networks have proven informative in the investigation of biological functions,such as in the field of DNA damage repair.In recent years,a number of proteins involved in DNA damage response and DNA repair pathways have been uncovered with MS-based protein-protein interaction studies.As the technologies for enriching associated proteins and MS become more sophisticated,the studies of protein-protein interactions are entering a new era.In this review,we summarize the strategies and recent developments for exploring protein-protein interaction.In addition,we discuss the application of these tools in the investigation of protein-protein interaction networks involved in DNA damage response and DNA repair.
文摘Systemic lupus erythematosus(SLE),the most common form of lupus,is a chronic autoimmune disorder characterized by a global loss of self-tolerance and hyper-activation of both innate and adaptive immune systems(Kaul et al.,2016).Neutrophils,the most abundant leukocytes in human blood,have a critical role in maintaining immune surveillance and tissue homeostasis,and its dysregulation is of high relevance to SLE(Ricklin et al.,2010).In patients with SLE,accelerated neutrophil death and the deficiency in clearing dying neutrophils cause nuclear and cytoplasmic antigen exposure,excessive production of type I interferon(IFN),and neutrophil extracellular trap(NET)release,subsequently inducing autoimmune responses(Garcia-Romo et al.,2011).Dysregulated neutrophil death is believed to be a major cause of SLE;however,the underlying mechanism of neutrophil death in SLE is not well-defined.
基金supported by The University of Texas MD Anderson Cancer Center,National Institutes of Health grants R01CA181196,R01CA244144,R01CA247992Cancer Prevention&Research Institute of Texas grant RP220258(to BG)Cancer Center Support(Core)grant P30 CA016672 from the National Cancer Institute,National Institutes of Health(to The University of Texas MD Anderson Cancer Center).
文摘Ferroptosis represents an oxidative form of iron-dependent cell death resulting from unrestrained peroxidized phospholipids on cellular membranes(Jiang et al.,2021).In recent years,research interest in ferroptosis has increased steeply partly due to its high relevance to diverse diseases(such as cancer and neurodegener-ative diseases)and the enormous potential of ferroptosis induc-ers and inhibitors to treat these diseases(Jiang et al.,2021;Tang et al.,2021.
基金University of Texas MD Anderson Cancer Center,National Institutes of Health,Grant/Award Numbers:R01CA181196,R01CA244144,R01CA247992,R01CA269646,U54CA274220Cancer Prevention&Research Institute of Texas,Grant/Award Numbers:RP220258,RP230072+1 种基金Cancer Center Support,Grant/Award Number:P30 CA016672National Cancer Institute。
文摘Chronic inflammation is recognized as a crucial hallmark of cancer.Interleukin-1β(IL-1β),one of the proinflammatory cytokines,plays an ambiguous or even contradictory role in cancer development[1].While increased expression of IL-1βin the tumor microenvironment is associated with tumor development,and invasiveness[1],it has also shown anti-tumorigenic effects in other contexts[2].Therefore,it is difficult to define IL-1β’s role as either tumor-promoting or anti-tumorigenic in cancers.Further investigation of IL-1βin specific contexts is essential to comprehensively understand its role in cancers.
文摘Dear Editor,Accumulating evidence suggests that dysregulated lysosomal membrane proteins,including vacuolar ATPase(v-ATPase)and the mammalian target of rapamycin(mTOR),are involved in tumorigenesis[1].Therefore,lysosomal proteins were proposed as potential therapeutic targets in cancer[1].As one of the lysosome-related signaling pathways,mTOR signaling regulates cell proliferation,survival,motility,and metabolism[2].SincemTOR signaling activation promotes tumorigenesis,mTOR inhibitors(mTORi),AZD8055[3],MLN0128[4],and Rapalink-1(the latest third-generation mTORi)[4],have been applied to several cancers.However,the limitations of mTORi include drug resistance and the lack of biomarkers.
基金Research in the authors’laboratory has been supported by the University of Texas MD Anderson Cancer Center,National Institutes of Health grants R01CA181196,R01CA244144,R01CA247992,R01CA269646,and U54CA274220Cancer Prevention&Research Institute of Texas grant RP230072(to B.G.)Cancer Center Support(Core)Grant P30 CA016672 from The National Cancer Institute(to the University of Texas MD Anderson Cancer Center).
文摘The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has identified hyperoxidized perox-iredoxin 3(PRDX3)as a promising marker for ferroptosis,open-ing up new avenues for monitoring and targeting ferroptosis in disease treatment.
基金supported by a US National Institutes of Health(NIH)grant R01CA166051a Cancer Prevention and Research Institute of Texas(CPRIT)grant RP190029+1 种基金M.-C.H.was supported by the Sister Institution Fund of MD Anderson Cancer Center and China Medical UniversityThe cores are supported by MD Anderson's Cancer Center Support Grant(CCSG,No.P30CA016672)from NIH.
文摘Poly(ADP-ribose)polymerase inhibitors(PARPi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair pathways.However,de novo and acquired PARPi resistance limits clinical benefits.1 The MRE11-RAD50-NBS1(MRN)complex mediates the sensing,processing,and signaling of DNA double-strand breaks(DSBs)and plays important roles in the efficacy of PARPi and radiation treatment,2 and yet the mechanisms for the regulation and degradation of the MRN complex are not well understood.ZRANB1,also known as Trabid,is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-,K33-,and K63-linked ubiquitin chains,3 but its role in therapy resistance remains unknown.
基金The research in authors'lab has been supported by The University of Texas MD Anderson Cancer Center,KC180131 from Department of Defense Kidney Cancer Research Program,R01CA181196,R01CA190370,R01CA244144 from the National Institutes of Health(to BG)CPRIT Research Training Grant(RP170067)Dr.John J.Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences(to PK).
文摘The cystine/glutamate antiporter SLC7A11(also commonly known as xCT)functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers.Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis,a form of regulated cell death induced by excessive lipid peroxidation.However,cancer cells with high expression of SLC7A11(SLC7A11^(high))also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming,leading to glucose-and glutamine-dependency in SLC7A11^(high) cancer cells,which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11^(high) cancer.In this review,we summarize diverse regulatory mechanisms of SLC7A11 in cancer,discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development,explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells,and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment.This review will provide the foundation for further understanding SLC7A11 in ferroptosis,nutrient dependency,and tumor biology and for developing novel effective cancer therapies.
基金Radiation Oncology Strategic Initiatives(ROSI)from The University of Texas MD Anderson Cancer Center。
文摘Ferroptosis,an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsatu-rated-fatty-acid-containing phospholipids in cellular membranes,has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression,and to mediate the synergy between radiotherapy and immunotherapy.In this review,we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and fer-roptosis,discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy,and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy.This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.