AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with ris...AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.展开更多
18-fluorodeoxygluocose positron emission tomography/computed tomography(18FDG-PET/CT) provides significant information in multiple settings in the management of head and neck cancers(HNC). This article seeks to define...18-fluorodeoxygluocose positron emission tomography/computed tomography(18FDG-PET/CT) provides significant information in multiple settings in the management of head and neck cancers(HNC). This article seeks to define the additional benefit of PET/CT as related to radiation treatment planning for squamous cell carcinomas(SCCs) of the head and neck through a review of relevant literature. By helping further define both primary and nodal volumes, radiation treatment planning can be improved using PET/CT. Special attention is paid to the independent benefit of PET/CT in targeting mucosal primaries as well as in detecting nodal metastases. The utility of PET/CT is also explored for treatment planning in the setting of SCC of unknown primary as PET/CT may help define a mucosal target volume by guiding biopsies for examination under anesthesia thus changing the treatment paradigm and limiting the extent of therapy. Implications of the use of PET/CT for proper target delineation in patients with artifact from dental procedures are discussed and the impact of dental artifact on CT-based PET attenuation correction is assessed. Finally, comment is made upon the role of PET/CT in the high-risk post-operative setting, particularly in the context of radiation dose escalation. Real case examples are used in these settings to elucidate the practical benefits of PET/CT as related to radiation treatment planning in HNCs.展开更多
The accumulated evidence from two decades of randomized controlled trials has not yet resolved the question of how best to monitor colorectal cancer(CRC)survivors for early detection of recurrent and metachronous dise...The accumulated evidence from two decades of randomized controlled trials has not yet resolved the question of how best to monitor colorectal cancer(CRC)survivors for early detection of recurrent and metachronous disease or even whether doing so has its intended effect.A new wave of trial data in the coming years and an evolving knowledge of relevant biomarkers may bring us closer to understanding what surveillance strategies are most effective for a given subset of patients.To best apply these insights,a number of important research questions need to be addressed,and new decision making tools must be developed.In this review,we summarize available randomized controlled trial evidence comparing alternative surveillance testing strategies,describe ongoing trials in the area,and compare professional society recommendations for surveillance.In addition,we discuss innovations relevant to CRC surveillance and outline a research agenda which will inform a more risk-stratified and personalized approach to follow-up.展开更多
AIM: To investigate the association between single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) tumor suppressor gene and risk of colon cancer. METHODS: We utilized a population-based c...AIM: To investigate the association between single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) tumor suppressor gene and risk of colon cancer. METHODS: We utilized a population-based casecontrol study of incident colon cancer individuals (n= 421) and controls (n = 483) aged ≥ 30 years to conduct a comprehensive tagSNP association analysis of the PTEN gene. RESULTS: None of the PTEN SNPs were statistically significantly associated with colon cancer when controlled for age, gender, and race, or when additionally adjusted for other known risk factors (P > 0.05). Haplotype analyses similarly showed no association between the PTEN gene and colon cancer. CONCLUSION: Our study does not support PTEN as a colon cancer susceptibility gene.展开更多
Most patients treated with curative intent for colorectal cancer(CRC) are included in a follow-up program involving periodic evaluations. The survival benefits of a follow-up program are well delineated, and previous ...Most patients treated with curative intent for colorectal cancer(CRC) are included in a follow-up program involving periodic evaluations. The survival benefits of a follow-up program are well delineated, and previous meta-analyses have suggested an overall survival improvement of 5%-10% by intensive follow-up. However, in a recent randomized trial, there was no survival benefit when a minimal vs an intensive follow-up program was compared. Less is known about the potential side effects of follow-up. Well-known side effects of preventive programs are those of somatic complications caused by testing, negative psychological conse-quences of follow-up itself, and the downstream impact of false positive or false negative tests. Accordingly, the potential survival benefits of CRC follow-up must be weighed against these potential negatives. The present review compares the benefits and side effects of CRC follow-up, and we propose future areas for research.展开更多
Purpose:This study aimed to examine the effect of radiation esophagitis(RE)and the dynamics of RE on subse-quent survival in non-small cell lung cancer(NSCLC)patients who underwent radiotherapy.Experimental Design:Pat...Purpose:This study aimed to examine the effect of radiation esophagitis(RE)and the dynamics of RE on subse-quent survival in non-small cell lung cancer(NSCLC)patients who underwent radiotherapy.Experimental Design:Patients with NSCLC treated with fractionated thoracic radiotherapy enrolled in prospective trials were eligible.RE was graded prospectively according to Common Terminology Criteria for Adverse Events(CTCAE)v3.0 per protocol requirement weekly during-RT and 1 month after RT.This study applied conditional survival assessment which has advantage over traditional survival analysis as it assesses the survival from the event instead of from the baseline.P-value less than 0.05 was considered to be significant.The primary endpoint is overall survival.Results:A total of 177 patients were eligible,with a median follow-up of 5 years.The presence of RE,the maximum RE grade,the evolution of RE and the onset timing of RE events were all correlated with subsequent survival.At all conditional time points,patients first presented with RE grade1(initial RE1)had significant inferior subsequent survival(multivariable HRs median:1.63,all P-values<0.05);meanwhile those with RE progressed had significant inferior subsequent survival than those never develop RE(multivariable HRs median:2.08,all P-values<0.05).Multivariable Cox proportional-hazards analysis showed significantly higher C-indexes for models with inclusion of RE events than those without(all P-values<0.05).Conclusion:This study comprehensively evaluated the impact of RE with conditional survival assessment and demonstrated that RE is associated with inferior survival in NSCLC patients treated with RT.展开更多
Phosphoinositide 3-kinases(PI3Ks)are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit.The PlIK3CA gene,which encodes the p110a,is the most frequently mutated oncogene in cancer.Oncogeni...Phosphoinositide 3-kinases(PI3Ks)are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit.The PlIK3CA gene,which encodes the p110a,is the most frequently mutated oncogene in cancer.Oncogenic PIK3CA mutations activate the PI3K pathway,promote tumor initiation and development,and mediate resistance to anti-tumor treatments,making the mutant p110a an excellent target for cancer therapy.PIK3CA mutations occur in two hotspot regions:one in the helical domain and the other in the kinase domain.The PIK3CA helical and kinase domain mutations exert their oncogenic function through distinct mechanisms.For example,helical domain mutations of p110a gained direct interaction with insulin receptor substrate 1(IRs-1)to activate the downstream signaling path-ways.Moreover,p85βproteins disassociate from helical domain mutant p110a,translocate into the nucleus,and stabilize enhancer of zeste homolog 1/2(EzH1/2).Due to the funda-mental role of Pl3Ka in tumor initiation and development,Pl3Ka-specific inhibitors,repre-sented by FDA-approved alpelisib,have developed rapidly in recent decades.However,side effects,including on-target side effects such as hyperglycemia,restrict the maximum dose and thus clinical efficacy of alpelisib.Therefore,developing p110a mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant can-cers.In this review,we briefly introduce the function of the Pl3K pathway and discuss how PIK3CA mutations rewire cell signaling,metabolism,and tumor microenvironment,as well as therapeutic strategies under development to treat patients with tumors harboring a PIK3CA mutation.展开更多
HER3,formally referred to as ERB-B2 receptor tyrosine kinase 3,is a member of the ErbB receptor tyrosine kinases(also known as EGFR)family.HER3 plays a significant pro-cancer role in various types of cancer due to its...HER3,formally referred to as ERB-B2 receptor tyrosine kinase 3,is a member of the ErbB receptor tyrosine kinases(also known as EGFR)family.HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation,which initi-ates downstream signaling pathways crucial in cancer cell survival and progression.As a result,numerous monoclonal antibodies have been developed to block HER3 activation and subse-quent signaling pathways.While pre-clinical investigations have effectively showcased signif-icant anti-cancer effects of HER3-targeted therapies,these therapies have had little impact on cancer patient outcomes in the clinic,except for patients with rare NRG1 fusion mutations.This review offers a comprehensive description of the oncogenic functions of HER3,encom-passing its structure and mediating signaling pathways.More importantly,it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical de-terminants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies.Lastly,we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.展开更多
Sebaceous carcinoma (SC) of the eyelid is a rare but aggressive malignancy, accounting for 3%—5% of eyelid malignancies in the United States, and up to 35% in Asian populations (Deprez and Uffer, 2009;Xu et al., 2018...Sebaceous carcinoma (SC) of the eyelid is a rare but aggressive malignancy, accounting for 3%—5% of eyelid malignancies in the United States, and up to 35% in Asian populations (Deprez and Uffer, 2009;Xu et al., 2018;Yu et al., 2018). It is frequently mistaken for benign conditions or less aggressive malignancies such as basal cell carcinoma (Muqit et al., 2013), and the effects of delay in diagnosis can be devastating to patients. Aggressive surgical resection is the primary treatment of these tumors and often invoIves orbital exenteration with significant morbidity to patients, and these tumors frequently recur, with local recurrence rate as high as 18%. Importantly, this disease has a high metastatic potential, and there are very limited data guiding systemic treatment options;ultimately 6%—18% of patients diagnosed with SC of the eyelid succumb to metastatic disease (Zurcher et al., 1998;Shields et al., 2004).展开更多
Many cancer types reprogram their metabolism to become addicted to glutamine.One of the critical enzymes in the utilization of glutamine in these cells is glutaminase.CB-839(telaglenastat)is a drug that targets glutam...Many cancer types reprogram their metabolism to become addicted to glutamine.One of the critical enzymes in the utilization of glutamine in these cells is glutaminase.CB-839(telaglenastat)is a drug that targets glutaminase that is currently being evaluated in many clinical trials for efficacy in various cancer types that are known to be driven by glutamine metabolism.Despite its use,there are limited assays available for testing the pharmacodynamic on-target effects of CB-839 on the limited,small-volume patient samples that are obtained in early-phase clinical trials.Thus,we developed an assay based on the cellular thermal shift assay technique using AlphalLlSA technology to show that CB-839 specifically engages glutaminase in colon cancer cell lines in vitro and in minute quantities of mouse xenograft tumors.Notably,we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial.This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful infuture studies designed to screen other in hibitors of glutaminase.展开更多
AIM: To determine the role for the intermediate filament protein nestin in glioma invasion. METHODS: We examined the expression and function of nestin in gliomas(Grades Ⅱ-Ⅳ as defined by the World Health Organizatio...AIM: To determine the role for the intermediate filament protein nestin in glioma invasion. METHODS: We examined the expression and function of nestin in gliomas(Grades Ⅱ-Ⅳ as defined by the World Health Organization). We determined nestin expression using Immunohistochemical methods. To elucidate nestin's biological function(s), we reduced m RNA levels by 61% and 87% in two glioblastomaderived neurosphere lines using short hairpin RNAs and determined the effect of reduced nestin expression on glioma cell proliferation and invasion using MTS and matrigel migration assays, respectively. We also utilized quantitative real time polymerase chain reaction assaysto determine the effect of reduced nestin expression on the expression of other markers associated with glioma stem cells and their differentiated progenies. RESULTS: We found a significant correlation between nestin immunoreactivity and astrocytoma tumor grade, with 36% of grade Ⅱ, 75% of grade Ⅲ, and 100% of grade Ⅳtumors expressing significant levels of the protein when assessed using immunohistochemistry. Reduction in nestin expression had no effect on cell growth in culture, but did retard the capacity of one line to migrate in-vitro on matrigel. Interestingly, in the line whose migration was not affected, m RNA levels of a second intermediate filament, synemin(also knowns as desmuslin), were elevated following introduction of sh RNA targeting nestin. As synemin was not induced in the line which required nestin for migration, it is a possibility that synemin may compensate for the loss of nestin in this process. CONCLUSION: Nestin expression is prominent in high-grade astrocytomas. Nestin is not required for cell growth but it may, however, be required for cell motility.展开更多
Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic,transcriptomic,and epigenomic scales.The significant molecular heterogenei...Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic,transcriptomic,and epigenomic scales.The significant molecular heterogeneity across individual tumors even within the same tissue context complicates decoding the key etiologic mechanisms of this disease.Furthermore,it is increasingly likely that biologic mechanisms underlying the pathobiology of cancer involve multiple molecular entities interacting across functional scales.This has motivated the development of computational approaches that integrate molecular measurements with prior biological knowledge in increasingly intricate ways to enable the discovery of driver genomic aberrations across cancers.Here,we review diverse methodological approaches that have powered significant advances in our understanding of the genomic underpinnings of cancer at the cohort and at the individual tumor scales.We outline the key advances and challenges in the computational discovery of cancer mechanisms while motivating the development of systems biology approaches to comprehensively decode the biologic drivers of this complex disease.展开更多
Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality rout...Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer.Extradomain B fibronectin(EDBFN)is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers,including prostate cancer.It is a promising molecular target for the detection and risk-stratification of prostate cancer with high-resolution MR molecular imaging(MRMI).In this study,we investigated the effectiveness of MRMI with an EDB-FN specific contrast agent MT218 for assessing the progression and therapy resistance of prostate cancer.Low grade LNCaP prostate cancer cells became an invasive phenotype LNCaP-CXCR2 with elevated EDB-FN expression after acquisition of the C-X-C motif chemokine receptor 2(CXCR2).MT218-MRMI showed brighter signal enhancement in LNCaP-CXCR2 tumor xenografts with a∼2-fold contrast-to-noise(CNR)increase than in LNCaP tumors in mice.Enzalutamide-resistant C4-2-DR prostate cancer cells were more invasive,with higher EDB-FN expression than parental C4-2 cells.Brighter signal enhancement with a∼2-fold CNR increase was observed in the C4-2-DR xenografts compared to that of C4-2 tumors in mice with MT218-MRMI.Interestingly,when invasive PC3 prostate cancer cells developed resistance to paclitaxel,the drug-resistant PC3-DR cells became less invasive with reduced EDB-FN expression than the parental PC3 cells.MT218-MRMI detected reduced brightness in the PC3-DR xenografts with more than 2-fold reduction of CNR compared to PC3 tumors in mice.The signal enhancement in all tumors was supported by the immunohistochemical staining of EDB-FN with the G4 monoclonal antibody.The results indicate that MRMI of EDB-FN with MT218 has promise for detection,risk stratification,and monitoring the progression and therapy response of invasive prostate cancer.展开更多
Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchyma...Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchymal transition(EMT)programs that promote breast cancer dissemination,stemness and chemoresistance.The impact of EMT programs on nongenomic ER-αsignaling remains unknown and was studied herein.Methods:MCF-7 and BT474 cells were stimulated with TGF-βto induce EMT programs,at which point ER-αexpression,localization,and nongenomic interactions with receptor tyrosine kinases and MAP kinases(MAPKs)were determined.Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.Results:TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes,which enhanced cytoplasmic accumulation of ER-αwithout altering its expression.Post-EMT cells exhibited:(1)elevated expression of EGFR and IGF1R,which together with Src formed cytoplasmic complexes with ER-α;(2)enhanced coupling of EGF,IGF-1 and estrogen to the activation of MAPKs;and(3)reduced sensitivity to tamoxifen,an event reversed by administration of small molecule inhibitors against the receptors for TGF-β,EGF,and IGF-1,as well as those against MAPKs.Conclusion:EMT stimulated by TGF-βpromotes anti-estrogen resistance by activating EGFR-,IGF1R-,and MAPK-dependent nongenomic ER-αsignaling.展开更多
We recently reported that PIK3CA mutant colorectal cancers(CRCs)are addicted to glutamine through up-regulation of glutamate pyruvate transaminase 2(GPT2).A GPT2 inhibitor suppresses in vivo growth of PIK3CA mutant,bu...We recently reported that PIK3CA mutant colorectal cancers(CRCs)are addicted to glutamine through up-regulation of glutamate pyruvate transaminase 2(GPT2).A GPT2 inhibitor suppresses in vivo growth of PIK3CA mutant,but not wild-type,CRCs.This study indicates that targeting glutamine may be an effective approach to treat CRCs with PIK3CA mutations.展开更多
Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional stu...Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.展开更多
Breast cancer is the second leading cause of cancer-associated death in women in the United States, with more than 90% of those deaths attributed to metastasis. Breast cancer metastasis is incurable and possesses few ...Breast cancer is the second leading cause of cancer-associated death in women in the United States, with more than 90% of those deaths attributed to metastasis. Breast cancer metastasis is incurable and possesses few treatment options and a poor overall prognosis due in part to confounding metastatic attributes, particularly the acquisition of dormancy-associated phenotypes. Dormant disseminated tumor cells can persist for years-to-decades before recurring as highly aggressive, secondary lesions. Dormancy-associated phenotypes are exhibited by breast cancer stem cells (BCSCs), which undergo tumor initiation and unlimited self-renewal. In addition to their specialized abilities to circumvent chemotherapeutic insults, BCSCs also upregulate autophagy during metastatic dormancy as a means to survive in nutrient poor conditions and environmental stress. As such, therapeutic targeting of autophagy is actively being pursued as an attractive strategy to alleviate metastatic disease and the recurrence of dormant BCSCs. Here we review the molecular and cellular features of autophagy, as well as its paradoxical role in both suppressing and promoting mammary tumor development and metastatic progression. Finally, we highlight the clinical challenges associated with therapeutic targeting of autophagy in metastatic breast cancers.展开更多
Objective:Stool DNA(sDNA)tests offer a noninvasive form of colon cancer screening for pa-tients,and although the test is expected to increase uptake of colon cancer screening,it is unknown if patients’perceptions of ...Objective:Stool DNA(sDNA)tests offer a noninvasive form of colon cancer screening for pa-tients,and although the test is expected to increase uptake of colon cancer screening,it is unknown if patients’perceptions of the sDNA test differ according to race and other patient characteristics.Methods:We conducted a self-administered survey of patients undergoing both a colonoscopy and an sDNA test to evaluate perceptions of sDNA testing.Results:Of the 613 participants who were sent surveys,423 responded(69%response rate).Respondents self-identified as African American(n=127,30%),Caucasian(n=284,67%),and other ethnicity(n=12,3%).In general,participants found the sDNA test more suitable than a colonos-copy(n=309,75%).In univariate analyses,a higher percentage of Caucasians as compared with African Americans found the sDNA test more suitable than a colonoscopy(89%vs.76%,p<0.01),and more Caucasians than African Americans preferred the sDNA test(43%vs.32%,p<0.05).Ad-justment for covariates reduced these racial differences to no significance.A family history of colo-rectal cancer remains a significant factor for patient’s preferences for screening regardless of race.Conclusions:Our study shows no racial differences in the perception of and preference for sDNA testing for colon screening.Intervention to increase the uptake of sDNA testing may help reduce racial disparities in colorectal cancer.展开更多
Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate ...Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.展开更多
基金Supported by A Damon Runyon Cancer Research Foundation Clinical Investigator Award,CI-8An R25 training grant from the National Cancer Institute,R25T CA094186+1 种基金The Case Center for Transdisciplinary Research on Energetics and Cancer,1U54 CA-116867-01A National Cancer Institute K22 Award,1K22 CA120545-01
文摘AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.
文摘18-fluorodeoxygluocose positron emission tomography/computed tomography(18FDG-PET/CT) provides significant information in multiple settings in the management of head and neck cancers(HNC). This article seeks to define the additional benefit of PET/CT as related to radiation treatment planning for squamous cell carcinomas(SCCs) of the head and neck through a review of relevant literature. By helping further define both primary and nodal volumes, radiation treatment planning can be improved using PET/CT. Special attention is paid to the independent benefit of PET/CT in targeting mucosal primaries as well as in detecting nodal metastases. The utility of PET/CT is also explored for treatment planning in the setting of SCC of unknown primary as PET/CT may help define a mucosal target volume by guiding biopsies for examination under anesthesia thus changing the treatment paradigm and limiting the extent of therapy. Implications of the use of PET/CT for proper target delineation in patients with artifact from dental procedures are discussed and the impact of dental artifact on CT-based PET attenuation correction is assessed. Finally, comment is made upon the role of PET/CT in the high-risk post-operative setting, particularly in the context of radiation dose escalation. Real case examples are used in these settings to elucidate the practical benefits of PET/CT as related to radiation treatment planning in HNCs.
基金Supported by National Cancer Institute Program Grant,No.5P30 CA043703-21American Cancer Society Mentored Research Scholar Grant,No.124673-MRSG-13-315-01-CPHPS
文摘The accumulated evidence from two decades of randomized controlled trials has not yet resolved the question of how best to monitor colorectal cancer(CRC)survivors for early detection of recurrent and metachronous disease or even whether doing so has its intended effect.A new wave of trial data in the coming years and an evolving knowledge of relevant biomarkers may bring us closer to understanding what surveillance strategies are most effective for a given subset of patients.To best apply these insights,a number of important research questions need to be addressed,and new decision making tools must be developed.In this review,we summarize available randomized controlled trial evidence comparing alternative surveillance testing strategies,describe ongoing trials in the area,and compare professional society recommendations for surveillance.In addition,we discuss innovations relevant to CRC surveillance and outline a research agenda which will inform a more risk-stratified and personalized approach to follow-up.
文摘AIM: To investigate the association between single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) tumor suppressor gene and risk of colon cancer. METHODS: We utilized a population-based casecontrol study of incident colon cancer individuals (n= 421) and controls (n = 483) aged ≥ 30 years to conduct a comprehensive tagSNP association analysis of the PTEN gene. RESULTS: None of the PTEN SNPs were statistically significantly associated with colon cancer when controlled for age, gender, and race, or when additionally adjusted for other known risk factors (P > 0.05). Haplotype analyses similarly showed no association between the PTEN gene and colon cancer. CONCLUSION: Our study does not support PTEN as a colon cancer susceptibility gene.
基金Supported by Norwegian Health Authorities Research Grant
文摘Most patients treated with curative intent for colorectal cancer(CRC) are included in a follow-up program involving periodic evaluations. The survival benefits of a follow-up program are well delineated, and previous meta-analyses have suggested an overall survival improvement of 5%-10% by intensive follow-up. However, in a recent randomized trial, there was no survival benefit when a minimal vs an intensive follow-up program was compared. Less is known about the potential side effects of follow-up. Well-known side effects of preventive programs are those of somatic complications caused by testing, negative psychological conse-quences of follow-up itself, and the downstream impact of false positive or false negative tests. Accordingly, the potential survival benefits of CRC follow-up must be weighed against these potential negatives. The present review compares the benefits and side effects of CRC follow-up, and we propose future areas for research.
基金supported by Shenzhen Fundamental Research Program(JCYJ2020109150427184)Shenzhen Science and Technology Program(KQTD20180411185028798)Shenzhen Fun-damental Research Program(JCYJ20180508153249223).
文摘Purpose:This study aimed to examine the effect of radiation esophagitis(RE)and the dynamics of RE on subse-quent survival in non-small cell lung cancer(NSCLC)patients who underwent radiotherapy.Experimental Design:Patients with NSCLC treated with fractionated thoracic radiotherapy enrolled in prospective trials were eligible.RE was graded prospectively according to Common Terminology Criteria for Adverse Events(CTCAE)v3.0 per protocol requirement weekly during-RT and 1 month after RT.This study applied conditional survival assessment which has advantage over traditional survival analysis as it assesses the survival from the event instead of from the baseline.P-value less than 0.05 was considered to be significant.The primary endpoint is overall survival.Results:A total of 177 patients were eligible,with a median follow-up of 5 years.The presence of RE,the maximum RE grade,the evolution of RE and the onset timing of RE events were all correlated with subsequent survival.At all conditional time points,patients first presented with RE grade1(initial RE1)had significant inferior subsequent survival(multivariable HRs median:1.63,all P-values<0.05);meanwhile those with RE progressed had significant inferior subsequent survival than those never develop RE(multivariable HRs median:2.08,all P-values<0.05).Multivariable Cox proportional-hazards analysis showed significantly higher C-indexes for models with inclusion of RE events than those without(all P-values<0.05).Conclusion:This study comprehensively evaluated the impact of RE with conditional survival assessment and demonstrated that RE is associated with inferior survival in NSCLC patients treated with RT.
基金supported by the National Institutes of Health (USA)grantsSR01CA196643,R01CA264320,R01CA260629,P50CA150964,and P30CA043703 to Zhenghe Wang.
文摘Phosphoinositide 3-kinases(PI3Ks)are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit.The PlIK3CA gene,which encodes the p110a,is the most frequently mutated oncogene in cancer.Oncogenic PIK3CA mutations activate the PI3K pathway,promote tumor initiation and development,and mediate resistance to anti-tumor treatments,making the mutant p110a an excellent target for cancer therapy.PIK3CA mutations occur in two hotspot regions:one in the helical domain and the other in the kinase domain.The PIK3CA helical and kinase domain mutations exert their oncogenic function through distinct mechanisms.For example,helical domain mutations of p110a gained direct interaction with insulin receptor substrate 1(IRs-1)to activate the downstream signaling path-ways.Moreover,p85βproteins disassociate from helical domain mutant p110a,translocate into the nucleus,and stabilize enhancer of zeste homolog 1/2(EzH1/2).Due to the funda-mental role of Pl3Ka in tumor initiation and development,Pl3Ka-specific inhibitors,repre-sented by FDA-approved alpelisib,have developed rapidly in recent decades.However,side effects,including on-target side effects such as hyperglycemia,restrict the maximum dose and thus clinical efficacy of alpelisib.Therefore,developing p110a mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant can-cers.In this review,we briefly introduce the function of the Pl3K pathway and discuss how PIK3CA mutations rewire cell signaling,metabolism,and tumor microenvironment,as well as therapeutic strategies under development to treat patients with tumors harboring a PIK3CA mutation.
基金supported by the National Institutes of Health(No.R00CA225756,R37CA278982 to R.W.)the U.S.Department of Defense(No.HT9425-23-1-0657 to R.W.).
文摘HER3,formally referred to as ERB-B2 receptor tyrosine kinase 3,is a member of the ErbB receptor tyrosine kinases(also known as EGFR)family.HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation,which initi-ates downstream signaling pathways crucial in cancer cell survival and progression.As a result,numerous monoclonal antibodies have been developed to block HER3 activation and subse-quent signaling pathways.While pre-clinical investigations have effectively showcased signif-icant anti-cancer effects of HER3-targeted therapies,these therapies have had little impact on cancer patient outcomes in the clinic,except for patients with rare NRG1 fusion mutations.This review offers a comprehensive description of the oncogenic functions of HER3,encom-passing its structure and mediating signaling pathways.More importantly,it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical de-terminants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies.Lastly,we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.
基金supported by the merge funding 2016e17, the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicinesupported by the Harrington Physician Scientist Pathway at University Hospitals Cleveland Medical Centerthe Clinical Translational Science Training Program TL1 grant at Case Western Reserve University
文摘Sebaceous carcinoma (SC) of the eyelid is a rare but aggressive malignancy, accounting for 3%—5% of eyelid malignancies in the United States, and up to 35% in Asian populations (Deprez and Uffer, 2009;Xu et al., 2018;Yu et al., 2018). It is frequently mistaken for benign conditions or less aggressive malignancies such as basal cell carcinoma (Muqit et al., 2013), and the effects of delay in diagnosis can be devastating to patients. Aggressive surgical resection is the primary treatment of these tumors and often invoIves orbital exenteration with significant morbidity to patients, and these tumors frequently recur, with local recurrence rate as high as 18%. Importantly, this disease has a high metastatic potential, and there are very limited data guiding systemic treatment options;ultimately 6%—18% of patients diagnosed with SC of the eyelid succumb to metastatic disease (Zurcher et al., 1998;Shields et al., 2004).
基金the Case Comprehensive Cancer Center's K12 award(5K12CA076917-22)the Clinical and Translational Science Collaborative TL1 training grant(1TL1TRO02549-01)+1 种基金NIH grants RO1CA196643,UH2CA223670,P5OCA150964,and P30 CA043703a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant(SU2C-AACR-DT22-17).Stand Up to Cancer is a program of the Entertainment Industry Foundation.
文摘Many cancer types reprogram their metabolism to become addicted to glutamine.One of the critical enzymes in the utilization of glutamine in these cells is glutaminase.CB-839(telaglenastat)is a drug that targets glutaminase that is currently being evaluated in many clinical trials for efficacy in various cancer types that are known to be driven by glutamine metabolism.Despite its use,there are limited assays available for testing the pharmacodynamic on-target effects of CB-839 on the limited,small-volume patient samples that are obtained in early-phase clinical trials.Thus,we developed an assay based on the cellular thermal shift assay technique using AlphalLlSA technology to show that CB-839 specifically engages glutaminase in colon cancer cell lines in vitro and in minute quantities of mouse xenograft tumors.Notably,we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial.This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful infuture studies designed to screen other in hibitors of glutaminase.
文摘AIM: To determine the role for the intermediate filament protein nestin in glioma invasion. METHODS: We examined the expression and function of nestin in gliomas(Grades Ⅱ-Ⅳ as defined by the World Health Organization). We determined nestin expression using Immunohistochemical methods. To elucidate nestin's biological function(s), we reduced m RNA levels by 61% and 87% in two glioblastomaderived neurosphere lines using short hairpin RNAs and determined the effect of reduced nestin expression on glioma cell proliferation and invasion using MTS and matrigel migration assays, respectively. We also utilized quantitative real time polymerase chain reaction assaysto determine the effect of reduced nestin expression on the expression of other markers associated with glioma stem cells and their differentiated progenies. RESULTS: We found a significant correlation between nestin immunoreactivity and astrocytoma tumor grade, with 36% of grade Ⅱ, 75% of grade Ⅲ, and 100% of grade Ⅳtumors expressing significant levels of the protein when assessed using immunohistochemistry. Reduction in nestin expression had no effect on cell growth in culture, but did retard the capacity of one line to migrate in-vitro on matrigel. Interestingly, in the line whose migration was not affected, m RNA levels of a second intermediate filament, synemin(also knowns as desmuslin), were elevated following introduction of sh RNA targeting nestin. As synemin was not induced in the line which required nestin for migration, it is a possibility that synemin may compensate for the loss of nestin in this process. CONCLUSION: Nestin expression is prominent in high-grade astrocytomas. Nestin is not required for cell growth but it may, however, be required for cell motility.
基金supported by PHS awards:T32 CA094186 to S.K.,K25 DK115904 to V.V.,P30 CA043703 to V.V.,and P20 CA233216 to V.V.
文摘Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic,transcriptomic,and epigenomic scales.The significant molecular heterogeneity across individual tumors even within the same tissue context complicates decoding the key etiologic mechanisms of this disease.Furthermore,it is increasingly likely that biologic mechanisms underlying the pathobiology of cancer involve multiple molecular entities interacting across functional scales.This has motivated the development of computational approaches that integrate molecular measurements with prior biological knowledge in increasingly intricate ways to enable the discovery of driver genomic aberrations across cancers.Here,we review diverse methodological approaches that have powered significant advances in our understanding of the genomic underpinnings of cancer at the cohort and at the individual tumor scales.We outline the key advances and challenges in the computational discovery of cancer mechanisms while motivating the development of systems biology approaches to comprehensively decode the biologic drivers of this complex disease.
基金supported by the Tissue Resources Shared Resource of the Case Comprehensive Cancer Center(P30CA043703).
文摘Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease.MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer.Extradomain B fibronectin(EDBFN)is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers,including prostate cancer.It is a promising molecular target for the detection and risk-stratification of prostate cancer with high-resolution MR molecular imaging(MRMI).In this study,we investigated the effectiveness of MRMI with an EDB-FN specific contrast agent MT218 for assessing the progression and therapy resistance of prostate cancer.Low grade LNCaP prostate cancer cells became an invasive phenotype LNCaP-CXCR2 with elevated EDB-FN expression after acquisition of the C-X-C motif chemokine receptor 2(CXCR2).MT218-MRMI showed brighter signal enhancement in LNCaP-CXCR2 tumor xenografts with a∼2-fold contrast-to-noise(CNR)increase than in LNCaP tumors in mice.Enzalutamide-resistant C4-2-DR prostate cancer cells were more invasive,with higher EDB-FN expression than parental C4-2 cells.Brighter signal enhancement with a∼2-fold CNR increase was observed in the C4-2-DR xenografts compared to that of C4-2 tumors in mice with MT218-MRMI.Interestingly,when invasive PC3 prostate cancer cells developed resistance to paclitaxel,the drug-resistant PC3-DR cells became less invasive with reduced EDB-FN expression than the parental PC3 cells.MT218-MRMI detected reduced brightness in the PC3-DR xenografts with more than 2-fold reduction of CNR compared to PC3 tumors in mice.The signal enhancement in all tumors was supported by the immunohistochemical staining of EDB-FN with the G4 monoclonal antibody.The results indicate that MRMI of EDB-FN with MT218 has promise for detection,risk stratification,and monitoring the progression and therapy response of invasive prostate cancer.
基金Research support was provided in part by the National Institutes of Health to W.P.S.(CA129359,CA177069,and CA194518).
文摘Aim:Estrogen receptor-α(ER-α)activation drives the progression of luminal breast cancers.Signaling by transforming growth factor-β(TGF-β)typically opposes the actions of ER-α;it also induces epithelial-mesenchymal transition(EMT)programs that promote breast cancer dissemination,stemness and chemoresistance.The impact of EMT programs on nongenomic ER-αsignaling remains unknown and was studied herein.Methods:MCF-7 and BT474 cells were stimulated with TGF-βto induce EMT programs,at which point ER-αexpression,localization,and nongenomic interactions with receptor tyrosine kinases and MAP kinases(MAPKs)were determined.Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.Results:TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes,which enhanced cytoplasmic accumulation of ER-αwithout altering its expression.Post-EMT cells exhibited:(1)elevated expression of EGFR and IGF1R,which together with Src formed cytoplasmic complexes with ER-α;(2)enhanced coupling of EGF,IGF-1 and estrogen to the activation of MAPKs;and(3)reduced sensitivity to tamoxifen,an event reversed by administration of small molecule inhibitors against the receptors for TGF-β,EGF,and IGF-1,as well as those against MAPKs.Conclusion:EMT stimulated by TGF-βpromotes anti-estrogen resistance by activating EGFR-,IGF1R-,and MAPK-dependent nongenomic ER-αsignaling.
基金This work is supported by National Institutes of Health grants R01CA196643,R01CA127590,P50CA150964 and P30 CA043703.
文摘We recently reported that PIK3CA mutant colorectal cancers(CRCs)are addicted to glutamine through up-regulation of glutamate pyruvate transaminase 2(GPT2).A GPT2 inhibitor suppresses in vivo growth of PIK3CA mutant,but not wild-type,CRCs.This study indicates that targeting glutamine may be an effective approach to treat CRCs with PIK3CA mutations.
基金This manuscript has been partially supported by NIH/NCI grants R00CA160638 and R01CA245699(H.L.),and Supple-ment for Diversity(V.A.),T32 CA080621-15(R.T.),and R01CA213843(R.A.K),American Cancer Society grant ACS127951-RSG-15-025-01-CSM(H.L.)the Susan G.Komen Foundation CCR15332826(H.L.)and CCR18548501(X.L.)+3 种基金the Department of Defense W81XWH-16-1-0021(H.L.)the Lynn Sage Cancer Research Foundation(X.L.and H.L.)North-western University’s Endocrinology Training Grant T32DK007169-39(A.H.)and start-up funds fromCaseWestern Reserve University and at Northwestern University(H.L.).
文摘Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.
基金Research support was provided in part by the National Institutes of Health(CA236273)to Schiemann WP,and(T32GM008803 and T32CA059366)to Flynn ALB.Additional support was graciously provided by the METAvivor Foundation to Schiemann WP,and by pilot funding from the Case Comprehensive Cancer Center's Research Innovation Fund,which is supported by the Case Council and Friends of the Case Comprehensive Cancer Center to Schiemann WP,and from the Case Clinical&Translational Science Collaborative to Schiemann WP
文摘Breast cancer is the second leading cause of cancer-associated death in women in the United States, with more than 90% of those deaths attributed to metastasis. Breast cancer metastasis is incurable and possesses few treatment options and a poor overall prognosis due in part to confounding metastatic attributes, particularly the acquisition of dormancy-associated phenotypes. Dormant disseminated tumor cells can persist for years-to-decades before recurring as highly aggressive, secondary lesions. Dormancy-associated phenotypes are exhibited by breast cancer stem cells (BCSCs), which undergo tumor initiation and unlimited self-renewal. In addition to their specialized abilities to circumvent chemotherapeutic insults, BCSCs also upregulate autophagy during metastatic dormancy as a means to survive in nutrient poor conditions and environmental stress. As such, therapeutic targeting of autophagy is actively being pursued as an attractive strategy to alleviate metastatic disease and the recurrence of dormant BCSCs. Here we review the molecular and cellular features of autophagy, as well as its paradoxical role in both suppressing and promoting mammary tumor development and metastatic progression. Finally, we highlight the clinical challenges associated with therapeutic targeting of autophagy in metastatic breast cancers.
基金the National Cancer Institute(R01 CA136726 and U01CA181770 to L.Li,and P50CA50964 to L.Li and G.Cooper).
文摘Objective:Stool DNA(sDNA)tests offer a noninvasive form of colon cancer screening for pa-tients,and although the test is expected to increase uptake of colon cancer screening,it is unknown if patients’perceptions of the sDNA test differ according to race and other patient characteristics.Methods:We conducted a self-administered survey of patients undergoing both a colonoscopy and an sDNA test to evaluate perceptions of sDNA testing.Results:Of the 613 participants who were sent surveys,423 responded(69%response rate).Respondents self-identified as African American(n=127,30%),Caucasian(n=284,67%),and other ethnicity(n=12,3%).In general,participants found the sDNA test more suitable than a colonos-copy(n=309,75%).In univariate analyses,a higher percentage of Caucasians as compared with African Americans found the sDNA test more suitable than a colonoscopy(89%vs.76%,p<0.01),and more Caucasians than African Americans preferred the sDNA test(43%vs.32%,p<0.05).Ad-justment for covariates reduced these racial differences to no significance.A family history of colo-rectal cancer remains a significant factor for patient’s preferences for screening regardless of race.Conclusions:Our study shows no racial differences in the perception of and preference for sDNA testing for colon screening.Intervention to increase the uptake of sDNA testing may help reduce racial disparities in colorectal cancer.
文摘Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.
