Objective:We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus(hrHPV)-positive women in primary healthcare settings in China.Methods:This study was undertaken in 11 ...Objective:We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus(hrHPV)-positive women in primary healthcare settings in China.Methods:This study was undertaken in 11 rural and 9 urban sites.Women aged 35-64 years old were enrolled.HrHPV-positive women were randomly allocated to liquid-based cytology(LBC),visual inspection with acetic acid and Lugol’s iodine(VIA/VILI)(rural only)triage,or directly referred to colposcopy(direct COLP).At 24 months,hrHPV testing,LBC and VIA/VILI were conducted for combined screening.Results:In rural sites,1,949 hrHPV-positive women were analyzed.A total of 852,218 and 480 women were randomly assigned to direct COLP,LBC and VIA/VILI.At baseline,colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%.LBC(n=3 and n=7)or VIA/VILI(n=8 and n=26)could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia(CIN)2 or worse and CIN3+compared with direct COLP(n=14 and n=23).For the 24-month cumulative detection rate of CIN2+,VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP.When stratified by age,baseline LBC triage+performed best(P<0.001),peaking among women aged 35-44 years(Ptrend=0.002).In urban sites,1,728 women were hrHPV genotyping test positive.A total of 408,571 and 568women were randomly assigned to direct COLP for HPV16/18+,direct COLP for other hrHPV subtypes+,and LBC triage for other hrHPV subtypes+.LBC(n=12 and n=31)significantly decreased the number of colposcopies needed to detect one CIN2+and CIN3+compared with direct COLP(n=14 and n=44).HPV16/18+increased the 24-month cumulative detection rate of CIN2+(17.89%,P<0.001).Conclusions:LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+women and LBC triage for other hrHPV subtype+women in urban settings might be feasible strategies.展开更多
Background:The long-term outcomes of robotic-assisted surgery and the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio(NLR)in locally advanced rectal cancer(LARC)remain uncertain.This study a...Background:The long-term outcomes of robotic-assisted surgery and the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio(NLR)in locally advanced rectal cancer(LARC)remain uncertain.This study aimed to assess the long-term outcomes of patients with LARC undergoing robotic-assisted surgery and to determine the prognostic value of pretreatment NLR.Methods:We retrospectively reviewed 252 patients with LARC who were treated at a single medical center in Taiwan between January 2012 and January 2023.All patients underwent neoadjuvant concurrent chemoradiotherapy(CRT)followed by robotic-assisted surgery with total mesorectal excision(TME).Patients were stratified into four groups on the basis of pretreatment NLRs and carcinoembryonic antigen(CEA)levels.Univariate and multivariate analyses were conducted to identify prognostic indicators for overall survival(OS)and disease-free survival(DFS).Results:Patients with a pretreatment NLR of≥3.2 exhibited significantly worse OS and DFS compared with those with an NLR of<3.2(OS:94.4 vs.116.5 months,p=0.001;DFS:78.8 vs.101.7 months,p=0.003).Group A exhibited the poorest prognosis,whereas Group D had the most favorable outcomes.Multivariate analysis revealed NLR≥3.2 as an independent predictor of poor OS(hazard ratio[HR]=2.306,95%CI:1.149-3.747;p=0.001)and DFS(HR=2.055,95%CI:1.341-3.148;p=0.001).Conclusion:Neoadjuvant concurrent CRT followed by robotic-assisted TME is an effective treatment strategy for LARC.A higher pretreatment NLR(≥3.2)independently predicted worse OS and DFS.Stratification using the NLR in combination with CEA levels may enhance prognostic accuracy for patients undergoing robotic-assisted surgery for LARC.展开更多
Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor ...Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.展开更多
Early screening for colorectal cancer(CRC) holds the key to combat and control the increasing global burden of CRC morbidity and mortality. However, the current available screening modalities are severely inadequate b...Early screening for colorectal cancer(CRC) holds the key to combat and control the increasing global burden of CRC morbidity and mortality. However, the current available screening modalities are severely inadequate because of their high cost and cumbersome preparatory procedures that ultimately lead to a low participation rate. People simply do not like to have colonoscopies. It would be ideal, therefore, to develop an alternative modality based on blood biomarkers as the first line screening test. This will allow for the differentiation of the general population from high risk individuals. Colonoscopy would then become the secondary test, to further screen the high risk segment of the population. This will encourage participation and therefore help to reach the goal of early detection and thereby reduce the anticipated increasing global CRC incidence rate. A blood-based screening test is anappealing alternative as it is non-invasive and poses minimal risk to patients. It is easy to perform, can be repeated at shorter intervals, and therefore would likely lead to a much higher participation rate. This review surveys various blood-based test strategies currently under investigation, discusses the potency of what is available, and assesses how new technology may contribute to future test design.展开更多
AIM:To develop a panel of blood-based diagnostic biomarkers consisting of circulating microRNAs for the detection of pancreatic cancer at an early stage.METHODS:Blood-based circulating microRNAs were profiled by high ...AIM:To develop a panel of blood-based diagnostic biomarkers consisting of circulating microRNAs for the detection of pancreatic cancer at an early stage.METHODS:Blood-based circulating microRNAs were profiled by high throughput screening using microarray analysis,comparing differential expression between early stage pancreatic cancer patients(n = 8) and healthy controls(n = 11).A panel of candidate microRNAs was generated based on the microarray signature profiling,including unsupervised clustering and statistical analysis of differential expression levels,and findings from the published literature.The selected candidate microRNAs were then confirmed using TaqMan real-time quantitative reverse transcription polymerase chain reaction(RT-qPCR) to further narrow down to a three-microRNA diagnostic panel.The three-microRNA diagnostic panel was validated with independent experimental proce-dures and instrumentation of RT-qPCR at an independent venue with a new cohort of cancer patients(n = 11),healthy controls(n = 11),and a group of high risk controls(n = 11).Receiver operating characteristic curve analysis was performed to assess the diagnostic capability of the three-microRNA panel.RESULTS:In the initial high throughput screening,1220 known human microRNAs were screened for differential expression in pancreatic cancer patients versus controls.A subset of 42 microRNAs was then generated based on this data analysis and current published literature.Eight microRNAs were selected from the list of 42 targets for confirmation study,and three-microRNAs,miR-642b,miR-885-5p,and miR-22,were confirmed to show consistent expression between microarray and RT-qPCR.These three microRNAs were then validated and evaluated as a diagnostic panel with a new cohort of patients and controls and found to yield high sensitivity(91%) and specificity(91%) with an area under the curve of 0.97(P < 0.001).Compared to the CA19-9 marker at 73%,the three-microRNA panel has higher sensitivity although CA19-9 has higher specificity of 100%.CONCLUSION:The identified panel of three microRNA biomarkers can potentially be used as a diagnostic tool for early stage pancreatic cancer.展开更多
Surgical resection is the only option of cure for patients with metastatic colorectal cancer(CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent sit...Surgical resection is the only option of cure for patients with metastatic colorectal cancer(CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent site of relapse. The current international guidelines recommend an adjuvant therapy after surgical resection of CRC metastases despite the lower level of evidence(based on the quality of studies in this setting). However, there is still no standard treatment and the effective role of an adjuvant therapy remains controversial. The aim of this review is to report the state-of-art of systemic chemotherapy and regional chemotherapy with hepatic arterial infusion in the management of patients after resection of metastases from CRC, with a literature review and meta-analysis of the relevant randomized controlled trials.展开更多
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in response to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is histo...The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in response to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is historically characterized for its role in mediating the toxicity and adaptive responses to these chemicals, however mounting evidence has established a role for it in ligand-independent physiological processes and pathological conditions, including cancer. The AhR is overexpressed and constitutively activated in advanced breast cancer cases and was shown to drive the progression of breast cancer. In this article we will review the current state of knowledge on the possible role of AhR in breast cancer and how it will be exploited in targeting AhR for breast cancer therapy.展开更多
There is currently a split within the cancer research community between traditional molecular biological hypothesis-driven and the more recent "omic" forms or research. While the molecular biological approac...There is currently a split within the cancer research community between traditional molecular biological hypothesis-driven and the more recent "omic" forms or research. While the molecular biological approach employs the tried and true single alteration-single response formulations of experimentation,the omic employs broad-based assay or sample collection approaches that generate large volumes of data. How to integrate the benefits of these two approaches in an efficient and productive fashion remains an outstanding issue. Ideally,one would merge the understandability,exactness,simplicity,and testability of the molecular biological approach,with the larger amounts of data,simultaneous consideration of multiple alterations,consideration of genes both of known interest along with the novel,cross-sample comparisons among cell lines and patient samples,and consideration of directed questions while simultaneously gaining exposure to the novel provided by the omic approach. While at the current time integration of the two disciplines remains problematic,attempts to do so are ongoing,and will be necessary for the understanding of the large cell line screens including the Developmental Therapeutics Program's NCI-60,the Broad Institute's Cancer Cell Line Encyclopedia,and the Wellcome Trust Sanger Institute's Cancer Genome Project,as well as the the Cancer Genome Atlas clinical samples project. Going forward there is significant benefit to be had from the integration of the molecular biological and the omic forms or research,with the desired goal being improved translational understanding and application.展开更多
Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There ...Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapy regimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry. We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceutical SFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.展开更多
Abstract:Background:The pTNM staging system is widely recognized as the most effective prognostic indicator for cancer.The latest update of this staging system introduced a new pathological staging system(ypTNM)for pa...Abstract:Background:The pTNM staging system is widely recognized as the most effective prognostic indicator for cancer.The latest update of this staging system introduced a new pathological staging system(ypTNM)for patients receiving neoadjuvant chemoradiotherapy(NACRT).However,whether the prognostic value of the ypTNM staging system for rectal cancer is similar to that of the pTNM staging system remains unclear.This study was conducted to compare the ypTNM and pTNM staging systems in terms of their prognostic value for patients with nonmetastatic rectal cancer undergoing proctectomy.Material and Methods:This study was conducted at a large teaching hospital.Between January 2014 and December 2022,542 patients with rectal cancer were analyzed(median follow-up period,60 months;range,6–105 months).Of them,258 and 284 were included in the pTNM and ypTNM groups,respectively.Inverse probability of treatment weighting(IPTW)was performed to account for the effects of confounders.Cox proportional-hazards regression was performed for the between-group comparison of overall survival(OS).Results:The crude model revealed that OS was similar between the two groups(p=0.607).After performing IPTW,we found that patients with the same ypTNM-and pTNM-classified stages had similar overall survival(hazard ratio=1.15;95%CI=0.76–1.73;p=0.5074).Conclusions:For patients with rectal cancer who have received preoperative NACRT,the prognostic value of ypTNM staging appears to be similar to that of pTNM staging,mostly because of the downstaging effect of neoadjuvant chemoradiotherapy。展开更多
In Western countries, prostate cancer is the most common malignancy in menand ranks third in mortality. In 2010, an estimated 217 730 new cases are anticipated in the United States, and about 32 050 men are expected t...In Western countries, prostate cancer is the most common malignancy in menand ranks third in mortality. In 2010, an estimated 217 730 new cases are anticipated in the United States, and about 32 050 men are expected to die from the disease. Until 2004, numerous clinical trials in men with metastatic castration-resistant prostate cancer （mCRPC） failed to demonstrate any signifi- cant change in overall survival.展开更多
The last decade has seen remarkable advances in the treatment of prostatecancer. Until 2010, only docetaxel had demonstrated the ability to improve the survival in metastatic castration-resistant prostate cancer （mC...The last decade has seen remarkable advances in the treatment of prostatecancer. Until 2010, only docetaxel had demonstrated the ability to improve the survival in metastatic castration-resistant prostate cancer （mCRPC）.展开更多
Objective:Breast cancer is the second most prevalent cause of mortality in women and the predominant malignancy type.However,breast cancer treatment faces challenges in managing aromatase inhibitor-induced arthralgia....Objective:Breast cancer is the second most prevalent cause of mortality in women and the predominant malignancy type.However,breast cancer treatment faces challenges in managing aromatase inhibitor-induced arthralgia.Aromatase inhibitors have been shown to decrease recurrence risk in hormone receptor-positive cases;however,joint discomfort remains the primary adverse effect.Randomized clinical trials have evaluated the therapeutic outcomes of acupuncture for medication-related musculoskeletal complications.This comprehensive analysis sought to elucidate both the therapeutic efficacy and placebo responses associated with acupuncture intervention.Methods:Two reviewers searched for randomized controlled trials(RCTs)in four English(PubMed,Embase,Web of Science,and the Cochrane Library)and four Chinese databases(CNKI,Wanfang Database,VIP,and SinoMed)from their inception to May 31,2024.Methodological quality was assessed using the Cochrane risk of bias tool.Data were synthesized using random effects models and presented with forest plots.Results:Seven trials involving 604 patients were included.The primary outcome and Brief Pain Inventory(BPI)score differed between the acupuncture and control groups(sham acupuncture or usual medication)in three subscales over the course of 6 weeks:worst pain:standardized mean difference(SMD)=-1.18,95%confidence interval(CI):-1.74,-0.63,P<0.001;painrelated interference:SMD=-0.87,95%CI:-1.70,-0.05,P=0.038;pain severity:SMD=-0.63,95%CI:-1.22,-0.04,P=0.036.No severe adverse events were reported in any study.Conclusions:This meta-analysis showed that acupuncture is a safe and effective treatment for patients with breast cancer with aromatase inhibitor-induced arthralgia during the course of 6 weeks.Improvements in the blinding method and clarification of the total treatment recommendations and intervals need to be explored further.展开更多
In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune ch...In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleuceI-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.展开更多
Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransfera...Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.展开更多
AIM： To assess the proteome of normal versus tumor tissue in squamous cell carcinoma of the esophagus （SCCE） in Iranian patients and compare our results with former reports by using proteomics. METHODS： Protein wa...AIM： To assess the proteome of normal versus tumor tissue in squamous cell carcinoma of the esophagus （SCCE） in Iranian patients and compare our results with former reports by using proteomics. METHODS： Protein was extracted from normal and tumor tissues. Two dimensional electrophoresis was carried out and spots with differential expression were identified with mass spectrometry. RNA extraction and RT-PCR along with immunodetection were performed. RESULTS： Fourteen proteins were found whose expression levels differed in tumor compared to normal tissues. Mass spectrometric analysis resulted in the identification of β-tropomyosin （TMβ）, myosin light chain 2 （and its isoform）, myosin regulatory light chain 2, peroxyredoxin 2, annexin I and an unknown polypeptide as the down regulated polypeptides in tumor tissue. Heat shock protein 70 （HSP70）, TPM4-ALK fusion oncoprotein 2, myosin light polypeptide 6, keratin I, GH16431p and calreticulin were the up-regulated polypeptides found in tumor tissue. Several of these proteins, such as TMβ, HSP70, annexin Ⅰ, calreticulin, TPM4-ALK and isoforms of myosins, have been well recognized in tumorigenesis of esophageal or other types of cancers. CONCLUSION： Our study not only supports the involvement of some of the formerly reported proteins in SCCE but also introduces additional proteins found to be lost in SCCE, including TMβ.展开更多
Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substan...Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.展开更多
Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. Duri...Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microR NAs(miR NAs), a class of noncoding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miR NAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mR NAs. Commonly, a particular mi RNA recognition sequence could be found in a number of genes, which allows a single miR-NA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miR NAs. However, previous studies have demonstrated that mi RNA functions are highly context-dependent,which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miR NA. Here we summarize recent progress in studies on miR NA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of mi RNAs and potential application of using miR NAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers.展开更多
Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-in...Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.展开更多
Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. SipuleuceI-T demonstrated a survival benefit...Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. SipuleuceI-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.展开更多
基金National Health Commission(formerly Health and Family Planning Commission)of China(No.201502004)CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-004)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT320010 and No.2018PT32025)。
文摘Objective:We aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus(hrHPV)-positive women in primary healthcare settings in China.Methods:This study was undertaken in 11 rural and 9 urban sites.Women aged 35-64 years old were enrolled.HrHPV-positive women were randomly allocated to liquid-based cytology(LBC),visual inspection with acetic acid and Lugol’s iodine(VIA/VILI)(rural only)triage,or directly referred to colposcopy(direct COLP).At 24 months,hrHPV testing,LBC and VIA/VILI were conducted for combined screening.Results:In rural sites,1,949 hrHPV-positive women were analyzed.A total of 852,218 and 480 women were randomly assigned to direct COLP,LBC and VIA/VILI.At baseline,colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%-80%.LBC(n=3 and n=7)or VIA/VILI(n=8 and n=26)could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia(CIN)2 or worse and CIN3+compared with direct COLP(n=14 and n=23).For the 24-month cumulative detection rate of CIN2+,VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP.When stratified by age,baseline LBC triage+performed best(P<0.001),peaking among women aged 35-44 years(Ptrend=0.002).In urban sites,1,728 women were hrHPV genotyping test positive.A total of 408,571 and 568women were randomly assigned to direct COLP for HPV16/18+,direct COLP for other hrHPV subtypes+,and LBC triage for other hrHPV subtypes+.LBC(n=12 and n=31)significantly decreased the number of colposcopies needed to detect one CIN2+and CIN3+compared with direct COLP(n=14 and n=44).HPV16/18+increased the 24-month cumulative detection rate of CIN2+(17.89%,P<0.001).Conclusions:LBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+women and LBC triage for other hrHPV subtype+women in urban settings might be feasible strategies.
基金supported by grants through funding from the National Science and Technology Council(NSTC112-2314-B-037-050-MY3,NSTC114-2314-B-037-103-MY3,NSTC114-2321-B-037-003)the Ministry of Health and Welfare(MOHW113-TDU-B-222-134014)+3 种基金funded by the health and welfare surcharge of on tobacco products,and the Kaohsiung Medical University Hospital(KMUH113-3R31,KMUH113-3R32,KMUH113-3R33,KMUH113-3M58,KMUH113-3M59,KMUH-S11412,KMUH-SH11403)Kaohsiung Medical University Research Center Grant(KMU-TC113A04)National Tsing Hua University-Kaohsiung Medical University Joint Research Project(NTHU-KMU-KT114P008)supported by the Grant of Taiwan Precision Medicine Initiative and Taiwan Biobank,Academia Sinica,Taiwan.
文摘Background:The long-term outcomes of robotic-assisted surgery and the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio(NLR)in locally advanced rectal cancer(LARC)remain uncertain.This study aimed to assess the long-term outcomes of patients with LARC undergoing robotic-assisted surgery and to determine the prognostic value of pretreatment NLR.Methods:We retrospectively reviewed 252 patients with LARC who were treated at a single medical center in Taiwan between January 2012 and January 2023.All patients underwent neoadjuvant concurrent chemoradiotherapy(CRT)followed by robotic-assisted surgery with total mesorectal excision(TME).Patients were stratified into four groups on the basis of pretreatment NLRs and carcinoembryonic antigen(CEA)levels.Univariate and multivariate analyses were conducted to identify prognostic indicators for overall survival(OS)and disease-free survival(DFS).Results:Patients with a pretreatment NLR of≥3.2 exhibited significantly worse OS and DFS compared with those with an NLR of<3.2(OS:94.4 vs.116.5 months,p=0.001;DFS:78.8 vs.101.7 months,p=0.003).Group A exhibited the poorest prognosis,whereas Group D had the most favorable outcomes.Multivariate analysis revealed NLR≥3.2 as an independent predictor of poor OS(hazard ratio[HR]=2.306,95%CI:1.149-3.747;p=0.001)and DFS(HR=2.055,95%CI:1.341-3.148;p=0.001).Conclusion:Neoadjuvant concurrent CRT followed by robotic-assisted TME is an effective treatment strategy for LARC.A higher pretreatment NLR(≥3.2)independently predicted worse OS and DFS.Stratification using the NLR in combination with CEA levels may enhance prognostic accuracy for patients undergoing robotic-assisted surgery for LARC.
文摘Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.
基金Supported by The Valley Hospital Foundation Research FundThe community of The Valley Hospital in Ridgewood,NJ,especially Ms.Audrey Meyers,CEO,Mr.Anastasios Kozaitis,president of the Valley Hospital Foundation
文摘Early screening for colorectal cancer(CRC) holds the key to combat and control the increasing global burden of CRC morbidity and mortality. However, the current available screening modalities are severely inadequate because of their high cost and cumbersome preparatory procedures that ultimately lead to a low participation rate. People simply do not like to have colonoscopies. It would be ideal, therefore, to develop an alternative modality based on blood biomarkers as the first line screening test. This will allow for the differentiation of the general population from high risk individuals. Colonoscopy would then become the secondary test, to further screen the high risk segment of the population. This will encourage participation and therefore help to reach the goal of early detection and thereby reduce the anticipated increasing global CRC incidence rate. A blood-based screening test is anappealing alternative as it is non-invasive and poses minimal risk to patients. It is easy to perform, can be repeated at shorter intervals, and therefore would likely lead to a much higher participation rate. This review surveys various blood-based test strategies currently under investigation, discusses the potency of what is available, and assesses how new technology may contribute to future test design.
基金Supported by The Valley Hospital Foundation Research Fund and private donations
文摘AIM:To develop a panel of blood-based diagnostic biomarkers consisting of circulating microRNAs for the detection of pancreatic cancer at an early stage.METHODS:Blood-based circulating microRNAs were profiled by high throughput screening using microarray analysis,comparing differential expression between early stage pancreatic cancer patients(n = 8) and healthy controls(n = 11).A panel of candidate microRNAs was generated based on the microarray signature profiling,including unsupervised clustering and statistical analysis of differential expression levels,and findings from the published literature.The selected candidate microRNAs were then confirmed using TaqMan real-time quantitative reverse transcription polymerase chain reaction(RT-qPCR) to further narrow down to a three-microRNA diagnostic panel.The three-microRNA diagnostic panel was validated with independent experimental proce-dures and instrumentation of RT-qPCR at an independent venue with a new cohort of cancer patients(n = 11),healthy controls(n = 11),and a group of high risk controls(n = 11).Receiver operating characteristic curve analysis was performed to assess the diagnostic capability of the three-microRNA panel.RESULTS:In the initial high throughput screening,1220 known human microRNAs were screened for differential expression in pancreatic cancer patients versus controls.A subset of 42 microRNAs was then generated based on this data analysis and current published literature.Eight microRNAs were selected from the list of 42 targets for confirmation study,and three-microRNAs,miR-642b,miR-885-5p,and miR-22,were confirmed to show consistent expression between microarray and RT-qPCR.These three microRNAs were then validated and evaluated as a diagnostic panel with a new cohort of patients and controls and found to yield high sensitivity(91%) and specificity(91%) with an area under the curve of 0.97(P < 0.001).Compared to the CA19-9 marker at 73%,the three-microRNA panel has higher sensitivity although CA19-9 has higher specificity of 100%.CONCLUSION:The identified panel of three microRNA biomarkers can potentially be used as a diagnostic tool for early stage pancreatic cancer.
文摘Surgical resection is the only option of cure for patients with metastatic colorectal cancer(CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent site of relapse. The current international guidelines recommend an adjuvant therapy after surgical resection of CRC metastases despite the lower level of evidence(based on the quality of studies in this setting). However, there is still no standard treatment and the effective role of an adjuvant therapy remains controversial. The aim of this review is to report the state-of-art of systemic chemotherapy and regional chemotherapy with hepatic arterial infusion in the management of patients after resection of metastases from CRC, with a literature review and meta-analysis of the relevant randomized controlled trials.
文摘The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in response to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is historically characterized for its role in mediating the toxicity and adaptive responses to these chemicals, however mounting evidence has established a role for it in ligand-independent physiological processes and pathological conditions, including cancer. The AhR is overexpressed and constitutively activated in advanced breast cancer cases and was shown to drive the progression of breast cancer. In this article we will review the current state of knowledge on the possible role of AhR in breast cancer and how it will be exploited in targeting AhR for breast cancer therapy.
文摘There is currently a split within the cancer research community between traditional molecular biological hypothesis-driven and the more recent "omic" forms or research. While the molecular biological approach employs the tried and true single alteration-single response formulations of experimentation,the omic employs broad-based assay or sample collection approaches that generate large volumes of data. How to integrate the benefits of these two approaches in an efficient and productive fashion remains an outstanding issue. Ideally,one would merge the understandability,exactness,simplicity,and testability of the molecular biological approach,with the larger amounts of data,simultaneous consideration of multiple alterations,consideration of genes both of known interest along with the novel,cross-sample comparisons among cell lines and patient samples,and consideration of directed questions while simultaneously gaining exposure to the novel provided by the omic approach. While at the current time integration of the two disciplines remains problematic,attempts to do so are ongoing,and will be necessary for the understanding of the large cell line screens including the Developmental Therapeutics Program's NCI-60,the Broad Institute's Cancer Cell Line Encyclopedia,and the Wellcome Trust Sanger Institute's Cancer Genome Project,as well as the the Cancer Genome Atlas clinical samples project. Going forward there is significant benefit to be had from the integration of the molecular biological and the omic forms or research,with the desired goal being improved translational understanding and application.
基金Institutional funds from Amrita Vishwa Vidyapeetham University,India,and Rutgersthe State University of New Jersey,USARO1 CA118947 and RO1 CA152826 from the National Institutes of Health(NIH),USA
文摘Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapy regimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry. We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceutical SFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.
基金supported by grants through funding from the National Science and Technology Council(MOST 111-2314-B-037-070-MY3,NSTC 112-2314-B-037-090,NSTC 112-2314-B-037-050-MY3)the Ministry of Health and Welfare(12D1-IVMOHW02)and funded by the Health and Welfare Surcharge of on Tobacco Products,and the Kaohsiung Medical University Hospital(KMUH112-2R37,KMUH112-2R38,KMUH112-2R39,KMUH112-2M27,KMUH112-2M28,KMUH112-2M29,KMUH-SH11207)Kaohsiung Medical University Research Center Grant(KMU-TC112A04).
文摘Abstract:Background:The pTNM staging system is widely recognized as the most effective prognostic indicator for cancer.The latest update of this staging system introduced a new pathological staging system(ypTNM)for patients receiving neoadjuvant chemoradiotherapy(NACRT).However,whether the prognostic value of the ypTNM staging system for rectal cancer is similar to that of the pTNM staging system remains unclear.This study was conducted to compare the ypTNM and pTNM staging systems in terms of their prognostic value for patients with nonmetastatic rectal cancer undergoing proctectomy.Material and Methods:This study was conducted at a large teaching hospital.Between January 2014 and December 2022,542 patients with rectal cancer were analyzed(median follow-up period,60 months;range,6–105 months).Of them,258 and 284 were included in the pTNM and ypTNM groups,respectively.Inverse probability of treatment weighting(IPTW)was performed to account for the effects of confounders.Cox proportional-hazards regression was performed for the between-group comparison of overall survival(OS).Results:The crude model revealed that OS was similar between the two groups(p=0.607).After performing IPTW,we found that patients with the same ypTNM-and pTNM-classified stages had similar overall survival(hazard ratio=1.15;95%CI=0.76–1.73;p=0.5074).Conclusions:For patients with rectal cancer who have received preoperative NACRT,the prognostic value of ypTNM staging appears to be similar to that of pTNM staging,mostly because of the downstaging effect of neoadjuvant chemoradiotherapy。
文摘In Western countries, prostate cancer is the most common malignancy in menand ranks third in mortality. In 2010, an estimated 217 730 new cases are anticipated in the United States, and about 32 050 men are expected to die from the disease. Until 2004, numerous clinical trials in men with metastatic castration-resistant prostate cancer （mCRPC） failed to demonstrate any signifi- cant change in overall survival.
文摘The last decade has seen remarkable advances in the treatment of prostatecancer. Until 2010, only docetaxel had demonstrated the ability to improve the survival in metastatic castration-resistant prostate cancer （mCRPC）.
基金supported by the National Key R&D Program of China(2019YFC1712200-2019YFC1712204)the National Natural Science Foundation of China(82004467,82030125)the Youth Project of Traditional Chinese Medicine-Integration of Traditional and Western Medicine Projects of Tianjin Health Commission(No.2025027).
文摘Objective:Breast cancer is the second most prevalent cause of mortality in women and the predominant malignancy type.However,breast cancer treatment faces challenges in managing aromatase inhibitor-induced arthralgia.Aromatase inhibitors have been shown to decrease recurrence risk in hormone receptor-positive cases;however,joint discomfort remains the primary adverse effect.Randomized clinical trials have evaluated the therapeutic outcomes of acupuncture for medication-related musculoskeletal complications.This comprehensive analysis sought to elucidate both the therapeutic efficacy and placebo responses associated with acupuncture intervention.Methods:Two reviewers searched for randomized controlled trials(RCTs)in four English(PubMed,Embase,Web of Science,and the Cochrane Library)and four Chinese databases(CNKI,Wanfang Database,VIP,and SinoMed)from their inception to May 31,2024.Methodological quality was assessed using the Cochrane risk of bias tool.Data were synthesized using random effects models and presented with forest plots.Results:Seven trials involving 604 patients were included.The primary outcome and Brief Pain Inventory(BPI)score differed between the acupuncture and control groups(sham acupuncture or usual medication)in three subscales over the course of 6 weeks:worst pain:standardized mean difference(SMD)=-1.18,95%confidence interval(CI):-1.74,-0.63,P<0.001;painrelated interference:SMD=-0.87,95%CI:-1.70,-0.05,P=0.038;pain severity:SMD=-0.63,95%CI:-1.22,-0.04,P=0.036.No severe adverse events were reported in any study.Conclusions:This meta-analysis showed that acupuncture is a safe and effective treatment for patients with breast cancer with aromatase inhibitor-induced arthralgia during the course of 6 weeks.Improvements in the blinding method and clarification of the total treatment recommendations and intervals need to be explored further.
文摘In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleuceI-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.
基金supported by the National Key Research and Development Program of China (Grant No. 2017YFE0109900)the National Natural Science Foundation of China (Grant Nos. 82025034 and 81973392)+5 种基金the Shenzhen Science and Technology Program (Grant No. KQTD20190929174023858)the Natural Science Foundation of Guangdong (Grant No. 2017A030311018)the 111 project (Grant No. B16047)the Key Laboratory Foundation of Guangdong Province (Grant No. 2017B030314030)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. 2017BT01Y093)the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant No. 2017B090903004)。
文摘Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.
基金Supported by National Institute of Genetic Engineering and Biotechnology, No. 199 and Digestive Disease Research Center, No. 18/81
文摘AIM： To assess the proteome of normal versus tumor tissue in squamous cell carcinoma of the esophagus （SCCE） in Iranian patients and compare our results with former reports by using proteomics. METHODS： Protein was extracted from normal and tumor tissues. Two dimensional electrophoresis was carried out and spots with differential expression were identified with mass spectrometry. RNA extraction and RT-PCR along with immunodetection were performed. RESULTS： Fourteen proteins were found whose expression levels differed in tumor compared to normal tissues. Mass spectrometric analysis resulted in the identification of β-tropomyosin （TMβ）, myosin light chain 2 （and its isoform）, myosin regulatory light chain 2, peroxyredoxin 2, annexin I and an unknown polypeptide as the down regulated polypeptides in tumor tissue. Heat shock protein 70 （HSP70）, TPM4-ALK fusion oncoprotein 2, myosin light polypeptide 6, keratin I, GH16431p and calreticulin were the up-regulated polypeptides found in tumor tissue. Several of these proteins, such as TMβ, HSP70, annexin Ⅰ, calreticulin, TPM4-ALK and isoforms of myosins, have been well recognized in tumorigenesis of esophageal or other types of cancers. CONCLUSION： Our study not only supports the involvement of some of the formerly reported proteins in SCCE but also introduces additional proteins found to be lost in SCCE, including TMβ.
基金supported by funds from the National Institutes of Health (1R15CA143701)St.John's University Research Seed Grant(579-1110-7002) to Dr.Zhe-Sheng Chen.Drs.Suneet ShuklaSuresh V.Ambudkar were supported by the Intramural Research Program,Center for Cancer Research, National Cancer Institute,National Institutes of Health
文摘Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.
文摘Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microR NAs(miR NAs), a class of noncoding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miR NAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mR NAs. Commonly, a particular mi RNA recognition sequence could be found in a number of genes, which allows a single miR-NA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miR NAs. However, previous studies have demonstrated that mi RNA functions are highly context-dependent,which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miR NA. Here we summarize recent progress in studies on miR NA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of mi RNAs and potential application of using miR NAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers.
文摘Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.
文摘Despite impressive survival benefits with immunotherapy in patients with various solid tumors, the full potential of these agents in prostate cancer has yet to be realized. SipuleuceI-T demonstrated a survival benefit in this population, indicating that prostate cancer is an immunoresponsive disease; however, these results have not been matched by other agents. A large trial with ipilimumab in prostate cancer failed to meet its primary objective, and small trials with PD-1/PD-L1 inhibitors did not yield a significant improvement in overall response. However, several late-stage clinical trials are underway with other vaccines in prostate cancer. Reports of clinical benefit with immunotherapies, particularly when used in combination or a select population, have provided the framework to develop sound clinical trials. Understanding immunogenic modulation, antigen spread, biomarkers, and DNA-repair defects will also help mold future strategies. Through rational patient selection and evidence-based combination approaches, patients with prostate cancer may soon derive durable survival benefits with immunotherapies.
