BACKGROUND T4 esophageal cancer portends a poor prognosis,particularly when it is complicated by a tracheoesophageal fistula(TEF)either resulting from disease or occurring as a complication of treatment.Patients with ...BACKGROUND T4 esophageal cancer portends a poor prognosis,particularly when it is complicated by a tracheoesophageal fistula(TEF)either resulting from disease or occurring as a complication of treatment.Patients with TEF that occurs during treatment are commonly treated with palliative intent because fistula-associated treatment complications such as aspiration pneumonia and mediastinitis are associated with high morbidity and mortality.To date,there is no clear evidence on the optimal treatment of T4 esophageal cancer,particularly when a TEF formation occurs.CASE SUMMARY A 67-year-old gentleman who presented with dysphagia and weight loss.Endoscopy and imaging revealed a T4N1M0 cervical esophageal squamous cell carcinoma.He received image-guided intensity-modulated radiation therapy,with concurrent weekly carboplatin(area under curve 2 mg/mL per minute)and paclitaxel(50 mg/m2 of body surface area).One week after treatment initiation(16.2 Gy thus far),he developed cough on swallowing.A TEF was detected on image-guided radiation therapy using cone-beam computed tomography during the treatment course,for which a tracheal stent was inserted.After discussing the risks and morbidity of continuing treatment,he resumed chemoradiotherapy with an additional radiation dose of 45 Gy in 25 fractions.Three months after completion of chemoradiotherapy,he developed an esophageal stricture that required esophageal stenting and dilatation.The patient remains cancer-free at two year on follow-up.Complete response of esophageal cancer was evident on post-treatment endoscopy and computed tomography imaging,with successful closure of TEF.CONCLUSION This case highlights that successful curative treatment for esophageal cancer complicated by a TEF is possible using novel chemotherapeutic regimens and modern radiation technologies.展开更多
OBJECTIVE To evaluate if RNA helicase DDX20,highly expressed in triple negative breast cancer(TNBC)cells,could serve as a surrogate marker for simvastatin treatment response.METHODS We first assessed correlation betwe...OBJECTIVE To evaluate if RNA helicase DDX20,highly expressed in triple negative breast cancer(TNBC)cells,could serve as a surrogate marker for simvastatin treatment response.METHODS We first assessed correlation between 17 mevalonate pathway-related genes and expression of DDX20 in a cohort of 1325 breast cancer tumors.TNBC cells,MDA-MB-231,were then treated with simvastatin and mevalonate pathway intermediates to assess the alteration in DDX20 expression.In the mouse model,MDA-MB-231 cells were injected to tail veins of mice,groups of 8mice each were injected intraperioneally with vehicle or simvastatin 25mg·kg-1 3times a week for 6weeks.The number of metastatic colonies formed was quantified and immunohistochemical(IHC)staining of DDX20 was carried out in the lung tissues.RESULTS Among the 17 genes evaluated,positive correlation with DDX20 expression was observed in eight of them,with HMGCR having the highest correlation.Our in vitro experiments show exposure of breast cancer cells to simvastatin lead to a Rho-dependent decrease in gene expression of DDX20,leading to decreased tumor proliferation in a mevalonate pathway-dependent manner.Conversely,ectopic overexpression of DDX20 significantly abrogated the anti-metastatic activity of simvastatin.A similar observation is seen in the mouse model,where simvastatin-injected mice show significantly fewer visible lung metastases compared to placebo-fed mice.IHC staining on these lung tissues showed decreased DDX20 expression in simvastatin-injected group,corroborating our observations in vitro.CONCLUSION DDX20 is a potential surrogate marker for simvastatin treatment response in breast cancer and a long term implication of our findings is the possibility of an effective combinatorial therapeutic intervention using statins(to suppress DDX20 gene expression)and a suitable firstline agent″for the kill″of invasive breast cancer.展开更多
Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or los...Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.展开更多
Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, ...Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, hematopoietic stem cells(HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normalHSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.展开更多
Objective： In this study, we examine the effects of recombinant adenovirus-p53 （rAd-p53） on the pancreatic carcinoma cell line SW1990. Specifically, we determine if expression of rAd-p53 sensitizes these cells to r...Objective： In this study, we examine the effects of recombinant adenovirus-p53 （rAd-p53） on the pancreatic carcinoma cell line SW1990. Specifically, we determine if expression of rAd-p53 sensitizes these cells to radiation. Methods： Following transfection of SW1990 cells with rAd-p53, we measured expression of P53, P21 and Bax by immunocytochemistry. Both transfected and control cell lines were irradiated with a range of doses, and the survival fractions （SF） were calculated. Dose survival cttrves were constructed and modeled for comparison. Results： Transfection of SW1990 cells with rAd-p53 resulted in increased expression of P53, P21 and Bax in a time-dependent manner. At 96 h after transfection, 89.92% of cells expressed P53, 56.8% expressed P21, and 76.50% expressed Bax. The SF following radiation was lower in the rAd-p53 transfected cells compared to the control cells, suggesting that rAd-p53 sensitizes SW1990 cells to radiation （Do for the experimental and control groups was 2.199 and 2.462, respectively）. Conclusions： Use of the adenoviral vector is an effective means of transfecting SW1990 cells with wild-type P53, and this sensitizes the cell line to irradiation. This work suggests that combining rAd-p53 with radiation therapy in pancreatic cancer may be therapeutically beneficial.展开更多
Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous d...Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit(PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20 S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20 S proteasome.展开更多
FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid l...FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.展开更多
AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assa...AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assays to examine the relation between NF-κB and LIN28 B. Western blot and q RT-PCR was employed to determine their protein and m RNA levels. Luciferase reporter was constructed and applied to explore the transcriptional regulation of LIN28 B. We manipulated LIN28 B level in acute myeloid leukemia(AML) cells and investigated LSC-like properties with colony forming and serial replating assays. RESULTS This study revealed the relationship between NF-κB and LIN28 B in AML cells through drug inhibition and overexpression experiments. Notably,inhibition of NF-κB by pharmacological inhibitors reduced LIN28 B expression and decreased cell proliferation. We demonstrated that NF-κB binds to the-819 to-811 region of LIN28 B promoter,and transcriptionally regulates LIN28 B expression. LIN28 B protein was significantly elevated in NFκB1 transfected cells compared to vector control. Importantly,ectopic expression of LIN28 B partially rescued the self-renewal capacity impaired by pharmacological inhibition of NF-κB activity. CONCLUSION These results uncover a regulatory signaling,NF-κB/LIN28 B,which plays a pivotal role in leukemia stem cell-like properties and it could serve as a promising intervening target for effective treatment of AML disease.展开更多
The use of immune checkpoint inhibitors(iCls)has increased exponentially in the past decade,although its progress specifically for breast cancer has been modest.The first U.S.Food and Drug Administration approval for ...The use of immune checkpoint inhibitors(iCls)has increased exponentially in the past decade,although its progress specifically for breast cancer has been modest.The first U.S.Food and Drug Administration approval for ICl in breast cancer came in 2019,eight years after the first-ever approval of an ICl.At present,current indications for ICls are relevant only to a subset of patients with triple-negative breast cancer,or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway.With an increasing understanding of the limitations of using ICls,which stem from breast cancer being innately poorly immunogenic,as well as the presence of various intrinsic and acquired resistance pathways,ongoing trials are evaluating different combination therapies to overcome these barriers.In this review,we aim to describe the development timeline of ICls and resistance mechanisms limiting their utility,and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.展开更多
Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of ...Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of a 60-year-old patient presenting with right scrotal pain immediately following aortoiliac stenting for right common iliac,proximal external iliac and proximal internal iliac arteries thrombosis.He was found to have testicular ischaemia with absent blood flow on duplex ultrasonography.The patient was managed expectantly and reduced blood flow spontaneously returned to the testis over the next few weeks.展开更多
Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR,...Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.展开更多
Chronicmyeloid leukemia(CML)is a lethal hematopoietic malignancy with a global incidence primarily attributed to the breakpoint cluster region-Abelson(BCR-ABL1)fusion oncogene in over 95%of cases.The introduction of t...Chronicmyeloid leukemia(CML)is a lethal hematopoietic malignancy with a global incidence primarily attributed to the breakpoint cluster region-Abelson(BCR-ABL1)fusion oncogene in over 95%of cases.The introduction of tyrosine kinase inhibitors(TKIs)has revolutionized CML management;however,a subset of patients encounters challenges such as resistance and relapse,hindering the achievement of complete remission.Overcoming these challenges in CML also requires addressing persistent leukemia stem cells(LSCs)with inherent resistance mechanisms.Key regulators of LSC metabolism,proliferation,and survival,as well as genetic and epigenetic alterations,provide potential targets[1].展开更多
Multiple myeloma （MM） is an incurable plasma cell malignancy and is the second most common hematological cancer. It is characterized by complex, recurrent genetic and epigenetic abnormalities. Recent publications ha...Multiple myeloma （MM） is an incurable plasma cell malignancy and is the second most common hematological cancer. It is characterized by complex, recurrent genetic and epigenetic abnormalities. Recent publications have linked miRNAs, a novel class of gene regulators to cancer including MM. miRNAs are about 20 nucleotide, single strand, non-coding RNAs that repress gene expression by mRNA degradation or translational repression. Aberrant miRNA expression profiles have been described in MM, and their functional roles in MM pathogenesis are being increasingly recognized. This review summarizes the current literature on the role of miRNAs in MM and offers perspectives on future research and utilization of miRNAs in MM management.展开更多
In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK ...In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.展开更多
Liver metastases can present synchronously or at different time points.While systemic therapy continues to be the mainstay of treatment for patients with liver metastases,it is unlikely to completely eradicate the dis...Liver metastases can present synchronously or at different time points.While systemic therapy continues to be the mainstay of treatment for patients with liver metastases,it is unlikely to completely eradicate the disease.Surgical“metastectomy”for patients with limited metastatic burden,particularly from colorectal cancers,has been shown to improve survival.However,owing to medical co-morbidities or tumour location,not all patients are eligible for surgical resection.In recent years,there has been an increase in the use of non-surgical techniques,including high dose radiation using stereotactic body radiotherapy,or brachytherapy,to ablate liver metastases.The purpose of this narrative review is to describe the role of radiotherapy in the management of liver metastases,both for local ablation and symptom palliation.We will elaborate on the techniques used,patient selection process,expected outcomes and toxicities based on the current literature.展开更多
文摘BACKGROUND T4 esophageal cancer portends a poor prognosis,particularly when it is complicated by a tracheoesophageal fistula(TEF)either resulting from disease or occurring as a complication of treatment.Patients with TEF that occurs during treatment are commonly treated with palliative intent because fistula-associated treatment complications such as aspiration pneumonia and mediastinitis are associated with high morbidity and mortality.To date,there is no clear evidence on the optimal treatment of T4 esophageal cancer,particularly when a TEF formation occurs.CASE SUMMARY A 67-year-old gentleman who presented with dysphagia and weight loss.Endoscopy and imaging revealed a T4N1M0 cervical esophageal squamous cell carcinoma.He received image-guided intensity-modulated radiation therapy,with concurrent weekly carboplatin(area under curve 2 mg/mL per minute)and paclitaxel(50 mg/m2 of body surface area).One week after treatment initiation(16.2 Gy thus far),he developed cough on swallowing.A TEF was detected on image-guided radiation therapy using cone-beam computed tomography during the treatment course,for which a tracheal stent was inserted.After discussing the risks and morbidity of continuing treatment,he resumed chemoradiotherapy with an additional radiation dose of 45 Gy in 25 fractions.Three months after completion of chemoradiotherapy,he developed an esophageal stricture that required esophageal stenting and dilatation.The patient remains cancer-free at two year on follow-up.Complete response of esophageal cancer was evident on post-treatment endoscopy and computed tomography imaging,with successful closure of TEF.CONCLUSION This case highlights that successful curative treatment for esophageal cancer complicated by a TEF is possible using novel chemotherapeutic regimens and modern radiation technologies.
基金The project supported by grants from the Academic Research Fund Tier 1(R-184-000-228-112)the Cancer Science Institute of Singapore,Experimental Therapeutics I Program(grant R-713-001-011-271)
文摘OBJECTIVE To evaluate if RNA helicase DDX20,highly expressed in triple negative breast cancer(TNBC)cells,could serve as a surrogate marker for simvastatin treatment response.METHODS We first assessed correlation between 17 mevalonate pathway-related genes and expression of DDX20 in a cohort of 1325 breast cancer tumors.TNBC cells,MDA-MB-231,were then treated with simvastatin and mevalonate pathway intermediates to assess the alteration in DDX20 expression.In the mouse model,MDA-MB-231 cells were injected to tail veins of mice,groups of 8mice each were injected intraperioneally with vehicle or simvastatin 25mg·kg-1 3times a week for 6weeks.The number of metastatic colonies formed was quantified and immunohistochemical(IHC)staining of DDX20 was carried out in the lung tissues.RESULTS Among the 17 genes evaluated,positive correlation with DDX20 expression was observed in eight of them,with HMGCR having the highest correlation.Our in vitro experiments show exposure of breast cancer cells to simvastatin lead to a Rho-dependent decrease in gene expression of DDX20,leading to decreased tumor proliferation in a mevalonate pathway-dependent manner.Conversely,ectopic overexpression of DDX20 significantly abrogated the anti-metastatic activity of simvastatin.A similar observation is seen in the mouse model,where simvastatin-injected mice show significantly fewer visible lung metastases compared to placebo-fed mice.IHC staining on these lung tissues showed decreased DDX20 expression in simvastatin-injected group,corroborating our observations in vitro.CONCLUSION DDX20 is a potential surrogate marker for simvastatin treatment response in breast cancer and a long term implication of our findings is the possibility of an effective combinatorial therapeutic intervention using statins(to suppress DDX20 gene expression)and a suitable firstline agent″for the kill″of invasive breast cancer.
基金Supported by National Medical Research Council IRG and NUHS Bench-to-Bedside grants(to Sethi G)grants from the National Medical Research Council of Singapore(R-713-000-177-511)+1 种基金the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative to Cancer Science Institute of SingaporeNational University of Singapore and by the NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust(to Kumar AP)
文摘Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.
基金Supported by National Research Foundation Singaporethe Singapore Ministry of Education under its Research Centres of Excellence initiativeNMRC Clinician-Scientist IRG Grant CNIG11nov38 and NMRC Clinician Scientist Investigator award
文摘Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, hematopoietic stem cells(HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normalHSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.
基金supported by Fujian Province Natural Science Foundation(No.2012J05139)Beijing Municipal Science & Technology Commission(No.Z111107058811021)
文摘Objective： In this study, we examine the effects of recombinant adenovirus-p53 （rAd-p53） on the pancreatic carcinoma cell line SW1990. Specifically, we determine if expression of rAd-p53 sensitizes these cells to radiation. Methods： Following transfection of SW1990 cells with rAd-p53, we measured expression of P53, P21 and Bax by immunocytochemistry. Both transfected and control cell lines were irradiated with a range of doses, and the survival fractions （SF） were calculated. Dose survival cttrves were constructed and modeled for comparison. Results： Transfection of SW1990 cells with rAd-p53 resulted in increased expression of P53, P21 and Bax in a time-dependent manner. At 96 h after transfection, 89.92% of cells expressed P53, 56.8% expressed P21, and 76.50% expressed Bax. The SF following radiation was lower in the rAd-p53 transfected cells compared to the control cells, suggesting that rAd-p53 sensitizes SW1990 cells to radiation （Do for the experimental and control groups was 2.199 and 2.462, respectively）. Conclusions： Use of the adenoviral vector is an effective means of transfecting SW1990 cells with wild-type P53, and this sensitizes the cell line to irradiation. This work suggests that combining rAd-p53 with radiation therapy in pancreatic cancer may be therapeutically beneficial.
文摘Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit(PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20 S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20 S proteasome.
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program(to Chng WJ)NMRC Clinician-Scientist IRG Grant,No.CNIG11nov38(to Zhou J)+1 种基金supported by NMRC Clinician Scientist Investigator awardsupported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 grants,No.MOE2014-T3-1-006
文摘FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program to WJ Chng and NMRC Clinician-Scientist IRG Grant CNIG11nov38(Zhou J)supported by NMRC Clinician Scientist Investigator awardpartially supported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 Grants,No.MOE2014-T3-1-006
文摘AIM To examine whether nuclear factor kappa B(NF-κB) activity regulates LIN28 B expression and their roles in leukemia stem cell(LSC)-like properties. METHODS We used pharmacological inhibitor and cell viability assays to examine the relation between NF-κB and LIN28 B. Western blot and q RT-PCR was employed to determine their protein and m RNA levels. Luciferase reporter was constructed and applied to explore the transcriptional regulation of LIN28 B. We manipulated LIN28 B level in acute myeloid leukemia(AML) cells and investigated LSC-like properties with colony forming and serial replating assays. RESULTS This study revealed the relationship between NF-κB and LIN28 B in AML cells through drug inhibition and overexpression experiments. Notably,inhibition of NF-κB by pharmacological inhibitors reduced LIN28 B expression and decreased cell proliferation. We demonstrated that NF-κB binds to the-819 to-811 region of LIN28 B promoter,and transcriptionally regulates LIN28 B expression. LIN28 B protein was significantly elevated in NFκB1 transfected cells compared to vector control. Importantly,ectopic expression of LIN28 B partially rescued the self-renewal capacity impaired by pharmacological inhibition of NF-κB activity. CONCLUSION These results uncover a regulatory signaling,NF-κB/LIN28 B,which plays a pivotal role in leukemia stem cell-like properties and it could serve as a promising intervening target for effective treatment of AML disease.
基金JSJ Lim is supported by the NMRC(NMRC/MOH/00414).All other authors have no funding to declare.
文摘The use of immune checkpoint inhibitors(iCls)has increased exponentially in the past decade,although its progress specifically for breast cancer has been modest.The first U.S.Food and Drug Administration approval for ICl in breast cancer came in 2019,eight years after the first-ever approval of an ICl.At present,current indications for ICls are relevant only to a subset of patients with triple-negative breast cancer,or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway.With an increasing understanding of the limitations of using ICls,which stem from breast cancer being innately poorly immunogenic,as well as the presence of various intrinsic and acquired resistance pathways,ongoing trials are evaluating different combination therapies to overcome these barriers.In this review,we aim to describe the development timeline of ICls and resistance mechanisms limiting their utility,and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.
文摘Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of a 60-year-old patient presenting with right scrotal pain immediately following aortoiliac stenting for right common iliac,proximal external iliac and proximal internal iliac arteries thrombosis.He was found to have testicular ischaemia with absent blood flow on duplex ultrasonography.The patient was managed expectantly and reduced blood flow spontaneously returned to the testis over the next few weeks.
文摘Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.
基金LBMCC:“Recherche Cancer et Sang”foundation,the“Recherches Scientifiques Luxembourg”,the“Een Harz fir kriibskrank Kanner”,the Action LIONS“Vaincre le Cancer”and Télévie Luxembourg.SNU:National Research Foundation(NRF)(Grant Number 370C-20220063)MEST of Korea for Tumor Microenvironment Global Core Research Center(GCRC)(Grant Number 2011-0030001)Brain Korea(BK21)PLUS program and Creative-Pioneering Researchers Program at Seoul National University(Funding number:370C-20160062).Sruthi Reddy Gajulapalli and Ridhika Rajora were supported by grants for the“Graduate Scholarship for Excellent Foreign Students”program.
文摘Chronicmyeloid leukemia(CML)is a lethal hematopoietic malignancy with a global incidence primarily attributed to the breakpoint cluster region-Abelson(BCR-ABL1)fusion oncogene in over 95%of cases.The introduction of tyrosine kinase inhibitors(TKIs)has revolutionized CML management;however,a subset of patients encounters challenges such as resistance and relapse,hindering the achievement of complete remission.Overcoming these challenges in CML also requires addressing persistent leukemia stem cells(LSCs)with inherent resistance mechanisms.Key regulators of LSC metabolism,proliferation,and survival,as well as genetic and epigenetic alterations,provide potential targets[1].
文摘Multiple myeloma （MM） is an incurable plasma cell malignancy and is the second most common hematological cancer. It is characterized by complex, recurrent genetic and epigenetic abnormalities. Recent publications have linked miRNAs, a novel class of gene regulators to cancer including MM. miRNAs are about 20 nucleotide, single strand, non-coding RNAs that repress gene expression by mRNA degradation or translational repression. Aberrant miRNA expression profiles have been described in MM, and their functional roles in MM pathogenesis are being increasingly recognized. This review summarizes the current literature on the role of miRNAs in MM and offers perspectives on future research and utilization of miRNAs in MM management.
基金This work was supported by grants from the Singapore Ministry of Health’s National Medical Research Council(NMRC/CSA/021/2010 to B.C.Goh)the National Research Foundation Singapore and Singapore Ministry of Education under their Research Centres of Excellence(RCE)Initiative.
文摘In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.
文摘Liver metastases can present synchronously or at different time points.While systemic therapy continues to be the mainstay of treatment for patients with liver metastases,it is unlikely to completely eradicate the disease.Surgical“metastectomy”for patients with limited metastatic burden,particularly from colorectal cancers,has been shown to improve survival.However,owing to medical co-morbidities or tumour location,not all patients are eligible for surgical resection.In recent years,there has been an increase in the use of non-surgical techniques,including high dose radiation using stereotactic body radiotherapy,or brachytherapy,to ablate liver metastases.The purpose of this narrative review is to describe the role of radiotherapy in the management of liver metastases,both for local ablation and symptom palliation.We will elaborate on the techniques used,patient selection process,expected outcomes and toxicities based on the current literature.
